基于诊断治疗学多功能纳米系统用于肝细胞癌的分子诊断与治疗
|
摘要
肝细胞癌(hepatocellular carcinoma, HCC)是严重威胁人类健康的恶性肿瘤之一,化学治疗是临床上主要的治疗手段之一。目前,化疗常常遇到以下两个难题：①治疗方式非个体化,所有病人基于群体通用剂量给药,会因病人个体差异等因素产生超敏或无效现象,导致用药失败；②疗效评估往往在一个治疗周期之后,具有时间滞后性,从而错过了使治疗最佳时机。
诊断治疗学(Theranostics)是一种将分子诊断与分子治疗相结合的治疗策略,近年来作为一种新型疾病治疗策略,特别是在肿瘤治疗方面受到了人们广泛的关注。基于诊断治疗学的治疗模式能够实现①可视化药物体内递送过程；②可视化药物在给药靶部位的分布和释放过程；③在治疗的同时进行诊断,实现肿瘤治疗的实时监控和个体化给药等。因此,诊断治疗学对HCC治疗过程中治疗效果的实时监控、及时调整给药剂量或治疗方案、实现病人个体化给药并提高肿瘤治疗效果具有重要意义。
本课题基于Theranostics理论,设计和制备一种多功能纳米载体用于HCC的个体化给药,以提高治疗效果,降低毒副作用。首先,选择聚合物纳米粒作为Theranostics载体,设计合成具有载药、长循环和方便后期修饰的多功能材料聚乳酸-聚乙二醇-聚赖氨酸(poly(lactic acid)-Poly(ethylene glycol)-Polylysine, PLA-PEG-PLL),具有pH敏感性和长循环性的多功能材料聚组氨酸-聚乙醇-生物素(Polyhistidine-Poly(ethylene glycol)-Biotin, PLH-PEG-Biotin);然后,选取紫杉醇(Paclitaxel, PTX)和索拉菲尼为治疗HCC的模型药物,基于钆(Gd)的磁共振显影(Magnetic Resonance Imaging, MRI)模式为诊断手段,分别以肿瘤微环境高表达的血管内皮生长因子(vascular endothelial growth factor, VEGF)、甲胎蛋白(Alpha-fetoprotein, AFP)和血管内皮生长因子受体(vascular endothelial growth factor receptor, VEGFR)为靶点,自组装手段制备了三种多功能聚合物纳米载体,分别为：①靶向治疗学多功能纳米粒(靶向VEGF载PTX聚合物纳米粒,Target PTX-loaded nanoparticles, TPN)、②诊断治疗学多功能纳米粒(靶向AFP载Gd/PTX聚合物纳米粒,Target Gd/PTX-loaded nanoparticles, TGPN)和③pH敏感诊断治疗学多功能纳米粒(pH敏感靶向VEGFR载Gd/PTX聚合物纳米粒,Target pH-sensitive theranostic nanoparticles, TPTN);最后,分别对三种多功能纳米载体的理化性质、体外释放行为、细胞毒性、细胞摄取、体外MRI性质、体内MRI性质、体内抑瘤性质和组织安全性等进行评价,以期提高HCC的分子靶向治疗和治疗监控效果,实现HCC病人个体化治疗。
课题主要研究方法与结果如下：
1.多功能材料的合成与表征
为构建多功能诊断治疗学聚合物纳米载体,课题首创聚合物缀合技术,合成两种新型多功能高分子材料PLA-PEG-PLL和PLH-PEG-Biotin。聚合物缀合技术是指利用化学反应,将具不同功能的单嵌段材料化学连接得到多嵌段多功能聚合物的技术。与传统聚合反应方法比较,该方法合成过程简单,无需严苛的反应条件,产物纯化简单,并能够相对准确地控制每一嵌段的分子量。此外,利用聚合物缀合技术可以将任意具有活性基团的嵌段相连接,具有多嵌段材料制备的可创造性。
1.1PLA-PEG-PLL的合成与表征
利用酰胺反应,将PLA-COOH分别连接NH2-PEG-NH2得到PLA-PEG-NH2,然后连接PLL(Cbz)-COOH得到PLA-PEG-PLL(Cbz),最后氨基脱保护得到结合载药、长循环和易于修饰多功能于一体的多功能材料PLA-PEG-PLL.通过核磁验证了每一步合成产物的结构。通过凝胶色谱得到PLA, PLA-PEG和PLA-PEG-PLL的数均分子量和多分散系数分别为13691(1.427)、16013(1.277)和20441(1.358)。利用芘荧光探针法测得PLA-PEG-PLL的临界胶束浓度值为7.70×10-3mg/mL (3.76×10-7Mol/L)。基于PLA-PEG-PLL,利用酰胺反应,合成了PLA-PEG-PLL-DTPA和PLA-PEG-PLL-Biotin,分别用于Gd装载和靶向抗体修饰。
1.2PLH-PEG-Biotin
利用酰胺反应,将Biotin-PEG-NH2与PLH-COOH反应得到PLH-PEG-Biotin,通过核磁验证了合成产物的结构。通过酸碱滴定实验证明PLH-PEG-Biotin pKb值在pH5-7之间,处于血液pH与肿瘤微环境pH之间,具有在肿瘤组织实现纳米粒pH敏感性释药的能力。
2.靶向治疗学多功能纳米粒的制备与表征
靶向治疗能够提高HCC的治疗效果,降低化疗药物对正常组织的毒性,是目前研究的热点之一。因此,本文首先制备TPN用于HCC的靶向治疗。首先建立PTX高效液相色谱检测方法,PTX在选定液相条件下峰型良好,符合方法学考察要求。利用自组装方法制得TPN外观圆整,呈球形或类球形,粒径为203.6±4.10nm, Zeta电位为20.76±0.34mv,包封率和载药量分别为86.23±1.79%和1.42±0.03%。在体外释放实验中,与Taxol(?)匕较,TPN表现出缓释特性,释放曲线符合Higuchi方程Q=8.0449t1/2-0.5721, R=0.9678.细胞毒性实验结果表明,TPN的细胞毒性(IC50=0.392±0.012μM)显著高于Taxol(?)(IC50=3.554μ0.233μM)和PN (IC50=1.510±0.099μM)(P＜0.01),具有良好的体外抗肿瘤活性。在细胞摄取实验中,FITC标记TPN的摄取具有时间依赖性和浓度依赖性,在不同浓度下,FITC标记TPN的摄取率显著高FITC标记PN(P<0.01)。在体内肿瘤抑制实验中,与NS、Taxol(?)、PN比较,TPN能够显著抑制小鼠体内肿瘤体积的增长(P＜0.01), TPN组生存时间(大于30d)长于Taxol(?)组(23d)和PN(27d),具有良好的体内抗肿瘤活性。以上实验结果表明TPN能够实现HCC的靶向治疗,提高治疗效果,具有重要的应用前景。
3.诊断治疗学多功能纳米粒的制备与表征
为实现HCC的Theranostics,需要在肿瘤靶向治疗的基础上添加实时诊断模式。课题基于功能集成组装的思路,将Gd的MRI显影模式添加至TPN中,制备TGPN用于HCC的Theranostics研究。利用自组装方法制得TGPN外观圆整,呈球形或类球形,粒径为147.50±4.71nm, Zeta电位为24.45±1.04mv,包封率和载药量分别为88.76±1.64%和1.59±0.06%。在体外释放实验中,与Taxol(?)比较,TGPN表现出缓释特性,释放曲线符合Weibull方程1nln[1/(1-Q/100)]=0.6961nt-6.5891(R=0.9533).在细胞毒性实验中,TGPN在24h的细胞毒性高于Taxol(?)和GPN(P<0.05),具有良好的体外抗肿瘤活性。FITC标记TGPN的细胞摄取具有时间依赖性和浓度依赖性,在AFP阳性HepG2细胞中,孵育0.5h后,FITC标记TGPN的摄取率显著高于FITC标记GPN(P<0.01),在AFP阴性B16细胞中,FITC标记TGPN与FITC标记GPN的摄取率之间没有显著性差异(P>0.05),证明AFP抗体能够促进TGPN在HepG2细胞中的摄取。体外MRI评价表明TGPN具有高弛豫率(25.388mM-1s-1),是马根维显(4.9mM-1s-1)的5.18倍。在体内MRI实验中,给药TGPN后,小鼠肿瘤区域的显影信号增强AUC值为马根维显的87.6倍,信号峰值为马根维显的2.94倍,并能显著延长诊断时间,从马根维显的小于1h延长至6h以上,具有良好的体内MRI诊断能力。与NS、Taxol(?)、比较,TGPN能够显著抑制小鼠体内肿瘤体积的增长(P<0.01),TPN组生存时间(20d)长于Taxol(?)组(11d)和PN(15d),具有良好的体内抗肿瘤活性。以上实验结果表明TGPN具有优秀的HCC诊断和治疗能力,能够实现治疗过程的实时检测,从而利于实现给药个体化,具有重要的应用潜力。
4.pH敏感诊断治疗学多功能纳米粒的制备与表征
肿瘤组织的定位释药策略能够提高诊断治疗学纳米载体治疗效果和诊断灵敏度,更有利于发挥Theranostics策略优势。因此,本文设计具有pH响应性释药能力的Theranostics纳米粒,制备TPTN用于HCC的诊断治疗研究。首先建立索拉菲尼高效液相色谱检测方法,索拉菲尼在选定的液相条件下峰型良好,符合方法学考察要求。利用自组装方法制得TPTN外观圆整,呈球形或类球形,粒径为181.4±3.4nm, Zeta电位为14.95±0.60mv,包封率和载药量分别为95.02±1.47%和2.38±0.04%。在含10%血清条件下,TPTN在2-4h内粒径保持稳定,证明稳定性良好。在体外释放实验中,TPTN的释放具有pH依赖性,其在pH=5.0的释放介质中释放速率显著高于pH=7.4的释放介质(P<0.01)。在细胞毒性实验中,TPTN在pH=5.0环境中孵育1h后的细胞毒性与索拉菲尼溶液相当,证明TPTN具有良好的体外抗肿瘤活性。FITC标记TPTN的细胞摄取具有时间依赖性和浓度依赖性,在不同浓度下,FITC标记TPTN的摄取率显著高于FITC标记PTN (P＜0.01)。体外MRI评价表明TPTN具有高弛豫率(17.300mM-1s-1),是马根维显(4.9mM-1s-1)的3.53倍。肿瘤模型小鼠静脉给药TPTN后,小鼠肿瘤区域与周围组织之间的信号对比明显,肉眼可以观察到明显的肿瘤边界,并能显著延长诊断时间,从马根维显的小于1h延长至1.5h以上,具有良好的体内MRI诊断能力。在体内肿瘤抑制实验中,与NS、索拉菲尼溶液(口服或静注)、PTN比较,TPTN能够显著抑制小鼠体内肿瘤生长(P<0.01),说明TPTN具有良好的体内抗肿瘤活性。通过组织免疫切片观察,小鼠静脉注射TBN后,各个脏器与注射生理盐水组相应脏器比较没有明显的组织毒性,证明TBN是一个相对安全的载体。以上实验结果表明TPTN在具有优秀的HCC诊断和治疗能力的同时,能够实现药物的肿瘤区域定位释放,进一步提高肿瘤诊断治疗能力,具有重要的研究价值。
综上,本研究基于Theranostics理论,设计合成新材料,构建新型多功能聚合物纳米载体,能够同时装载诊断因子和治疗药物,具有被动和主动肿瘤靶向、体内长循环、pH敏感释药等功能,能够实现肿瘤的靶向诊断、靶向治疗和治疗实时监控,为肿瘤Theranostics策略的发展提供了一种新思路和新手段。
Human hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Chemotherapy is one of the main treatment methods in clinic. However, Chemotherapy usually met the following two problems:a) the common dosage was based on the average dosage level of patients which might result in the failure of HCC therapy; b) the evaluation of the treatment was carried out after a treatment cycle, which mighy missed the best time of the treatment.
Recently, theranostics which combined cancer diagnosis and therapeutics in a single platform, received great attention in cancer treatment. Theranostics offered several advantages including the assessment of the biodistribution and accumulation of drugs at target sites noninvasively, the visualization of drug distribution and drug release at the target site, the optimization of formulation which relied on triggered drug release, and the real-time monitoring the therapeutic responses. So, theranostics therapy showed great potential in the individualized therapy and the real-time monitoring the treatment of HCC patients.
In this study, the multifunctional carriers were designed and prepared to achieve the individualized therapy of HCC based on theranostics. Firstly, the polymeric nanoparticles were selected as the theranostics carriers. The novel three block polymer PLA-PEG-PLL which combined drug-loading, long circulation time and easily modification functions and two block polymer PLH-PEG-Biotin which combined pH-sensitivity, long circulation time and active modification functions were designed and synthesized. Then, the HCC therapeutic drugs Paclitaxel (PTX) and sorafenib were employed as the model drug; Magnetic Resonance Imaging (MRI) was employed as the diagnosis method; vascular endothelial growth factor (VEGF), Alpha-fetoprotein (AFP) and vascular endothelial growth factor receptor (VEGFR) which were overexpressed in tumor microenvironment were selected as the delivery target; there multifunctional polymeric nanoparticles, including VEGF antibody modified PTX-loaded polymeric nanoparticles (TPN), AFP antibody modified Gd/PTX-loaded polymeric nanoparticles (TGPN) and pH-sensitive VEGFR antibody modified Gd/PTX-loaded polymeric nanoparticles (TPTN) were prepared by self-assembly method. At last, the basic properties, in vitro release profiles, cell cytotoxicity, cell uptake properties, in vitro MRI properties, in vivo MRI properties, in vivo anti-tumor ability and tissue safety were evaluated.
Above all, this article designed and synthesized two novel polymers, PLA-PEG-PLL and PLH-PEG-biotin, and prepared three kinds of multifunctional polymeric nanoparticles based on theranostics to achieve the target therapy, treatment monitoring, individualized therapy of HCC. The main study methods and results were showed as follows:
1. Synthesis and characterization of multifunctional materials
To fabricate multifunctional theranostic polymeric nanoparticles, the multifunctional polymer were firstly synthesized by polymer-polymer conjugation method which was first proposed by our group. Polymer-polymer conjugation is a novel multi-block polymers synthesis method that conjugated different polymer blocks by reactions between the terminal active groups of different blocks. The synthesis procedure was relatively simple without complex synthesis steps compared to traditional polymerization method. The synthesized multi-block polymers could have more relatively precise molecular weight of each block than that synthesized by traditional polymerization. Otherwise, different single block could be selected according to the expected functions of the multi-block polymers. Any single block that contained functional active groups for the conjugation could be used in this novel synthesis method. This facility and availability of different blocks indicated that multi-block polymers with various blocks or different block numbers could be synthesized theoretically by polymer-polymer conjugation.
1.1Synthesis and characterization of PLA-PEG-PLL
The carboxyl group of PLA-COOH reacted with the amino group of NH2-PEG-NH2to obtain PLA-PEG-NH2. Then, the amino group of PLA-PEG-NH2reacted with the carboxyl group ofPLL(Cbz)-COOH to obtain PLA-PEG-PLL(Cbz). After the deprotection of amino groups of PLA-PEG-PLL(Cbz), PLA-PEG-PLL was successfully synthesized. PLA-PEG-PLL combined drug loading, long circulating in vivo, and easy for modification functions. The structures of products were verified by NMR. GPC results showed that the number-average molar mass of PLA, PLA-PEG and PLA-PEG-PLL was13691,16013and20441Da and the molecular weight distribution (Mw/Mn) was1.427,1.277and1.358, respectively. These results indicated the successfully synthesis of PLA-PEG-PLL by polymer-polymer conjugation. The critical micelle concentration of PLA-PEG-PLL was determined using pyrene as an extrinsic probe and the critical micelle concentration of the PLA-PEG-PLL was7.70×10-3mg/mL. Based on PLA-PEG-PLL, two modified polymer PLA-PEG-PLL-DTPA and PLA-PEG-PLL-Biotin were synthesized by amide reaction for Gd loading and antibodies modification, respectively.
1.2Synthesis and characterization of PLH-PEG-Biotin
The carboxyl group of PLA-COOH reacted with the amino group of Biotin-PEG-NH2to obtain PLH-PEG-Biotin. The structures of PLH-PEG-Biotin were verified by NMR. The acid-base titration results showed that PLH-PEG-biotin exhibited great buffering capacity with a buffering zone within pH5-7, which could induce the solubility change of PLH from the blood (pH=7.4) to the tumor tissue (pH=5～7).
2. Preparation and characterization of TPN
Molecular therapy was the hot spot in recent years. It could increase the therapeutic effect of HCC and decrease the toxicity in the treatment. Thus, the VEGF antibody modified PTX-loaded polymeric nanoparticles (TPN) were prepared for the molecular therapy of HCC. PTX HPLC detection method was firstly established and the detection method reach the methodological study requirements. The TPN were prepared by solvent diffusion method. The morphology of TPN had spherical or ellipsoidal shapes without agglomeration. The particle size, zeta potential, EE%and DL%of TPN were203.6±4.10nm,20.76±0.34mv,86.23±1.79%and1.42±0.03%, respectively. In the release studies in vitro, compared to Taxol(?), TPN showed a controlled release profile and fitted Higuchi equation:Q=8.0449t1/2-0.5721, R=0.9678. The results of cell cytotoxicity studies showed that TPN (IC50=0.392±0.012μM) had significantly higher cytotoxicity compared to Taxol(?)(IC50=3.554±0.233μM) and non-target TPN (IC50=1.510±0.099μM)(P＜0.01), which indicated that TPN had good in vitro anti-tumor activity. In cell uptake studies, the cell uptake of FITC-labeled TPN was both time and concentration dependence. The cell uptake rates of FITC-labeled TPN were significantly higher than FITC-labeled non-target TPN at different incubation concentrations (P＜0.01). The results of in vivo tumor growth inhibition studies showed that TPN could significantly inhibit the growth of tumors compared to NS, Taxol(?), and non-target TPN (P＜0.01), which indicated that TPN had good in vivo anti-tumor activity. According to these results, TPN was an excellent drug carrier for the molecular therapy of HCC.
3. Preparation and characterization of TGPN
The achieve theranostic and individualized therapy of HCC, the diagnositic method should be added to the target therapy therapy carrier. Thus, the AFP antibody modified Gd/PTX-loaded polymeric nanoparticles (TGPN) was prepared for the theranostic therapy of HCC. The TGPN were prepared by solvent diffusion method. The morphology of TGPN had spherical or ellipsoidal shapes without agglomeration. The particle size, zeta potential, EE%and DL%of TPN were147.50±4.7nm,24.45±1.04mv,88.76±1.64%and1.59±0.06%, respectively. In the release studies in vitro, compared to Taxol(?), TGPN showed a controlled release profile and fitted Weibull equation:lnln[1/(1-Q/100)]=0.696ltt-6.5891, R=0.9533. The results of cell cytotoxicity studies showed that TGPN had higher cytotoxicity compared to Taxol(?) and non-target TGPN in24h (P＜0.05), which indicated that TGPN had good in vitro anti-tumor activity. In cell uptake studies, the cell uptake of FITC-labeled TGPN was both time and concentration dependence. The cell uptake rates of FITC-labeled TGPN were significantly higher than FITC-labeled non-target TGPN at different incubation concentrations in AFP-positive HepG2cells in0.5h (P＜0.01). While, the cell uptake rates did not showed any difference in AFP-nagetive B16cells, which proved the increased cell uptake was induced by AFP antibodies. The results of in vitro MRI studies showed that TGPN had high relaxivity (25.388nM-1s-1) which was5.18time to Magnevist(?)(4.9mM-1s-1). The results of in vivo MRI studies showed that the enhance signal area (AUC) of TGPN was87.6time to Magnevist(?) and the highest signal enhancement was2.94time to Magnevist(?). Meanwhile, the diagnosis time of TGPN was greatly prolonged from less than1h (Magnevist(?)) to more than6h. There results indicated that TGPN had good in vivo diagnosis ability. The results of in vivo tumor growth inhibition studies showed that TGPN could significantly inhibit the growth of tumors compared to NS, and Taxol(?)(P＜0.01), which indicated that TGPN had good in vivo anti-tumor activity. According to these results, TGPN had excellent HCC diagnosis and treatment ability, which showed great potential in the theranostic and individualized therapy of HCC.
4. Preparation and characterization of TPTN
The controlled and responsive release in the tumor area is important to increase the diagnostic sensitivity and therapeutic efficacy of HCC. Base on this consideration, the pH-sensitive VEGFR antibody modified Gd/PTX-loaded polymeric nanoparticles (TPTN) was prepared for the theranostic therapy of HCC. Sorafenib HPLC detection method was firstly established and the detection method reach the methodological study requirements. The TPTN were prepared by solvent diffusion method. The morphology of TPTN had spherical or ellipsoidal shapes without agglomeration. The particle size, zeta potential, EE%and DL%of TPN were181.4±3.4nm,14.95±0.60mv,95.02±1.47%and2.38±0.04%, respectively. TPTN showed good stability in the presence of10%serum in2-4h. In the release studies in vitro, TPTN showed pH-sensitive drug release profile. The release rate in the release media (pH=5.0) was significantly higher than in the release media (pH=7.4)(P＜0.01). The results of cell cytotoxicity studies showed that TPTN had similar cytotoxicity after incubated in pH5.0for1h compared to sorafenib silution, which indicated that TPTN had good in vitro anti-tumor activity. In cell uptake studies, the cell uptake of FITC-labeled TPTN was both time and concentration dependence. The cell uptake rates of FITC-labeled TPTN were significantly higher than FITC-labeled PTN at different incubation concentrations in VEGFR-positive HepG2cells (P＜0.01). The results of in vitro MRI studies showed that TPTN had high relaxivity (17.300mM-1s-1) which was3.53time to Magnevist(?)(4.9mM-1s-1). In MRI studies in vivo, after administration of TPTN, the tumor area showed visual brighter image than the surrounding tissue and the boundary of tumor tissue could be clearly demarcated. Meanwhile, the diagnosis time of TPTN was greatly prolonged from less than1h (Magnevist(?)) to more than1.5h. There results indicated that TPTN had good in vivo diagnosis ability. The results of in vivo tumor growth inhibition studies showed that TPTN could significantly inhibit the growth of tumors compared to NS, sorafenib solution and PTN (P＜0.01), which indicated that TPTN had good in vivo anti-tumor activity. The results of histological evaluation studies showed that TBN groups did not have visible difference compared to the control in different organs, which indicated that TBN was a safe carrier. According to these results, TPTN could achieve the target release of drug and imaging agent at tumor area to increase the diagnostic sensitivity and therapeutic efficacy. TPTN was a promising theranostic carrier for the individualized therapy of HCC.
Thus, this study synthesized novel multi-block materials and fabricated theranostic nanoparticles for the theranostic treatment of HCC. The theranostic nanoparticles combined pH-sensitivity, long circulating time, drug/imaging agent co-loading and active targeting functions showed great potential in target therapy, treatment monitoring, individualized therapy of HCC. All in all, the theranostic nanoparticles provided a new concept, new tool and new strategy to theranostic tumor therapy.
诊断治疗学(Theranostics)是一种将分子诊断与分子治疗相结合的治疗策略,近年来作为一种新型疾病治疗策略,特别是在肿瘤治疗方面受到了人们广泛的关注。基于诊断治疗学的治疗模式能够实现①可视化药物体内递送过程；②可视化药物在给药靶部位的分布和释放过程；③在治疗的同时进行诊断,实现肿瘤治疗的实时监控和个体化给药等。因此,诊断治疗学对HCC治疗过程中治疗效果的实时监控、及时调整给药剂量或治疗方案、实现病人个体化给药并提高肿瘤治疗效果具有重要意义。
本课题基于Theranostics理论,设计和制备一种多功能纳米载体用于HCC的个体化给药,以提高治疗效果,降低毒副作用。首先,选择聚合物纳米粒作为Theranostics载体,设计合成具有载药、长循环和方便后期修饰的多功能材料聚乳酸-聚乙二醇-聚赖氨酸(poly(lactic acid)-Poly(ethylene glycol)-Polylysine, PLA-PEG-PLL),具有pH敏感性和长循环性的多功能材料聚组氨酸-聚乙醇-生物素(Polyhistidine-Poly(ethylene glycol)-Biotin, PLH-PEG-Biotin);然后,选取紫杉醇(Paclitaxel, PTX)和索拉菲尼为治疗HCC的模型药物,基于钆(Gd)的磁共振显影(Magnetic Resonance Imaging, MRI)模式为诊断手段,分别以肿瘤微环境高表达的血管内皮生长因子(vascular endothelial growth factor, VEGF)、甲胎蛋白(Alpha-fetoprotein, AFP)和血管内皮生长因子受体(vascular endothelial growth factor receptor, VEGFR)为靶点,自组装手段制备了三种多功能聚合物纳米载体,分别为：①靶向治疗学多功能纳米粒(靶向VEGF载PTX聚合物纳米粒,Target PTX-loaded nanoparticles, TPN)、②诊断治疗学多功能纳米粒(靶向AFP载Gd/PTX聚合物纳米粒,Target Gd/PTX-loaded nanoparticles, TGPN)和③pH敏感诊断治疗学多功能纳米粒(pH敏感靶向VEGFR载Gd/PTX聚合物纳米粒,Target pH-sensitive theranostic nanoparticles, TPTN);最后,分别对三种多功能纳米载体的理化性质、体外释放行为、细胞毒性、细胞摄取、体外MRI性质、体内MRI性质、体内抑瘤性质和组织安全性等进行评价,以期提高HCC的分子靶向治疗和治疗监控效果,实现HCC病人个体化治疗。
课题主要研究方法与结果如下：
1.多功能材料的合成与表征
为构建多功能诊断治疗学聚合物纳米载体,课题首创聚合物缀合技术,合成两种新型多功能高分子材料PLA-PEG-PLL和PLH-PEG-Biotin。聚合物缀合技术是指利用化学反应,将具不同功能的单嵌段材料化学连接得到多嵌段多功能聚合物的技术。与传统聚合反应方法比较,该方法合成过程简单,无需严苛的反应条件,产物纯化简单,并能够相对准确地控制每一嵌段的分子量。此外,利用聚合物缀合技术可以将任意具有活性基团的嵌段相连接,具有多嵌段材料制备的可创造性。
1.1PLA-PEG-PLL的合成与表征
利用酰胺反应,将PLA-COOH分别连接NH2-PEG-NH2得到PLA-PEG-NH2,然后连接PLL(Cbz)-COOH得到PLA-PEG-PLL(Cbz),最后氨基脱保护得到结合载药、长循环和易于修饰多功能于一体的多功能材料PLA-PEG-PLL.通过核磁验证了每一步合成产物的结构。通过凝胶色谱得到PLA, PLA-PEG和PLA-PEG-PLL的数均分子量和多分散系数分别为13691(1.427)、16013(1.277)和20441(1.358)。利用芘荧光探针法测得PLA-PEG-PLL的临界胶束浓度值为7.70×10-3mg/mL (3.76×10-7Mol/L)。基于PLA-PEG-PLL,利用酰胺反应,合成了PLA-PEG-PLL-DTPA和PLA-PEG-PLL-Biotin,分别用于Gd装载和靶向抗体修饰。
1.2PLH-PEG-Biotin
利用酰胺反应,将Biotin-PEG-NH2与PLH-COOH反应得到PLH-PEG-Biotin,通过核磁验证了合成产物的结构。通过酸碱滴定实验证明PLH-PEG-Biotin pKb值在pH5-7之间,处于血液pH与肿瘤微环境pH之间,具有在肿瘤组织实现纳米粒pH敏感性释药的能力。
2.靶向治疗学多功能纳米粒的制备与表征
靶向治疗能够提高HCC的治疗效果,降低化疗药物对正常组织的毒性,是目前研究的热点之一。因此,本文首先制备TPN用于HCC的靶向治疗。首先建立PTX高效液相色谱检测方法,PTX在选定液相条件下峰型良好,符合方法学考察要求。利用自组装方法制得TPN外观圆整,呈球形或类球形,粒径为203.6±4.10nm, Zeta电位为20.76±0.34mv,包封率和载药量分别为86.23±1.79%和1.42±0.03%。在体外释放实验中,与Taxol(?)匕较,TPN表现出缓释特性,释放曲线符合Higuchi方程Q=8.0449t1/2-0.5721, R=0.9678.细胞毒性实验结果表明,TPN的细胞毒性(IC50=0.392±0.012μM)显著高于Taxol(?)(IC50=3.554μ0.233μM)和PN (IC50=1.510±0.099μM)(P＜0.01),具有良好的体外抗肿瘤活性。在细胞摄取实验中,FITC标记TPN的摄取具有时间依赖性和浓度依赖性,在不同浓度下,FITC标记TPN的摄取率显著高FITC标记PN(P<0.01)。在体内肿瘤抑制实验中,与NS、Taxol(?)、PN比较,TPN能够显著抑制小鼠体内肿瘤体积的增长(P＜0.01), TPN组生存时间(大于30d)长于Taxol(?)组(23d)和PN(27d),具有良好的体内抗肿瘤活性。以上实验结果表明TPN能够实现HCC的靶向治疗,提高治疗效果,具有重要的应用前景。
3.诊断治疗学多功能纳米粒的制备与表征
为实现HCC的Theranostics,需要在肿瘤靶向治疗的基础上添加实时诊断模式。课题基于功能集成组装的思路,将Gd的MRI显影模式添加至TPN中,制备TGPN用于HCC的Theranostics研究。利用自组装方法制得TGPN外观圆整,呈球形或类球形,粒径为147.50±4.71nm, Zeta电位为24.45±1.04mv,包封率和载药量分别为88.76±1.64%和1.59±0.06%。在体外释放实验中,与Taxol(?)比较,TGPN表现出缓释特性,释放曲线符合Weibull方程1nln[1/(1-Q/100)]=0.6961nt-6.5891(R=0.9533).在细胞毒性实验中,TGPN在24h的细胞毒性高于Taxol(?)和GPN(P<0.05),具有良好的体外抗肿瘤活性。FITC标记TGPN的细胞摄取具有时间依赖性和浓度依赖性,在AFP阳性HepG2细胞中,孵育0.5h后,FITC标记TGPN的摄取率显著高于FITC标记GPN(P<0.01),在AFP阴性B16细胞中,FITC标记TGPN与FITC标记GPN的摄取率之间没有显著性差异(P>0.05),证明AFP抗体能够促进TGPN在HepG2细胞中的摄取。体外MRI评价表明TGPN具有高弛豫率(25.388mM-1s-1),是马根维显(4.9mM-1s-1)的5.18倍。在体内MRI实验中,给药TGPN后,小鼠肿瘤区域的显影信号增强AUC值为马根维显的87.6倍,信号峰值为马根维显的2.94倍,并能显著延长诊断时间,从马根维显的小于1h延长至6h以上,具有良好的体内MRI诊断能力。与NS、Taxol(?)、比较,TGPN能够显著抑制小鼠体内肿瘤体积的增长(P<0.01),TPN组生存时间(20d)长于Taxol(?)组(11d)和PN(15d),具有良好的体内抗肿瘤活性。以上实验结果表明TGPN具有优秀的HCC诊断和治疗能力,能够实现治疗过程的实时检测,从而利于实现给药个体化,具有重要的应用潜力。
4.pH敏感诊断治疗学多功能纳米粒的制备与表征
肿瘤组织的定位释药策略能够提高诊断治疗学纳米载体治疗效果和诊断灵敏度,更有利于发挥Theranostics策略优势。因此,本文设计具有pH响应性释药能力的Theranostics纳米粒,制备TPTN用于HCC的诊断治疗研究。首先建立索拉菲尼高效液相色谱检测方法,索拉菲尼在选定的液相条件下峰型良好,符合方法学考察要求。利用自组装方法制得TPTN外观圆整,呈球形或类球形,粒径为181.4±3.4nm, Zeta电位为14.95±0.60mv,包封率和载药量分别为95.02±1.47%和2.38±0.04%。在含10%血清条件下,TPTN在2-4h内粒径保持稳定,证明稳定性良好。在体外释放实验中,TPTN的释放具有pH依赖性,其在pH=5.0的释放介质中释放速率显著高于pH=7.4的释放介质(P<0.01)。在细胞毒性实验中,TPTN在pH=5.0环境中孵育1h后的细胞毒性与索拉菲尼溶液相当,证明TPTN具有良好的体外抗肿瘤活性。FITC标记TPTN的细胞摄取具有时间依赖性和浓度依赖性,在不同浓度下,FITC标记TPTN的摄取率显著高于FITC标记PTN (P＜0.01)。体外MRI评价表明TPTN具有高弛豫率(17.300mM-1s-1),是马根维显(4.9mM-1s-1)的3.53倍。肿瘤模型小鼠静脉给药TPTN后,小鼠肿瘤区域与周围组织之间的信号对比明显,肉眼可以观察到明显的肿瘤边界,并能显著延长诊断时间,从马根维显的小于1h延长至1.5h以上,具有良好的体内MRI诊断能力。在体内肿瘤抑制实验中,与NS、索拉菲尼溶液(口服或静注)、PTN比较,TPTN能够显著抑制小鼠体内肿瘤生长(P<0.01),说明TPTN具有良好的体内抗肿瘤活性。通过组织免疫切片观察,小鼠静脉注射TBN后,各个脏器与注射生理盐水组相应脏器比较没有明显的组织毒性,证明TBN是一个相对安全的载体。以上实验结果表明TPTN在具有优秀的HCC诊断和治疗能力的同时,能够实现药物的肿瘤区域定位释放,进一步提高肿瘤诊断治疗能力,具有重要的研究价值。
综上,本研究基于Theranostics理论,设计合成新材料,构建新型多功能聚合物纳米载体,能够同时装载诊断因子和治疗药物,具有被动和主动肿瘤靶向、体内长循环、pH敏感释药等功能,能够实现肿瘤的靶向诊断、靶向治疗和治疗实时监控,为肿瘤Theranostics策略的发展提供了一种新思路和新手段。
Human hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Chemotherapy is one of the main treatment methods in clinic. However, Chemotherapy usually met the following two problems:a) the common dosage was based on the average dosage level of patients which might result in the failure of HCC therapy; b) the evaluation of the treatment was carried out after a treatment cycle, which mighy missed the best time of the treatment.
Recently, theranostics which combined cancer diagnosis and therapeutics in a single platform, received great attention in cancer treatment. Theranostics offered several advantages including the assessment of the biodistribution and accumulation of drugs at target sites noninvasively, the visualization of drug distribution and drug release at the target site, the optimization of formulation which relied on triggered drug release, and the real-time monitoring the therapeutic responses. So, theranostics therapy showed great potential in the individualized therapy and the real-time monitoring the treatment of HCC patients.
In this study, the multifunctional carriers were designed and prepared to achieve the individualized therapy of HCC based on theranostics. Firstly, the polymeric nanoparticles were selected as the theranostics carriers. The novel three block polymer PLA-PEG-PLL which combined drug-loading, long circulation time and easily modification functions and two block polymer PLH-PEG-Biotin which combined pH-sensitivity, long circulation time and active modification functions were designed and synthesized. Then, the HCC therapeutic drugs Paclitaxel (PTX) and sorafenib were employed as the model drug; Magnetic Resonance Imaging (MRI) was employed as the diagnosis method; vascular endothelial growth factor (VEGF), Alpha-fetoprotein (AFP) and vascular endothelial growth factor receptor (VEGFR) which were overexpressed in tumor microenvironment were selected as the delivery target; there multifunctional polymeric nanoparticles, including VEGF antibody modified PTX-loaded polymeric nanoparticles (TPN), AFP antibody modified Gd/PTX-loaded polymeric nanoparticles (TGPN) and pH-sensitive VEGFR antibody modified Gd/PTX-loaded polymeric nanoparticles (TPTN) were prepared by self-assembly method. At last, the basic properties, in vitro release profiles, cell cytotoxicity, cell uptake properties, in vitro MRI properties, in vivo MRI properties, in vivo anti-tumor ability and tissue safety were evaluated.
Above all, this article designed and synthesized two novel polymers, PLA-PEG-PLL and PLH-PEG-biotin, and prepared three kinds of multifunctional polymeric nanoparticles based on theranostics to achieve the target therapy, treatment monitoring, individualized therapy of HCC. The main study methods and results were showed as follows:
1. Synthesis and characterization of multifunctional materials
To fabricate multifunctional theranostic polymeric nanoparticles, the multifunctional polymer were firstly synthesized by polymer-polymer conjugation method which was first proposed by our group. Polymer-polymer conjugation is a novel multi-block polymers synthesis method that conjugated different polymer blocks by reactions between the terminal active groups of different blocks. The synthesis procedure was relatively simple without complex synthesis steps compared to traditional polymerization method. The synthesized multi-block polymers could have more relatively precise molecular weight of each block than that synthesized by traditional polymerization. Otherwise, different single block could be selected according to the expected functions of the multi-block polymers. Any single block that contained functional active groups for the conjugation could be used in this novel synthesis method. This facility and availability of different blocks indicated that multi-block polymers with various blocks or different block numbers could be synthesized theoretically by polymer-polymer conjugation.
1.1Synthesis and characterization of PLA-PEG-PLL
The carboxyl group of PLA-COOH reacted with the amino group of NH2-PEG-NH2to obtain PLA-PEG-NH2. Then, the amino group of PLA-PEG-NH2reacted with the carboxyl group ofPLL(Cbz)-COOH to obtain PLA-PEG-PLL(Cbz). After the deprotection of amino groups of PLA-PEG-PLL(Cbz), PLA-PEG-PLL was successfully synthesized. PLA-PEG-PLL combined drug loading, long circulating in vivo, and easy for modification functions. The structures of products were verified by NMR. GPC results showed that the number-average molar mass of PLA, PLA-PEG and PLA-PEG-PLL was13691,16013and20441Da and the molecular weight distribution (Mw/Mn) was1.427,1.277and1.358, respectively. These results indicated the successfully synthesis of PLA-PEG-PLL by polymer-polymer conjugation. The critical micelle concentration of PLA-PEG-PLL was determined using pyrene as an extrinsic probe and the critical micelle concentration of the PLA-PEG-PLL was7.70×10-3mg/mL. Based on PLA-PEG-PLL, two modified polymer PLA-PEG-PLL-DTPA and PLA-PEG-PLL-Biotin were synthesized by amide reaction for Gd loading and antibodies modification, respectively.
1.2Synthesis and characterization of PLH-PEG-Biotin
The carboxyl group of PLA-COOH reacted with the amino group of Biotin-PEG-NH2to obtain PLH-PEG-Biotin. The structures of PLH-PEG-Biotin were verified by NMR. The acid-base titration results showed that PLH-PEG-biotin exhibited great buffering capacity with a buffering zone within pH5-7, which could induce the solubility change of PLH from the blood (pH=7.4) to the tumor tissue (pH=5～7).
2. Preparation and characterization of TPN
Molecular therapy was the hot spot in recent years. It could increase the therapeutic effect of HCC and decrease the toxicity in the treatment. Thus, the VEGF antibody modified PTX-loaded polymeric nanoparticles (TPN) were prepared for the molecular therapy of HCC. PTX HPLC detection method was firstly established and the detection method reach the methodological study requirements. The TPN were prepared by solvent diffusion method. The morphology of TPN had spherical or ellipsoidal shapes without agglomeration. The particle size, zeta potential, EE%and DL%of TPN were203.6±4.10nm,20.76±0.34mv,86.23±1.79%and1.42±0.03%, respectively. In the release studies in vitro, compared to Taxol(?), TPN showed a controlled release profile and fitted Higuchi equation:Q=8.0449t1/2-0.5721, R=0.9678. The results of cell cytotoxicity studies showed that TPN (IC50=0.392±0.012μM) had significantly higher cytotoxicity compared to Taxol(?)(IC50=3.554±0.233μM) and non-target TPN (IC50=1.510±0.099μM)(P＜0.01), which indicated that TPN had good in vitro anti-tumor activity. In cell uptake studies, the cell uptake of FITC-labeled TPN was both time and concentration dependence. The cell uptake rates of FITC-labeled TPN were significantly higher than FITC-labeled non-target TPN at different incubation concentrations (P＜0.01). The results of in vivo tumor growth inhibition studies showed that TPN could significantly inhibit the growth of tumors compared to NS, Taxol(?), and non-target TPN (P＜0.01), which indicated that TPN had good in vivo anti-tumor activity. According to these results, TPN was an excellent drug carrier for the molecular therapy of HCC.
3. Preparation and characterization of TGPN
The achieve theranostic and individualized therapy of HCC, the diagnositic method should be added to the target therapy therapy carrier. Thus, the AFP antibody modified Gd/PTX-loaded polymeric nanoparticles (TGPN) was prepared for the theranostic therapy of HCC. The TGPN were prepared by solvent diffusion method. The morphology of TGPN had spherical or ellipsoidal shapes without agglomeration. The particle size, zeta potential, EE%and DL%of TPN were147.50±4.7nm,24.45±1.04mv,88.76±1.64%and1.59±0.06%, respectively. In the release studies in vitro, compared to Taxol(?), TGPN showed a controlled release profile and fitted Weibull equation:lnln[1/(1-Q/100)]=0.696ltt-6.5891, R=0.9533. The results of cell cytotoxicity studies showed that TGPN had higher cytotoxicity compared to Taxol(?) and non-target TGPN in24h (P＜0.05), which indicated that TGPN had good in vitro anti-tumor activity. In cell uptake studies, the cell uptake of FITC-labeled TGPN was both time and concentration dependence. The cell uptake rates of FITC-labeled TGPN were significantly higher than FITC-labeled non-target TGPN at different incubation concentrations in AFP-positive HepG2cells in0.5h (P＜0.01). While, the cell uptake rates did not showed any difference in AFP-nagetive B16cells, which proved the increased cell uptake was induced by AFP antibodies. The results of in vitro MRI studies showed that TGPN had high relaxivity (25.388nM-1s-1) which was5.18time to Magnevist(?)(4.9mM-1s-1). The results of in vivo MRI studies showed that the enhance signal area (AUC) of TGPN was87.6time to Magnevist(?) and the highest signal enhancement was2.94time to Magnevist(?). Meanwhile, the diagnosis time of TGPN was greatly prolonged from less than1h (Magnevist(?)) to more than6h. There results indicated that TGPN had good in vivo diagnosis ability. The results of in vivo tumor growth inhibition studies showed that TGPN could significantly inhibit the growth of tumors compared to NS, and Taxol(?)(P＜0.01), which indicated that TGPN had good in vivo anti-tumor activity. According to these results, TGPN had excellent HCC diagnosis and treatment ability, which showed great potential in the theranostic and individualized therapy of HCC.
4. Preparation and characterization of TPTN
The controlled and responsive release in the tumor area is important to increase the diagnostic sensitivity and therapeutic efficacy of HCC. Base on this consideration, the pH-sensitive VEGFR antibody modified Gd/PTX-loaded polymeric nanoparticles (TPTN) was prepared for the theranostic therapy of HCC. Sorafenib HPLC detection method was firstly established and the detection method reach the methodological study requirements. The TPTN were prepared by solvent diffusion method. The morphology of TPTN had spherical or ellipsoidal shapes without agglomeration. The particle size, zeta potential, EE%and DL%of TPN were181.4±3.4nm,14.95±0.60mv,95.02±1.47%and2.38±0.04%, respectively. TPTN showed good stability in the presence of10%serum in2-4h. In the release studies in vitro, TPTN showed pH-sensitive drug release profile. The release rate in the release media (pH=5.0) was significantly higher than in the release media (pH=7.4)(P＜0.01). The results of cell cytotoxicity studies showed that TPTN had similar cytotoxicity after incubated in pH5.0for1h compared to sorafenib silution, which indicated that TPTN had good in vitro anti-tumor activity. In cell uptake studies, the cell uptake of FITC-labeled TPTN was both time and concentration dependence. The cell uptake rates of FITC-labeled TPTN were significantly higher than FITC-labeled PTN at different incubation concentrations in VEGFR-positive HepG2cells (P＜0.01). The results of in vitro MRI studies showed that TPTN had high relaxivity (17.300mM-1s-1) which was3.53time to Magnevist(?)(4.9mM-1s-1). In MRI studies in vivo, after administration of TPTN, the tumor area showed visual brighter image than the surrounding tissue and the boundary of tumor tissue could be clearly demarcated. Meanwhile, the diagnosis time of TPTN was greatly prolonged from less than1h (Magnevist(?)) to more than1.5h. There results indicated that TPTN had good in vivo diagnosis ability. The results of in vivo tumor growth inhibition studies showed that TPTN could significantly inhibit the growth of tumors compared to NS, sorafenib solution and PTN (P＜0.01), which indicated that TPTN had good in vivo anti-tumor activity. The results of histological evaluation studies showed that TBN groups did not have visible difference compared to the control in different organs, which indicated that TBN was a safe carrier. According to these results, TPTN could achieve the target release of drug and imaging agent at tumor area to increase the diagnostic sensitivity and therapeutic efficacy. TPTN was a promising theranostic carrier for the individualized therapy of HCC.
Thus, this study synthesized novel multi-block materials and fabricated theranostic nanoparticles for the theranostic treatment of HCC. The theranostic nanoparticles combined pH-sensitivity, long circulating time, drug/imaging agent co-loading and active targeting functions showed great potential in target therapy, treatment monitoring, individualized therapy of HCC. All in all, the theranostic nanoparticles provided a new concept, new tool and new strategy to theranostic tumor therapy.
引文
[1]J.D. Yang, L.R. Roberts Hepatocellular carcinoma:A global view. Nat Rev Gastroenterol Hepatol,2010,7:448-458.
[2]H. Lin, J. van den Esschert, C. Liu, et al. Systematic review of hepatocellular adenoma in China and other regions. J Gastroenterol Hepatol,2011,26:28-35.
[3]S. Whittaker, R. Marais, A.X. Zhu The role of signaling pathways in the development and treatment of hepatocellular carcinoma. Oncogene,2010,29: 4989-5005.
[4]P. Stefaniuk, J. Cianciara, A. Wiercinska-Drapalo Present and future possibilities for early diagnosis of hepatocellular carcinoma. World J Gastroenterol,2010,16: 418-424.
[5]J.U. Marquardt, P.R. Galle, A. Teufel Molecular diagnosis and therapy of hepatocellular carcinoma (HCC):an emerging field for advanced technologies. J Hepatol,2012,56:267-275.
[6]Y. Liu, Z. Chen, C. Liu, et al. Gadolinium-loaded polymeric nanoparticles modified with Anti-VEGF as multifunctional MRI contrast agents for the diagnosis of liver cancer. Biomaterials,2011,32:5167-5176.
[7]R.R. Sawant, A.M. Jhaveri, V.P. Torchilin Immunomicelles for advancing personalized therapy. Adv Drug Deliv Rev,2012,64:1436-1446.
[8]S.S. Kelkar, T.M. Reineke Theranostics:combining imaging and therapy. Bioconjug Chem,2011,22:1879-1903.
[9]C.A. Hudis Trastuzumab--mechanism of action and use in clinical practice. N Engl J Med,2007,357:39-51.
[10]V. Ozdemir, B. Williams-Jones, S.J. Glatt, et al. Shifting emphasis from pharmacogenomics to theragnostics. Nat Biotechnol,2006,24:942-946.
[11]S. Mura, P. Couvreur Nanotheranostics for personalized medicine. Adv Drug Deliv Rev,2012,64:1394-1416.
[12]Y. Liu, N. Zhang Gadolinium loaded nanoparticles in theranostic magnetic resonance imaging. Biomaterials,2012,33:5363-5375.
[13]T. Liu, X. Li, Y. Qian, et al. Multifunctional pH-disintegrable micellar nanoparticles of asymmetrically functionalized beta-cyclodextrin-based star copolymer covalently conjugated with doxorubicin and DOTA-Gd moieties. Biomaterials,2012,33:2521-2531.
[14]M.S. Muthu, S.A. Kulkarni, A. Raju, et al. Theranostic liposomes of TPGS coating for targeted co-delivery of docetaxel and quantum dots. Biomaterials, 2012,33:3494-3501.
[15]L. Zhu, D. Wang, X. Wei, et al. Multifunctional pH-sensitive superparamagnetic iron-oxide nanocomposites for targeted drug delivery and MR imaging. J Control Release,2013,169:228-238.
[16]J.R. McCarthy The future of theranostic nanoagents. Nanomedicine (Lond), 2009,4:693-695.
[17]W.T. Al-Jamal, K. Kostarelos Liposomes:from a clinically established drug delivery system to a nanoparticle platform for theranostic nanomedicine. Ace Chem Res,2011,44:1094-1104.
[18]K.H. Bae, J.Y. Lee, S.H. Lee, et al. Optically traceable solid lipid nanoparticles loaded with siRNA and paclitaxel for synergistic chemotherapy with in situ imaging. Adv Healthc Mater,2013,2:576-584.
[19]S. Srinivasan, R. Manchanda, A. Fernandez-Fernandez, et al. Near-infrared fluorescing IR820-chitosan conjugate for multifunctional cancer theranostic applications. J Photochem Photobiol B,2013,119:52-59.
[20]Y. Xiao, H. Hong, A. Javadi, et al. Multifunctional unimolecular micelles for cancer-targeted drug delivery and positron emission tomography imaging. Biomaterials,2012,33:3071-3082.
[21]S.T. Lo, A. Kumar, J.T. Hsieh, et al. Dendrimer nanoscaffolds for potential theranostics of prostate cancer with a focus on radiochemistry. Mol Pharm,2013, 10:793-812.
[22]A. Tan, L. Yildirimer, J. Rajadas, et al. Quantum dots and carbon nanotubes in oncology:a review on emerging theranostic applications in nanomedicine. Nanomedicine (Lond),2011,6:1101-1114.
[23]D.N. Heo, D.H. Yang, H.J. Moon, et al. Gold nanoparticles surface-functionalized with paclitaxel drug and biotin receptor as theranostic agents for cancer therapy. Biomaterials,2012,33:856-866.
[24]S.P. Singh Multifunctional magnetic quantum dots for cancer theranostics. J Biomed Nanotechnol,2011,7:95-97.
[25]J. Huang, X. Zhong, L. Wang, et al. Improving the magnetic resonance imaging contrast and detection methods with engineered magnetic nanoparticles. Theranostics,2012,2:86-102.
[26]J.L. Vivero-Escoto, R.C. Huxford-Phillips, W. Lin Silica-based nanoprobes for biomedical imaging and theranostic applications. Chem Soc Rev,2012,41: 2673-2685.
[27]E. Engel, A. Michiardi, M. Navarro, et al. Nanotechnology in regenerative medicine:the materials side. Trends Biotechnol,2008,26:39-47.
[28]M.A. Stuart, W.T. Huck, J. Genzer, et al. Emerging applications of stimuli-responsive polymer materials. Nat Mater,2010,9:101-113.
[29]X. Yang, J.J. Grailer, S. Pilla, et al. Multifunctional polymeric vesicles for targeted drug delivery and imaging. Biofabrication,2010,2:025004.
[30]K. Madhavan Nampoothiri, N.R. Nair, R.P. John An overview of the recent developments in polylactide (PLA) research. Bioresour Technol,2010,101: 8493-8501.
[31]V. Torchilin Tumor delivery of macromolecular drugs based on the EPR effect. Adv Drug Deliv Rev,2011,63:131-135.
[32]M.L. Patil, M. Zhang, T. Minko Multifunctional triblock Nanocarrier (PAMAM-PEG-PLL) for the efficient intracellular siRNA delivery and gene silencing. ACS Nano,2011,5:1877-1887.
[33]H. Tian, Z. Tang, X. Zhuang, et al. Biodegradable synthetic polymers: Preparation, functionalization and biomedical application. Progress in Polymer Science,2012,37:237-280.
[34]J.W. Kramer, D.S. Treitler, E.W. Dunn, et al. Polymerization of enantiopure monomers using syndiospecific catalysts:a new approach to sequence control in polymer synthesis. J Am Chem Soc,2009,131:16042-16044.
[35]P. Gunatillake, R. Mayadunne, R. Adhikari Recent developments in biodegradable synthetic polymers. Biotechnol Annu Rev,2006,12:301-347.
[36]W. Krause,艇.T贸th, L. Helm, et al. Relaxivity of MRI Contrast Agents. Contrast Agents I:Springer Berlin Heidelberg,2002. p.61-101.
[37]许乙凯磁共振对比剂的发展概况及存在问题.第一军医大学学报,2002,22：769-771.
[38]J. Bruix, M. Sherman Management of hepatocellular carcinoma:an update. Hepatology,2011,53:1020-1022.
[39]V.J. Poirier, A.E. Hershey, K.E. Burgess, et al. Efficacy and toxicity of paclitaxel (Taxol) for the treatment of canine malignant tumors. J Vet Intern Med,2004,18:219-222.
[40]M.R. Green, GM. Manikhas, S. Orlov, et al. Abraxane, a novel Cremophor-free, albumin-bound particle form of paclitaxel for the treatment of advanced non-small-cell lung cancer. Ann Oncol,2006,17:1263-1268.
[41]Y. Chao, W.K. Chan, M.J. Birkhofer, et al. Phase II and pharmacokinetic study of paclitaxel therapy for unresectable hepatocellular carcinoma patients. Br J Cancer,1998,78:34-39.
[42]A. Hauschild, S.S. Agarwala, U. Trefzer, et al. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol,2009,27:2823-2830.
[43]J.M. Llovet, S. Ricci, V. Mazzaferro, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med,2008,359:378-390.
[44]D.H. Palmer Sorafenib in advanced hepatocellular carcinoma. N Engl J Med, 2008,359:2498; author reply 2498-2499.
[45]D. Kozlowska, P. Foran, P. MacMahon, et al. Molecular and magnetic resonance imaging:The value of immunoliposomes. Adv Drug Deliv Rev,2009,61: 1402-1411.
[46]Y. Saito, N. Oba, S. Nishinakagawa, et al. Identification of beta2-microgloblin as a candidate for early diagnosis of imaging-invisible hepatocellular carcinoma in patient with liver cirrhosis. Oncol Rep,2010,23:1325-1330.
[47]Y. Lu, P.S. Low Folate-mediated delivery of macromolecular anticancer therapeutic agents. Adv Drug Deliv Rev,2002,54:675-693.
[48]N. Yonenaga, E. Kenjo, T. Asai, et al. RGD-based active targeting of novel polycation liposomes bearing siRNA for cancer treatment. J Control Release, 2012,160:177-181.
[49]R. Kontermann Dual targeting strategies with bispecific antibodies. MAbs,2012,
[50]H.Y. Yoon, H. Koo, K.Y. Choi, et al. Tumor-targeting hyaluronic acid nanoparticles for photodynamic imaging and therapy. Biomaterials,2012,33: 3980-3989.
[51]L. Wang, J. Huang, M. Jiang, et al. AFP computational secreted network construction and analysis between human hepatocellular carcinoma (HCC) and no-tumor hepatitis/cirrhotic liver tissues. Tumour Biol,2010,31:417-425.
[52]G. Beale, D. Chattopadhyay, J. Gray, et al. AFP, PIVKAⅡ, GP3, SCCA-1 and follisatin as surveillance biomarkers for hepatocellular cancer in non-alcoholic and alcoholic fatty liver disease. BMC Cancer,2008,8:200.
[53]M. Patel, M.I. Shariff, N.G. Ladep, et al. Hepatocellular carcinoma:diagnostics and screening. J Eval Clin Pract,2011,18:335-342.
[54]B. Sitohy, J.A. Nagy, H.F. Dvorak Anti-VEGF/VEGFR therapy for cancer: reassessing the target. Cancer Res,2012,72:1909-1914.
[55]L. Zhang, J.N. Wang, J.M. Tang, et al. VEGF is essential for the growth and migration of human hepatocellular carcinoma cells. Mol Biol Rep,2012,39: 5085-5093.
[56]Y. Xu, Z. Wen, Z. Xu Chitosan nanoparticles inhibit the growth of human hepatocellular carcinoma xenografts through an antiangiogenic mechanism. Anticancer Res,2009,29:5103-5109.
[57]D. Liu, F. Liu, Z. Liu, et al. Tumor specific delivery and therapy by double-targeted nanostructured lipid carriers with anti-VEGFR-2 antibody. Mol Pharm,2011,8:2291-2301.
[58]H. Huang, S. Delikanli, H. Zeng, et al. Remote control of ion channels and neurons through magnetic-field heating of nanoparticles. Nat Nanotechnol, 2010,5:602-606.
[59]M. Rahimi, A. Wadajkar, K. Subramanian, et al. In vitro evaluation of novel polymer-coated magnetic nanoparticles for controlled drug delivery. Nanomedicine,2010,6:672-680.
[60]B. Yan, J.C. Boyer, D. Habault, et al. Near infrared light triggered release of biomacromolecules from hydrogels loaded with upconversion nanoparticles. J Am Chem Soc,2012,134:16558-16561.
[61]D.E. Lee, H. Koo, I.C. Sun, et al. Multifunctional nanoparticles for multimodal imaging and theragnosis. Chem Soc Rev,2012,41:2656-2672.
[62]W.B. Liechty, N.A. Peppas Expert opinion:Responsive polymer nanoparticles in cancer therapy. Eur J Pharm Biopharm,2012,80:241-246.
[63]X. He, J. Li, S. An, et al. pH-sensitive drug-delivery systems for tumor targeting. Ther Deliv,2011,4:1499-1510.
[64]C. Liu, F. Liu, L. Feng, et al. The targeted co-delivery of DNA and doxorubicin to tumor cells via multifunctional PEI-PEG based nanoparticles. Biomaterials, 2013,34:2547-2564.
[65]P. Li, D. Liu, L. Miao, et al. A pH-sensitive multifunctional gene carrier assembled via layer-by-layer technique for efficient gene delivery. Int J Nanomedicine,2012,7:925-939.
[66]H. Wu, L. Zhu, V.P. Torchilin pH-sensitive poly(histidine)-PEG/DSPE-PEG co-polymer micelles for cytosolic drug delivery. Biomaterials,2013,34: 1213-1222.
[67]D. Hoekstra, J. Rejman, L. Wasungu, et al. Gene delivery by cationic lipids:in and out of an endosome. Biochem Soc Trans,2007,35:68-71.
[68]T. Reuveni, M. Motiei, Z. Romman, et al. Targeted gold nanoparticles enable molecular CT imaging of cancer:an in vivo study. Int J Nanomedicine,2011,6: 2859-2864.
[69]Z. Chen, D. Yu, C. Liu, et al. Gadolinium-conjugated PLA-PEG nanoparticles as liver targeted molecular MRI contrast agent. J Drug Target,2011,19: 657-665.
[70]C. Liu, W. Yu, Z. Chen, et al. Enhanced gene transfection efficiency in CD 13-positive vascular endothelial cells with targeted poly(lactic acid)-poly(ethylene glycol) nanoparticles through caveolae-mediated endocytosis. J Control Release,2011,151:162-175.
[71]Y. Liu, C. Liu, M. Li, et al. Polymer-Polymer Conjugation to Fabricate Multi-Block Polymer as Novel Drug Carriers:Poly(lactic acid)-Poly(ethylene glycol)-Poly(L-lysine) to Enhance Paclitaxel Target Delivery. Journal of Biomedical Nanotechnology,2014,10:948-958.
[72]Z. Liu, Y. Wang, J. Zhang, et al. Pluronic P123-docetaxel conjugate micelles: synthesis, characterization, and antitumor activity. J Biomed Nanotechnol,2013, 9:2007-2016.
[73]K. Miyata, R.J. Christie, K. Kataoka Polymeric micelles for nano-scale drug delivery. Reactive and Functional Polymers,2011,71:227-234.
[74]Z. Liu, N. Zhang pH-Sensitive polymeric micelles for programmable drug and gene delivery. Curr Pharm Des,2012,18:3442-3451.
[75]I.-K. Park, K. Singha, R.B. Arote, et al. pH-Responsive Polymers as Gene Carriers. Macromolecular Rapid Communications,2010,31:1122-1133.
[76]O. Veiseh, J.W. Gunn, M. Zhang Design and fabrication of magnetic nanoparticles for targeted drug delivery and imaging. Advanced Drug Delivery Reviews,2010,62:284-304.
[77]M. Kudo Current status of molecularly targeted therapy for hepatocellular carcinoma:clinical practice. Int J Clin Oncol,2010,15:242-255.
[78]A.J. Cole, V.C. Yang, A.E. David Cancer theranostics:the rise of targeted magnetic nanoparticles. Trends Biotechnol,2011,29:323-332.
[79]L. Brannon-Peppas, J.O. Blanchette Nanoparticle and targeted systems for cancer therapy. Advanced Drug Delivery Reviews,2012,64, Supplement: 206-212.
[80]N. Kamaly, Z. Xiao, P.M. Valencia, et al. Targeted polymeric therapeutic nanoparticles:design, development and clinical translation. Chem Soc Rev, 2012,41:2971-3010.
[81]F. Danhier, N. Lecouturier, B. Vroman, et al. Paclitaxel-loaded PEGylated PLGA-based nanoparticles:in vitro and in vivo evaluation. J Control Release, 2009,133:11-17.
[82]B. Zhang, X. Li, B. Yan Advances in HPLC detection--towards universal detection. Anal Bioanal Chem,2008,390:299-301.
[83]S. Hirsjarvi, C. Passirani, J.P. Benoit Passive and active tumour targeting with nanocarriers. Curr Drug Discov Technol,2011,8:188-196.
[84]L. Mu, M.M. Teo, H.Z. Ning, et al. Novel powder formulations for controlled delivery of poorly soluble anticancer drug:application and investigation of TPGS and PEG in spray-dried particulate system. J Control Release,2005,103: 565-575.
[85]R. Ghosh, K.L. Lipson, K.E. Sargent, et al. Transcriptional regulation of VEGF-A by the unfolded protein response pathway. PLoS One,2010,5:e9575.
[86]K. Na, S.A. Lee, S.H. Jung, et al. Gadolinium-based cancer therapeutic liposomes for chemotherapeutics and diagnostics. Colloids Surf B Biointerfaces, 2011,84:82-87.
[87]M.A. Oghabian, N.M. Farahbakhsh Potential Use of Nanoparticle Based Contrast Agents in MRI:A Molecular Imaging Perspective. Journal of Biomedical Nanotechnology,2010,6:203-213.
[88]H.P. Lesch, M.U. Kaikkonen, J.T. Pikkarainen, et al. Avidin-biotin technology in targeted therapy. Expert Opinion on Drug Delivery,2010,7:551-564.
[89]C.H. Huang, K. Nwe, A. Al Zaki, et al. Biodegradable polydisulfide dendrimer nanoclusters as MRI contrast agents. ACS Nano,2012,6:9416-9424.
[90]M. Botta, L. Tei Relaxivity Enhancement in Macromolecular and Nanosized GdⅢ-Based MRI Contrast Agents. European Journal of Inorganic Chemistry, 2012,2012:1945-1960.
[91]O. Algin, B. Turkbey Intrathecal gadolinium-enhanced MR cisternography:a comprehensive review. AJNR Am J Neuroradiol,2013,34:14-22.
[92]J. Kost, R. Langer Responsive polymeric delivery systems. Adv Drug Deliv Rev, 2001,46:125-148.
[93]S. Yu, G. Wu, X. Gu, et al. Magnetic and pH-sensitive nanoparticles for antitumor drug delivery. Colloids Surf B Biointerfaces,2013,103:15-22.
[94]S. Manchun, C.R. Dass, P. Sriamornsak Targeted therapy for cancer using pH-responsive nanocarrier systems. Life Sciences,2012,90:381-387.
[95]J.-Z. Du, X.-J. Du, C.-Q. Mao, et al. Tailor-Made Dual pH-Sensitive Polymer 鈥 揇 oxorubicin Nanoparticles for Efficient Anticancer Drug Delivery. Journal of the American Chemical Society,2011,133:17560-17563.
[96]N. Abed, P. Couvreur Nanocarriers for antibiotics:A promising solution to treat intracellular bacterial infections. International Journal of Antimicrobial Agents, 2014,
[97]X.Q. Wang, J.M. Fan, Y.O. Liu, et al. Bioavailability and pharmacokinetics of sorafenib suspension, nanoparticles and nanomatrix for oral administration to rat. Int J Pharm,2011,419:339-346.
[98]R.K. Ambasta, A. Sharma, P. Kumar Nanoparticle mediated targeting of VEGFR and cancer stem cells for cancer therapy. Vasc Cell,2011,3:26.
[99]X. Chen, S.S. Gambhir, J. Cheon Theranostic nanomedicine. Acc Chem Res, 2011,44:841.
[100]A. Rode, B. Bancel, P. Douek, et al. Small nodule detection in cirrhotic livers: evaluation with US, spiral CT, and MRI and correlation with pathologic examination of explanted liver. J Comput Assist Tomogr,2001,25:327-336.
[101]C. Wischke, S.P. Schwendeman Principles of encapsulating hydrophobic drugs in PLA/PLGA microparticles. Int J Pharm,2008,364:298-327.
[102]M. Rimann, T. Luhmann, M. Textor, et al. Characterization of PLL-g-PEG-DNA nanoparticles for the delivery of therapeutic DNA. Bioconjug Chem,2008,19: 548-557.
[103]R. Webster, E. Didier, P. Harris, et al. PEGylated Proteins:Evaluation of Their Safety in the Absence of Definitive Metabolism Studies. Drug Metabolism and Disposition,2007,35:9-16.
[1]VMaY C. Nanoparticles-a review. J Pharmaceut Res 2006; 5:561-73.
[2]Cho K, Wang X, Nie S, Chen Z G.Shin D M. Therapeutic nanoparticles for drug delivery in cancer. Clin Cancer Res 2008; 14:1310-6.
[3]Janib S M, Moses A S.Mackay J A. Imaging and drug delivery using theranostic nanoparticles. Adv Drug Deliv Rev 2010; 1052-63.
[4]Liu F, Park J Y, Zhang Y, Conwell C, Liu Y, Bathula S R, et al. Targeted cancer therapy with novel high drug-loading nanocrystals. J Pharm Sci 2010; 99:3542-51.
[5]ICHIKAWA Y F a H. Nanoparticles for cancer therapy and diagnosis. Adv Powder Technol 2006; 17:1-28.
[6]Zhang M Q, Sun C.Lee J S H. Magnetic nanoparticles in mr imaging and drug delivery. Adv Drug Deliv Rev 2008; 60:1252-65.
[7]Ozdemir V, Williams-Jones B, Glatt S J, Tsuang M T, Lohr J B.Reist C. Shifting emphasis from pharmacogenomics to theragnostics. Nat Biotechnol 2006; 24:942-6.
[8]Hudis C A. Trastuzumab--mechanism of action and use in clinical practice. N Engl J Med 2007; 357:39-51.
[9]Pene F, Courtine E, Cariou A.Mira J P. Toward theragnostics. Crit Care Med 2009; 37:S50-8.
[10]Bhojani M S, Van Dort M, Rehemtulla A.Ross B D. Targeted imaging and therapy of brain cancer using theranostic nanoparticles. Mol Pharmaceut 2010; 7:1921-9.
[11]Lammers T, Kiessling F, Hennink W E.Storm G. Nanotheranostics and image-guided drug delivery:Current concepts and future directions. Mol Pharmaceut 2010; 7:1899-912.
[12]Hong H, Zhang Y, Sun J.Cai W. Molecular imaging and therapy of cancer with radiolabeled nanoparticles. Nano Today 2009; 4:399-413.
[13]Lanza G M, Winter P M, Caruthers S D, Hughes M S, Hu G, Schmieder A H, et al. Theragnostics for tumor and plaque angiogenesis with perfluorocarbon nanoemulsions. Angiogenesis 2010;
[14]Weissleder R. Molecular imaging in cancer. Science 2006; 312:1168-71.
[15]Guo-Ping Yan LR P H. Magnetic resonance imaging contrast agents:Overview and perspective. Radiography 2007; 13:e5-e19.
[16]Caravan P. Strategies for increasing the sensitivity of gadolinium based mri contrast agents. Chem Soc Rev 2006; 35:512-23.
[17]Sharma P, Brown S C, Walter G, Santra S, Scott E, Ichikawa H, et al. Gd nanoparticulates:From magnetic resonance imaging to neutron capture therapy. Adv Powder Technol 2007; 18:663-98.
[18]Wang Y X, Hussain S M.Krestin G P. Superparamagnetic iron oxide contrast agents: Physicochemical characteristics and applications in mr imaging. Eur Radiol 2001; 11:2319-31.
[19]Bellin M F. Mr contrast agents, the old and the new. Eur J Radiol 2006; 60:314-23.
[20]Thorek D L, Chen A K, Czupryna J.Tsourkas A. Superparamagnetic iron oxide nanoparticle probes for molecular imaging. Ann Biomed Eng 2006; 34:23-38.
[21]Yang X Q, Grailer J J, Rowland I J, Javadi A, Hurley S A, Steeber D A, et al. Multifunctional spio/dox-loaded wormlike polymer vesicles for cancer therapy and mr imaging. Biomaterials 2010; 31:9065-73.
[22]Yang X Q, Grailer J J, Rowland I J, Javadi A, Hurley S A, Matson V Z, et al. Multifunctional stable and ph-responsive polymer vesicles formed by heterofunctional triblock copolymer for targeted anticancer drug delivery and ultrasensitive mr imaging. ACS Nano 2010; 4:6805-17.
[23]Na K, Lee S A, Jung S H.Shin B C. Gadolinium-based cancer therapeutic liposomes for chemotherapeutics and diagnostics. Colloids Surf B Biointerfaces 2011; 84:82-7.
[24]de Smet M, Langereis S, van den Bosch S.Grull H. Temperature-sensitive liposomes for doxorubicin delivery under mri guidance. J Control Release 2010; 143:120-7.
[25]Shubayev V 1, Pisanic T R.Jin S H. Magnetic nanoparticles for theragnostics. Adv Drug Deliv Rev 2009; 61:467-77.
[26]McCarthy J R.Weissleder R. Multifunctional magnetic nanoparticles for targeted imaging and therapy. Adv Drug Deliv Rev 2008; 60:1241-51.
[27]Yoo D, Lee J H, Shin T H.Cheon J. Theranostic magnetic nanoparticles. Acc Chem Res 2011; 44: 863-74.
[28]Arruebo M, Femandez-Pacheco R, Ibarra M R.Santamaria J. Magnetic nanoparticles for drug delivery. Nano Today 2007; 2:22-32.
[29]Bentzen S M. Theragnostic imaging for radiation oncology:Dose-painting by numbers. Lancet Oncol 2005; 6:112-7.
[30]Bentzen S M. Dose painting and theragnostic imaging:Towards the prescription, planning and delivery of biologically targeted dose distributions in external beam radiation oncology. Cancer Treat Res 2008; 139:41-62.
[31]Manus L M, Mastarone D J, Waters E A, Zhang X Q, Schultz-Sikma E A, MacRenaris K W, et al. Gd(ⅲ)-nanodiamond conjugates for mri contrast enhancement. Nano Letters 2010; 10:484-9.
[32]Cabella C, Crich S G, Corpillo D, Barge A, Ghirelli C, Bruno E, et al. Cellular labeling with gd(ⅲ) chelates:Only high thermodynamic stabilities prevent the cells acting as 'sponges' of gd3+ions. Contrast Media Mol Imaging 2006; 1:23-9.
[33]Morcos S K. Extracellular gadolinium contrast agents:Differences in stability. Eur J Radiol 2008; 66:175-9.
[34]Caravan P. Strategies for increasing the sensitivity of gadolinium based mri contrast agents. Chem Soc Rev 2006; 35:512-23.
[35]Bernini A, Venditti V, Spiga O, Ciutti A, Prischi F, Consonni R, et al. Nmr studies on the surface accessibility of the archaeal protein sso7d by using tempol and gd(iii)(dtpa-bma) as paramagnetic probes. Biophys Chem 2008; 137:71-5.
[36]Chen Z J, Yu D X, Wang S J, Zhang N, Ma C H.Lu Z J. Biocompatible nanocomplexes for molecular targeted mri contrast agent. Nanoscale Res Lett 2009; 4:618-26.
[37]Hu K W, Hsu K C.Yeh C S. Ph-dependent biodegradable silica nanotubes derived from gd(oh)(3) nanorods and their potential for oral drug delivery and mr imaging. Biomaterials 2010; 31: 6843-8.
[38]Chapman P. Nanotechnology in the pharmaceutical industry. Expert Opin Ther Pat 2005; 15: 249-51.
[39]Medina C, Santos-Martinez M J, Radomski A, Corrigan O I.Radomski M W. Nanoparticles: Pharmacological and toxicological significance. Brit J Pharmacol 2007; 150:552-8.
[40]Rinaudo M. Main properties and current applications of some polysaccharides as biomaterials. Polym Int 2008; 57:397-430.
[41]Yan G P, Xu W, Yang L A, Li L A, Liu F.Guo Q Z. Dextran gadolinium complexes as contrast agents for magnetic resonance imaging to sentinel lymph nodes. Pharmaceut Res 2010; 27: 1884-92.
[42]Kim I Y, Seo S J, Moon H S, Yoo M K, Park I Y, Kim B C, et al. Chitosan and its derivatives for tissue engineering applications. Biotechnol Adv 2008; 26:1-21.
[43]Ge Y, Zhang Y, He S, Nie F, Teng G.Gu N. Fluorescence modified chitosan-coated magnetic nanoparticles for high-efficient cellular imaging. Nanoscale Res Lett 2009; 4:287-95.
[44]Darras V, Nelea M, Winnik F M.Buschmann M D. Chitosan modified with gadolinium diethylenetriaminepentaacetic acid for magnetic resonance imaging of DNA/chitosan nanoparticles. Carbohyd Polym 2010; 80:1137-46.
[45]Poger D, Van Gunsteren W F.Mark A E. A new force field for simulating phosphatidylcholine bilayers. J Comput Chem 2010; 31:1117-25.
[46]Huang S L. Liposomes in ultrasonic drug and gene delivery. Adv Drug Deliv Rev 2008; 60: 1167-76.
[47]Spanoghe M, Lanens D, Dommisse R, Van der Linden A.Alderweireldt F. Proton relaxation enhancement by means of serum albumin and poly-1-lysine labeled with dtpa-gd3+:Relaxivities as a function of molecular weight and conjugation efficiency. Magn Reson Imaging 1992; 10: 913-7.
[48]Shiraishi K, Kawano K, Minowa T, Maitani Y.Yokoyama M. Preparation and in vivo imaging of peg-poly(l-lysine)-based polymeric micelle mri contrast agents. J Control Release 2009; 136: 14-20.
[49]Liu Y, Chen Z, Liu C, Yu D, Lu Z.Zhang N. Gadolinium-loaded polymeric nanoparticles modified with anti-vegf as multifunctional mri contrast agents for the diagnosis of liver cancer. Biomaterials 2011; 32:5167-76.
[50]Wijagkanalan W, Kawakami S.Hashida M. Designing dendrimers for drug delivery and imaging: Pharmacokinetic considerations. Pharmaceut Res 2011; 28:1500-19.
[51]Nwe K, Bryant L H, Jr..Brechbiel M W. Poly(amidoamine) dendrimer based mri contrast agents exhibiting enhanced relaxivities derived via metal preligation techniques. Bioconjug Chem 2010; 21:1014-7.
[52]Svenson S. Dendrimers as versatile platform in drug delivery applications. Eur J Pharm Biopharm 2009; 71:445-62.
[53]Dreis S, Rothweiler F, Michaelis M, Cinatl J, Jr., Kreuter J.Langer K. Preparation, characterisation and maintenance of drug efficacy of doxorubicin-loaded human serum albumin (hsa) nanoparticles. Int J Pharm 2007; 341:207-14.
[54]Schmiedl U, Ogan M, Paajanen H, Marotti M, Crooks L E, Brito A C, et al. Albumin labeled with gd-dtpa as an intravascular, blood pool-enhancing agent for mr imaging:Biodistribution and imaging studies. Radiology 1987; 162:205-10.
[55]Schmiedl U, Moseley M E, Ogan M D, Chew W M.Brasch R C. Comparison of initial biodistribution patterns of gd-dtpa and albumin-(gd-dtpa) using rapid spin echo mr imaging. J Comput Assist Tomogr 1987; 11:306-13.
[56]Aime S, Botta M.Terreno E. Gd(iii)-based contrast agents for mri. Adv Inorg Chem 2005; 57: 173-237.
[57]Nakamura E, Makino K, Okano T, Yamamoto T.Yokoyama M. A polymeric micelle mri contrast agent with changeable relaxivity. J Control Release 2006; 114:325-33.
[58]Ratzinger G, Agrawal P, Korner W, Lonkai J, Sanders H M, Terreno E, et al. Surface modification of plga nanospheres with gd-dtpa and gd-dota for high-relaxivity mri contrast agents. Biomaterials 2010; 31:8716-23.
[59]Chen Z, Yu D, Liu C, Yang X, Zhang N, Ma C, et al. Gadolinium-conjugated pla-peg nanoparticles as liver targeted molecular mri contrast agent. J Drug Target 2011; 19:657-65.
[60]Jeong S Y, Kim H J, Kwak B-K, Lee H-Y.Cho S H. Biocompatible polyhydroxyethylaspartamide-based micelles with gadolinium for mri contrast agents. Nanoscale Res Lett 2010; 5:1970-6.
[61]Hak S, Sanders H M, Agrawal P, Langereis S, Grull H, Keizer H M, et al. A high relaxivity gd(iii)dota-dspe-based liposomal contrast agent for magnetic resonance imaging. Eur J Pharm Biopharm 2009; 72:397-404.
[62]Nwe K, Bernardo M, Regino C A S, Williams M.Brechbiel M W. Comparison of mri properties between derivatized dtpa and dota gadolinium-dendrimer conjugates. Bioorgan Med Chem 2010; 18:5925-31.
[63]Zhang M Q, Veiseh O.Gunn J W. Design and fabrication of magnetic nanoparticles for targeted drug delivery and imaging. Adv Drug Deliv Rev 2010; 62:284-304.
[64]Veiseh O, Gunn J W.Zhang M Q. Design and fabrication of magnetic nanoparticles for targeted drug delivery and imaging. Adv Drug Deliv Rev 2010; 62:284-304.
[65]Fang J, Nakamura H.Maeda H. The epr effect:Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv Drug Deliv Rev 2011; 136-51.
[66]Li S D.Huang L. Pharmacokinetics and biodistribution of nanoparticles. Mol Pharm 2008; 5: 496-504.
[67]Liu D, Mori A.Huang L. Role of liposome size and res blockade in controlling biodistribution and tumor uptake of gml-containing liposomes. Biochim Biophys Acta 1992; 1104:95-101.
[68]Delgado C, Francis G E.Fisher D. The uses and properties of peg-linked proteins. Crit Rev Ther Drug Carrier Syst 1992; 9:249-304.
[69]Mok H, Palmer D J, Ng P.Barry M A. Evaluation of polyethylene glycol modification of first-generation and helper-dependent adenoviral vectors to reduce innate immune responses. Mol Ther 2005; 11:66-79.
[70]Blume G.Cevc G. Molecular mechanism of the lipid vesicle longevity in vivo. Biochim Biophys Acta 1993; 1146:157-68.
[71]Kumar R, Ohulchanskyy T Y, Turowski S G, Thompson M E, Seshadri M.Prasad P N. Combined magnetic resonance and optical imaging of head and neck tumor xenografts using gadolinium-labelled phosphorescent polymeric nanomicelles. Head Neck Oncol 2010; 2:35.
[72]Caruso F, Johnston A P R, Such G K.Ng S L. Challenges facing colloidal delivery systems:From synthesis to the clinic. Curr Opin Colloid In 2011; 16:171-81.
[73]Kozlowska D, Foran P, MacMahon P, Shelly M J, Eustace S.O'Kennedy R. Molecular and magnetic resonance imaging:The value of immunoliposomes. Adv Drug Deliv Rev 2009; 61: 1402-11.
[74]Saito Y, Oba N, Nishinakagawa S, Mizuguchi Y, Kojima T, Nomura K, et al. Identification of beta 2-microgloblin as a candidate for early diagnosis of imaging-invisible hepatocellular carcinoma in patient with liver cirrhosis. Oncol Rep 2010; 23:1325-30.
[75]Ke J H, Lin J J, Carey J R, Chen J S, Chen C Y.Wang L F. A specific tumor-targeting magnetofluorescent nanoprobe for dual-modality molecular imaging. Biomaterials 2010; 31: 1707-15.
[76]Wang K, Pruthodam S, Lee J Y, Na M H, Park H, Oh S J, et al. In vivo imaging of tumor apoptosis using histone hl-targeting peptide. J Control Release 2010;
[77]Zhang D, Feng X Y, Henning T D, Wen L, Lu W Y, Pan H, et al. Mr imaging of tumor angiogenesis using sterically stabilized gd-dtpa liposomes targeted to cd105. Eur J Radiol 2009; 70:180-9.
[78]Esposito G, Geninatti Crich S.Aime S. Efficient cellular labeling by cd44 receptor-mediated uptake of cationic liposomes functionalized with hyaluronic acid and loaded with mri contrast agents. ChemMedChem 2008; 3:1858-62.
[79]Leamon C P.Reddy J A. Folate-targeted chemotherapy. Adv Drug Deliv Rev 2004; 56:1127-41.
[80]Chen W T, Thirumalai D, Shih T T, Chen R C, Tu S Y, Lin C I, et al. Dynamic contrast-enhanced folate-receptor-targeted mr imaging using a gd-loaded peg-dendrimer-folate conjugate in a mouse xenograft tumor model. Mol Imaging Biol 2010; 12:145-54.
[81]Hu Z, Luo F, Pan Y, Hou C, Ren L, Chen J, et al. Arg-gly-asp (rgd) peptide conjugated poly(lactic acid)-poly(ethylene oxide) micelle for targeted drug delivery. J Biomed Mater Res A 2008; 85:797-807.
[82]Corti A, Curnis F, Arap W.Pasqualini R. The neovasculature homing motif ngr:More than meets the eye. Blood 2008; 112:2628-35.
[83]Li W, Su B, Meng S, Ju L, Yan L, Ding Y, et al. Rgd-targeted paramagnetic liposomes for early detection of tumor:In vitro and in vivo studies. Eur J Radiol 2011; 80:598-606.
[84]Couvreur P, Bildstein L.Dubernet C. Prodrug-based intracellular delivery of anticancer agents. Adv Drug Deliv Rev 2011; 63:3-23.
[85]Fay F.Scott C J. Antibody-targeted nanoparticles for cancer therapy. Immunotherapy 2011; 3: 381-94.
[86]Amiji M, Milane L.Duan Z F. Pharmacokinetics and biodistribution of lonidamine/paclitaxel loaded, egfr-targeted nanoparticles in an orthotopic animal model of multi-drug resistant breast cancer. Nanomedicine:NBM 2011; 7:435-44.
[87]Hun X.Zhang Z J. Anti-epidermal growth factor receptor (anti-egfr) antibody conjugated fluorescent nanoparticles probe for breast cancer imaging. Spectrochim Acta A 2009; 74:410-4.
[88]Yang L L, Mao H, Wang Y A, Cao Z H, Peng X H, Wang X X, et al. Single chain epidermal growth factor receptor antibody conjugated nanoparticles for in vivo tumor targeting and imaging. Small 2009; 5:235-43.
[89]Kreuter J, Ulbrich K, Hekmatara T.Herbert E. Transferrin- and transferrin-receptor-antibody-modified nanoparticles enable drug delivery across the blood-brain barrier (bbb). Eur J Pharm Biopharm 2009; 71:251-6.
[90]Ossipov D A. Nanostructured hyaluronic acid-based materials for active delivery to cancer. Expert Opin Drug Deliv 2010; 7:681-703.
[91]Buffa R, Betak J, Kettou S, Hermannova M, Pospisilova L.Velebny V. A novel dtpa cross-linking of hyaluronic acid and metal complexation thereof. Carbohydr Res 2011; 346: 1909-15.
[92]Kohane D S. Microparticles and nanoparticles for drug delivery. Biotechnol Bioeng 2007; 96: 203-9.
[93]Bhalgat C M, Mudshinge S R, Deore A B.Patil S. Nanoparticles:Emerging carriers for drug delivery. Saudi Pharm J 2011; 19:129-41.
[94]Greene M E. Nanoparticles deliver the goods. Nano Today 2006; 1:16-.
[95]Gregoriadis G. The carrier potential of liposomes in biology and medicine (first of two parts). N Engl J Med 1976; 295:704-10.
[96]Torchilin V P. Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov 2005; 4:145-60.
[97]Mody V V, Nounou M I.Bikram M. Novel nanomedicine-based mri contrast agents for gynecological malignancies. Adv Drug Deliv Rev 2009; 61:795-807.
[98]Unger E C, Winokur T, MacDougall P, Rosenblum J, Clair M, Gatenby R, et al. Hepatic metastases:Liposomal gd-dtpa-enhanced mr imaging. Radiology 1989; 171:81-5.
[99]Fritz T, Unger E, Wilson-Sanders S, Ahkong Q F.Tilcock C. Detailed toxicity studies of liposomal gadolinium-dtpa. Invest Radiol 1991; 26:960-8.
[100]Tilcock C, Unger E, Cullis P.MacDougall P. Liposomal gd-dtpa:Preparation and characterization of relaxivity. Radiology 1989; 171:77-80.
[101]Sibson N R, Blamire A M, Bernades-Silva M, Laurent S, Boutry S, Muller R N, et al. Mri detection of early endothelial activation in brain inflammation. Magn Reson Med 2004; 51: 248-52.
[102]Fossheim S L, Il'yasov K A, Hennig J.Bjornerud A. Thermosensitive paramagnetic liposomes for temperature control during mr imaging-guided hyperthermia:In vitro feasibility studies. Acad Radiol 2000; 7:1107-15.
[103]McDannold N, Fossheim S L, Rasmussen H, Martin H, Vykhodtseva N.Hynynen K. Heat-activated liposomal mr contrast agent:Initial in vivo results in rabbit liver and kidney. Radiology 2004; 230:743-52.
[104]Delli Castelli D, Dastru W, Terreno E, Cittadino E, Mainini F, Torres E, et al. In vivo mri multicontrast kinetic analysis of the uptake and intracellular trafficking of paramagnetically labeled liposomes. J Control Release 2010; 144:271-9.
[105]Andre J P, Toth E, Fischer H, Seelig A, Macke H R.Merbach A E. High relaxivity for monomeric gd(dota)-based mri contrast agents, thanks to micellar self-organization. Chem-Eur J 1999; 5: 2977-83.
[106]Terreno E, Sanino A, Carrera C, Castelli D D, Glovenzana G B, Lombardi A, et al. Determination of water permeability of paramagnetic liposomes of interest in mri field. J Inorg Biochem 2008; 102:1112-9.
[107]Koenig S H, Ahkong Q F, Brown R D,3rd, Lafleur M, Spiller M, Unger E, et al. Permeability of liposomal membranes to water:Results from the magnetic field dependence of t1 of solvent protons in suspensions of vesicles with entrapped paramagnetic ions. Magn Reson Med 1992; 23: 275-86.
[108]Ghaghada K, Hawley C, Kawaji K, Annapragada A.Mukundan S, Jr. T1 relaxivity of core-encapsulated gadolinium liposomal contrast agents--effect of liposome size and internal gadolinium concentration. Acad Radiol 2008; 15:1259-63.
[109]Kamaly N.Miller A D. Paramagnetic liposome nanoparticles for cellular and tumour imaging. Int JMol Sci 2010;11:1759-76.
[110]Kamaly N, Kalber T, Ahmad A, Oliver M H, So P W, Herlihy A H, et al. Bimodal paramagnetic and fluorescent liposomes for cellular and tumor magnetic resonance imaging. Bioconjug Chem 2008; 19:118-29.
[111]Weissig V V, Babich J.Torchilin V V. Long-circulating gadolinium-loaded liposomes:Potential use for magnetic resonance imaging of the blood pool. Colloids Surf B Biointerfaces 2000; 18: 293-9.
[112]Kielar F, Tei L, Terreno E.Botta M. Large relaxivity enhancement of paramagnetic lipid nanoparticles by restricting the local motions of the gd(iii) chelates. J Am Chem Soc 2010; 132: 7836-7.
[113]Tournier H, Hyacinthe R.Schneider M. Gadolinium-containing mixed micelle formulations:A new class of blood pool mri/mra contrast agents. Acad Radiol 2002; 9:20-8.
[114]Lattuada L.Lux G. Synthesis of gd-dtpa-cholesterol:A new lipophilic gadolinium complex as a potential mri contrast agent. Tetrahedron Lett 2003; 44:3893-5.
[115]Parac-Vogt T N, Kimpe K, Laurent S, Pierart C, Elst L V, Muller R N, et al. Paramagnetic liposomes containing amphiphilic bisamide derivatives of gd-dtpa with aromatic side chain groups as possible contrast agents for magnetic resonance imaging. Eur Biophys J 2006; 35: 136-44.
[116]Kimpe K, Parac-Vogt T N, Laurent S, Pierart C, Vander Elst L, Muller R N, et al. Potential mri contrast agents based on micellar incorporation of amphiphilic bis(alkylamide) derivatives of [(gd-dtpa)(h2o)](2-). Eur J Inorg Chem 2003; 3021-7.
[117]Anelli P L, Lattuada L, Gabellini M.Recanati P. Dota tris(phenylmethyl) ester:A new useful synthon for the synthesis of dota monoamides containing acid-labile bonds. Bioconjug Chem 2001; 12:1081-4.
[118]Laurent S, Vander Elst L, Thirifays C.Muller R N. Relaxivities of paramagnetic liposomes:On the importance of the chain type and the length of the amphiphilic complex. Eur Biophys J 2008; 37:1007-14.
[119]Georgiev G A, Sarker D K, Al-Hanbali O, Georgiev G D.Lalchev Z. Effects of poly (ethylene glycol) chains conformational transition on the properties of mixed dmpc/dmpe-peg thin liquid films and monolayers. Colloids Surf B Biointerfaces 2007; 59:184-93.
[120]Erdogan S, Medarova Z O, Roby A, Moore A.Torchilin V P. Enhanced tumor mr imaging with gadolinium-loaded polychelating polymer-containing tumor-targeted liposomes. J Magn Reson Imaging 2008; 27:574-80.
[121]Maruyama K. Intracellular targeting delivery of liposomal drugs to solid tumors based on epr effects. Adv Drug Deliv Rev 2010;
[122]Kullberg M, Owens J L.Mann K. Listeriolysin o enhances cytoplasmic delivery by her-2 targeting liposomes. J Drug Target 2010; 18:313-20.
[123]Zhang D, Feng X Y, Henning T D, Wen L, Lu W Y, Pan H, et al. Mr imaging of tumor angiogenesis using sterically stabilized gd-dtpa liposomes targeted to cd105. Eur J Radiol 2009; 70:180-9.
[124]Pan X, Wu G, Yang W, Barth R F, Tjarks W.Lee R J. Synthesis of cetuximab-immunoliposomes via a cholesterol-based membrane anchor for targeting of egfr. Bioconjug Chem 2007; 18: 101-8.
[125]Kamaly N, Kalber T, Thanou M, Bell J D.Miller A D. Folate receptor targeted bimodal liposomes for tumor magnetic resonance imaging. Bioconjug Chem 2009; 20:648-55.
[126]Lu Y.Ballauff M. "Smart" Nanoparticles:Preparation, characterization and applications. Polymer 2007; 48:1815-23.
[127]Terreno E, Figueiredo S, Moreira J N, Geraldes C F G C.Aime S. Supramolecular protamine/gd-loaded liposomes adducts as relaxometric protease responsive probes. Bioorg Med Chem 2011; 19:1131-5.
[128]Figueiredo S, Moreira J N, Geraldes C F, Aime S.Terreno E. Supramolecular protamine/gd-loaded liposomes adducts as relaxometric protease responsive probes. Bioorg Med Chem 2010;
[129]Terreno E, Boffa C, Menchise V, Fedeli F, Carrera C, Castelli D D, et al. Gadolinium-doped lipocest agents:A potential novel class of dual (1)h-mri probes. Chem Commun (Camb) 2011; 47:4667-9.
[130]Lokling K E, Fossheim S L, Skurtveit R, Bjornerud A.Klaveness J. Ph-sensitive paramagnetic liposomes as mri contrast agents:In vitro feasibility studies. Magn Reson Imaging 2001; 19: 731-8.
[131]Torres E, Mainini F, Napolitano R, Fedeli F, Cavalli R, Aime S, et al. Improved paramagnetic liposomes for mri visualization of ph triggered release. J Control Release 2011; 154:196-202.
[132]Gerasimov O V, Boomer J A, Qualls M M.Thompson D H. Cytosolic drug delivery using ph-and light-sensitive liposomes. Adv Drug Deliv Rev 1999; 38:317-38.
[133]Moghimi S M. Recent developments in polymeric nanoparticle engineering and their applications in experimental and clinical oncology. Anticancer Agents Med Chem 2006; 6: 553-61.
[134]Wischke C.Schwendeman S P. Principles of encapsulating hydrophobic drugs in pla/plga microparticles. Int J Pharm 2008; 364:298-327.
[135]Mainardes R M, Gremiao M P, Brunetti I L, da Fonseca L M.Khalil N M. Zidovudine-loaded pla and pla-peg blend nanoparticles:Influence of polymer type on phagocytic uptake by polymorphonuclear cells. J Pharm Sci 2009; 98:257-67.
[136]Shikata F, Tokumitsu H, Ichikawa H.Fukumori Y. In vitro cellular accumulation of gadolinium incorporated into chitosan nanoparticles designed for neutron-capture therapy of cancer. Eur J Pharm Biopharm 2002; 53:57-63.
[137]Fujimoto T, Ichikawa H, Akisue T, Fujita I, Kishimoto K, Hara H, et al. Accumulation of mri contrast agents in malignant fibrous histiocytoma for gadolinium neutron capture therapy. Appl Radiat Isot 2009; 67:S355-8.
[138]Kundu A, Peterlik H, Krssak M, Bytzek A K, Pashkunova-Martic I, Arion V B, et al. Strategies for the covalent conjugation of a bifunctional chelating agent to albumin:Synthesis and characterization of potential mri contrast agents. J Inorg Biochem 2011; 105:250-5.
[139]Tseng H R, Chen K J, Wolahan S M, Wang H, Hsu C H, Chang H W, et al. A small mri contrast agent library of gadolinium(iii)-encapsulated supramolecular nanoparticles for improved relaxivity and sensitivity. Biomaterials 2011; 32:2160-5.
[140]Lu Z R, Tan M Q, Wu X M, Jeong E K.Chen Q J. Peptide-targeted nanoglobular gd-dota monoamide conjugates for magnetic resonance cancer molecular imaging. Biomacromolecules 2010; 11:754-61.
[141]Liu J, Lee H.Allen C. Formulation of drugs in block copolymer micelles:Drug loading and release. Curr Pharm Des 2006; 12:4685-701.
[142]Kabalka G W, Davis M A, Holmberg E, Maruyama K.Huang L. Gadolinium-labeled liposomes containing amphiphilic gd-dtpa derivatives of varying chain length:Targeted mri contrast enhancement agents for the liver. Magn Reson Imaging 1991; 9:373-7.
[143]Schwendener R A, Wuthrich R, Duewell S, Wehrli E.von Schulthess G K. A pharmacokinetic and mri study of unilamellar gadolinium-, manganese-, and iron-dtpa-stearate liposomes as organ-specific contrast agents. Invest Radiol 1990; 25:922-32.
[144]Grogna M, Cloots R, Luxen A e, Jerome C.Detrembleur C. Polymer micelles decorated by gadolinium complexes as mri blood contrast agents:Design, synthesis and properties. Polym Chem 2010; 1:1485-90.
[145]Miyata K, Christie R J.Kataoka K. Polymeric micelles for nano-scale drug delivery. React Funct Polym 2011; 71:227-34.
[146]Shiraishi K, Kawano K, Maitani Y.Yokoyama M. Polyion complex micelle mri contrast agents from poly(ethylene glycol)-b-poly(l-lysine) block copolymers having gd-dota; preparations and their control of t(1)-relaxivities and blood circulation characteristics. J Control Release 2010; 148:160-7.
[147]Buhleier E, Wehner W.Vogtle F. "Cascade"- and "Nonskid-chain-like" Syntheses of molecular cavity topologies. Synthesis 1978; 2:155-8.
[148]Alper J. Rising chemical "Stars" Could play many roles. Science 1991; 251:1562-4.
[149]Rupp R, Rosenthal S L.Stanberry L R. Vivagel (tm) (spl7013 gel):A candidate dendrimer microbicide for the prevention of hiv and hsv infection. Int J Nanomed 2007; 2:561-6.
[150]Oliveira J M, Salgado A J, Sousa N, Mano J F.Reis R L. Dendrimers and derivatives as a potential therapeutic tool in regenerative medicine strategies-a review. Prog Polym Sci 2010; 35: 1163-94.
[151]Nanjwade B K, Bechra H M, Derkar G K, Manvi F V.Nanjwade V K. Dendrimers:Emerging polymers for drug-delivery systems. Eur J Pharm Sci 2009; 38:185-96.
[152]Caminade A M, Laurent R.Majoral J P. Characterization of dendrimers. Adv Drug Deliv Rev 2005; 57:2130-46.
[153]Wiener E C, Brechbiel M W, Brothers H, Magin R L, Gansow O A, Tomalia D A, et al. Dendrimer-based metal chelates:A new class of magnetic resonance imaging contrast agents. Magn Reson Med 1994; 31:1-8.
[154]Toth E E, Helm L, Merbach A E, Hedinger R, Hegetschweiler K.Janossy A. Structure and dynamics of a trinuclear gadolinium(iii) complex:The effect of intramolecular electron spin relaxation on its proton relaxivity(1). Inorg Chem 1998; 37:4104-13.
[155]Brechbiel M W, Nwe K, Xu H, Regino C A S, Bernardo M, Ileva L, et al. A new approach in the preparation of dendrimer-based bifunctional diethylenetriaminepentaacetic acid mr contrast agent derivatives. Bioconjugate Chem 2009; 20:1412-8.
[156]Swanson S D, Kukowska-Latallo J F, Patri A K, Chen C Y, Ge S, Cao Z Y, et al. Targeted gadolinium-loaded dendrimer nanoparticles for tumor-specific magnetic resonance contrast enhancement. International Journal of Nanomedicine 2008; 3:201-10.
[157]Zhu W, Okollie B, Bhujwalla Z M.Artemov D. Pamam dendrimer-based contrast agents for mr imaging of her-2/neu receptors by a three-step pretargeting approach. Magn Reson Med 2008; 59:679-85.
[158]Nwe K, Milenic D E, Ray G L, Kim Y S.Brechbiel M W. Preparation of cystamine core dendrimer and antibody-dendrimer conjugates for mri angiography. Mol Pharm 2012;
[159]Langereis S, de Lussanet Q G, van Genderen M H, Meijer E W, Beets-Tan R G, Griffioen A W, et al. Evaluation of gd(iii)dtpa-terminated poly(propylene imine) dendrimers as contrast agents for mr imaging. NMR Biomed 2006; 19:133-41.
[160]Huang R, Han L, Li J, Liu S, Shao K, Kuang Y, et al. Chlorotoxin-modified macromolecular contrast agent for mri tumor diagnosis. Biomaterials 2011; 32:5177-86.
[161]Gu Z W, Luo K, Liu G, He B, Wu Y, Gong Q Y, et al. Multifunctional gadolinium-based dendritic macromolecules as liver targeting imaging probes. Biomaterials 2011; 32:2575-85.
[162]Luo K, Liu G, She W, Wang Q, Wang G, He B, et al. Gadolinium-labeled peptide dendrimers with controlled structures as potential magnetic resonance imaging contrast agents. Biomaterials 2011; 32:7951-60.
[163]Slowing, Ⅱ, Vivero-Escoto J L, Wu C W.Lin V S. Mesoporous silica nanoparticles as controlled release drug delivery and gene transfection carriers. Adv Drug Deliv Rev 2008; 60:1278-88.
[164]Li S Z, Ma Y, Yue X L, Cao Z.Dai Z F. One-pot construction of doxorubicin conjugated magnetic silica nanoparticles. New J Chem 2009; 33:2414-8.
[165]Lin Y S, Hung Y, Su J K, Lee R, Chang C, Lin M L, et al. Gadolinium(iii)-incorporated nanosized mesoporous silica as potential magnetic resonance imaging contrast agents. J Phys Chem B 2004; 108:15608-11.
[166]Taylor K M L, Kim J S, Rieter W J, An H, Lin W L.Lin W B. Mesoporous silica nanospheres as highly efficient mri contrast agents. J Am Chem Soc 2008; 130:2154-5.
[2]H. Lin, J. van den Esschert, C. Liu, et al. Systematic review of hepatocellular adenoma in China and other regions. J Gastroenterol Hepatol,2011,26:28-35.
[3]S. Whittaker, R. Marais, A.X. Zhu The role of signaling pathways in the development and treatment of hepatocellular carcinoma. Oncogene,2010,29: 4989-5005.
[4]P. Stefaniuk, J. Cianciara, A. Wiercinska-Drapalo Present and future possibilities for early diagnosis of hepatocellular carcinoma. World J Gastroenterol,2010,16: 418-424.
[5]J.U. Marquardt, P.R. Galle, A. Teufel Molecular diagnosis and therapy of hepatocellular carcinoma (HCC):an emerging field for advanced technologies. J Hepatol,2012,56:267-275.
[6]Y. Liu, Z. Chen, C. Liu, et al. Gadolinium-loaded polymeric nanoparticles modified with Anti-VEGF as multifunctional MRI contrast agents for the diagnosis of liver cancer. Biomaterials,2011,32:5167-5176.
[7]R.R. Sawant, A.M. Jhaveri, V.P. Torchilin Immunomicelles for advancing personalized therapy. Adv Drug Deliv Rev,2012,64:1436-1446.
[8]S.S. Kelkar, T.M. Reineke Theranostics:combining imaging and therapy. Bioconjug Chem,2011,22:1879-1903.
[9]C.A. Hudis Trastuzumab--mechanism of action and use in clinical practice. N Engl J Med,2007,357:39-51.
[10]V. Ozdemir, B. Williams-Jones, S.J. Glatt, et al. Shifting emphasis from pharmacogenomics to theragnostics. Nat Biotechnol,2006,24:942-946.
[11]S. Mura, P. Couvreur Nanotheranostics for personalized medicine. Adv Drug Deliv Rev,2012,64:1394-1416.
[12]Y. Liu, N. Zhang Gadolinium loaded nanoparticles in theranostic magnetic resonance imaging. Biomaterials,2012,33:5363-5375.
[13]T. Liu, X. Li, Y. Qian, et al. Multifunctional pH-disintegrable micellar nanoparticles of asymmetrically functionalized beta-cyclodextrin-based star copolymer covalently conjugated with doxorubicin and DOTA-Gd moieties. Biomaterials,2012,33:2521-2531.
[14]M.S. Muthu, S.A. Kulkarni, A. Raju, et al. Theranostic liposomes of TPGS coating for targeted co-delivery of docetaxel and quantum dots. Biomaterials, 2012,33:3494-3501.
[15]L. Zhu, D. Wang, X. Wei, et al. Multifunctional pH-sensitive superparamagnetic iron-oxide nanocomposites for targeted drug delivery and MR imaging. J Control Release,2013,169:228-238.
[16]J.R. McCarthy The future of theranostic nanoagents. Nanomedicine (Lond), 2009,4:693-695.
[17]W.T. Al-Jamal, K. Kostarelos Liposomes:from a clinically established drug delivery system to a nanoparticle platform for theranostic nanomedicine. Ace Chem Res,2011,44:1094-1104.
[18]K.H. Bae, J.Y. Lee, S.H. Lee, et al. Optically traceable solid lipid nanoparticles loaded with siRNA and paclitaxel for synergistic chemotherapy with in situ imaging. Adv Healthc Mater,2013,2:576-584.
[19]S. Srinivasan, R. Manchanda, A. Fernandez-Fernandez, et al. Near-infrared fluorescing IR820-chitosan conjugate for multifunctional cancer theranostic applications. J Photochem Photobiol B,2013,119:52-59.
[20]Y. Xiao, H. Hong, A. Javadi, et al. Multifunctional unimolecular micelles for cancer-targeted drug delivery and positron emission tomography imaging. Biomaterials,2012,33:3071-3082.
[21]S.T. Lo, A. Kumar, J.T. Hsieh, et al. Dendrimer nanoscaffolds for potential theranostics of prostate cancer with a focus on radiochemistry. Mol Pharm,2013, 10:793-812.
[22]A. Tan, L. Yildirimer, J. Rajadas, et al. Quantum dots and carbon nanotubes in oncology:a review on emerging theranostic applications in nanomedicine. Nanomedicine (Lond),2011,6:1101-1114.
[23]D.N. Heo, D.H. Yang, H.J. Moon, et al. Gold nanoparticles surface-functionalized with paclitaxel drug and biotin receptor as theranostic agents for cancer therapy. Biomaterials,2012,33:856-866.
[24]S.P. Singh Multifunctional magnetic quantum dots for cancer theranostics. J Biomed Nanotechnol,2011,7:95-97.
[25]J. Huang, X. Zhong, L. Wang, et al. Improving the magnetic resonance imaging contrast and detection methods with engineered magnetic nanoparticles. Theranostics,2012,2:86-102.
[26]J.L. Vivero-Escoto, R.C. Huxford-Phillips, W. Lin Silica-based nanoprobes for biomedical imaging and theranostic applications. Chem Soc Rev,2012,41: 2673-2685.
[27]E. Engel, A. Michiardi, M. Navarro, et al. Nanotechnology in regenerative medicine:the materials side. Trends Biotechnol,2008,26:39-47.
[28]M.A. Stuart, W.T. Huck, J. Genzer, et al. Emerging applications of stimuli-responsive polymer materials. Nat Mater,2010,9:101-113.
[29]X. Yang, J.J. Grailer, S. Pilla, et al. Multifunctional polymeric vesicles for targeted drug delivery and imaging. Biofabrication,2010,2:025004.
[30]K. Madhavan Nampoothiri, N.R. Nair, R.P. John An overview of the recent developments in polylactide (PLA) research. Bioresour Technol,2010,101: 8493-8501.
[31]V. Torchilin Tumor delivery of macromolecular drugs based on the EPR effect. Adv Drug Deliv Rev,2011,63:131-135.
[32]M.L. Patil, M. Zhang, T. Minko Multifunctional triblock Nanocarrier (PAMAM-PEG-PLL) for the efficient intracellular siRNA delivery and gene silencing. ACS Nano,2011,5:1877-1887.
[33]H. Tian, Z. Tang, X. Zhuang, et al. Biodegradable synthetic polymers: Preparation, functionalization and biomedical application. Progress in Polymer Science,2012,37:237-280.
[34]J.W. Kramer, D.S. Treitler, E.W. Dunn, et al. Polymerization of enantiopure monomers using syndiospecific catalysts:a new approach to sequence control in polymer synthesis. J Am Chem Soc,2009,131:16042-16044.
[35]P. Gunatillake, R. Mayadunne, R. Adhikari Recent developments in biodegradable synthetic polymers. Biotechnol Annu Rev,2006,12:301-347.
[36]W. Krause,艇.T贸th, L. Helm, et al. Relaxivity of MRI Contrast Agents. Contrast Agents I:Springer Berlin Heidelberg,2002. p.61-101.
[37]许乙凯磁共振对比剂的发展概况及存在问题.第一军医大学学报,2002,22：769-771.
[38]J. Bruix, M. Sherman Management of hepatocellular carcinoma:an update. Hepatology,2011,53:1020-1022.
[39]V.J. Poirier, A.E. Hershey, K.E. Burgess, et al. Efficacy and toxicity of paclitaxel (Taxol) for the treatment of canine malignant tumors. J Vet Intern Med,2004,18:219-222.
[40]M.R. Green, GM. Manikhas, S. Orlov, et al. Abraxane, a novel Cremophor-free, albumin-bound particle form of paclitaxel for the treatment of advanced non-small-cell lung cancer. Ann Oncol,2006,17:1263-1268.
[41]Y. Chao, W.K. Chan, M.J. Birkhofer, et al. Phase II and pharmacokinetic study of paclitaxel therapy for unresectable hepatocellular carcinoma patients. Br J Cancer,1998,78:34-39.
[42]A. Hauschild, S.S. Agarwala, U. Trefzer, et al. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol,2009,27:2823-2830.
[43]J.M. Llovet, S. Ricci, V. Mazzaferro, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med,2008,359:378-390.
[44]D.H. Palmer Sorafenib in advanced hepatocellular carcinoma. N Engl J Med, 2008,359:2498; author reply 2498-2499.
[45]D. Kozlowska, P. Foran, P. MacMahon, et al. Molecular and magnetic resonance imaging:The value of immunoliposomes. Adv Drug Deliv Rev,2009,61: 1402-1411.
[46]Y. Saito, N. Oba, S. Nishinakagawa, et al. Identification of beta2-microgloblin as a candidate for early diagnosis of imaging-invisible hepatocellular carcinoma in patient with liver cirrhosis. Oncol Rep,2010,23:1325-1330.
[47]Y. Lu, P.S. Low Folate-mediated delivery of macromolecular anticancer therapeutic agents. Adv Drug Deliv Rev,2002,54:675-693.
[48]N. Yonenaga, E. Kenjo, T. Asai, et al. RGD-based active targeting of novel polycation liposomes bearing siRNA for cancer treatment. J Control Release, 2012,160:177-181.
[49]R. Kontermann Dual targeting strategies with bispecific antibodies. MAbs,2012,
[50]H.Y. Yoon, H. Koo, K.Y. Choi, et al. Tumor-targeting hyaluronic acid nanoparticles for photodynamic imaging and therapy. Biomaterials,2012,33: 3980-3989.
[51]L. Wang, J. Huang, M. Jiang, et al. AFP computational secreted network construction and analysis between human hepatocellular carcinoma (HCC) and no-tumor hepatitis/cirrhotic liver tissues. Tumour Biol,2010,31:417-425.
[52]G. Beale, D. Chattopadhyay, J. Gray, et al. AFP, PIVKAⅡ, GP3, SCCA-1 and follisatin as surveillance biomarkers for hepatocellular cancer in non-alcoholic and alcoholic fatty liver disease. BMC Cancer,2008,8:200.
[53]M. Patel, M.I. Shariff, N.G. Ladep, et al. Hepatocellular carcinoma:diagnostics and screening. J Eval Clin Pract,2011,18:335-342.
[54]B. Sitohy, J.A. Nagy, H.F. Dvorak Anti-VEGF/VEGFR therapy for cancer: reassessing the target. Cancer Res,2012,72:1909-1914.
[55]L. Zhang, J.N. Wang, J.M. Tang, et al. VEGF is essential for the growth and migration of human hepatocellular carcinoma cells. Mol Biol Rep,2012,39: 5085-5093.
[56]Y. Xu, Z. Wen, Z. Xu Chitosan nanoparticles inhibit the growth of human hepatocellular carcinoma xenografts through an antiangiogenic mechanism. Anticancer Res,2009,29:5103-5109.
[57]D. Liu, F. Liu, Z. Liu, et al. Tumor specific delivery and therapy by double-targeted nanostructured lipid carriers with anti-VEGFR-2 antibody. Mol Pharm,2011,8:2291-2301.
[58]H. Huang, S. Delikanli, H. Zeng, et al. Remote control of ion channels and neurons through magnetic-field heating of nanoparticles. Nat Nanotechnol, 2010,5:602-606.
[59]M. Rahimi, A. Wadajkar, K. Subramanian, et al. In vitro evaluation of novel polymer-coated magnetic nanoparticles for controlled drug delivery. Nanomedicine,2010,6:672-680.
[60]B. Yan, J.C. Boyer, D. Habault, et al. Near infrared light triggered release of biomacromolecules from hydrogels loaded with upconversion nanoparticles. J Am Chem Soc,2012,134:16558-16561.
[61]D.E. Lee, H. Koo, I.C. Sun, et al. Multifunctional nanoparticles for multimodal imaging and theragnosis. Chem Soc Rev,2012,41:2656-2672.
[62]W.B. Liechty, N.A. Peppas Expert opinion:Responsive polymer nanoparticles in cancer therapy. Eur J Pharm Biopharm,2012,80:241-246.
[63]X. He, J. Li, S. An, et al. pH-sensitive drug-delivery systems for tumor targeting. Ther Deliv,2011,4:1499-1510.
[64]C. Liu, F. Liu, L. Feng, et al. The targeted co-delivery of DNA and doxorubicin to tumor cells via multifunctional PEI-PEG based nanoparticles. Biomaterials, 2013,34:2547-2564.
[65]P. Li, D. Liu, L. Miao, et al. A pH-sensitive multifunctional gene carrier assembled via layer-by-layer technique for efficient gene delivery. Int J Nanomedicine,2012,7:925-939.
[66]H. Wu, L. Zhu, V.P. Torchilin pH-sensitive poly(histidine)-PEG/DSPE-PEG co-polymer micelles for cytosolic drug delivery. Biomaterials,2013,34: 1213-1222.
[67]D. Hoekstra, J. Rejman, L. Wasungu, et al. Gene delivery by cationic lipids:in and out of an endosome. Biochem Soc Trans,2007,35:68-71.
[68]T. Reuveni, M. Motiei, Z. Romman, et al. Targeted gold nanoparticles enable molecular CT imaging of cancer:an in vivo study. Int J Nanomedicine,2011,6: 2859-2864.
[69]Z. Chen, D. Yu, C. Liu, et al. Gadolinium-conjugated PLA-PEG nanoparticles as liver targeted molecular MRI contrast agent. J Drug Target,2011,19: 657-665.
[70]C. Liu, W. Yu, Z. Chen, et al. Enhanced gene transfection efficiency in CD 13-positive vascular endothelial cells with targeted poly(lactic acid)-poly(ethylene glycol) nanoparticles through caveolae-mediated endocytosis. J Control Release,2011,151:162-175.
[71]Y. Liu, C. Liu, M. Li, et al. Polymer-Polymer Conjugation to Fabricate Multi-Block Polymer as Novel Drug Carriers:Poly(lactic acid)-Poly(ethylene glycol)-Poly(L-lysine) to Enhance Paclitaxel Target Delivery. Journal of Biomedical Nanotechnology,2014,10:948-958.
[72]Z. Liu, Y. Wang, J. Zhang, et al. Pluronic P123-docetaxel conjugate micelles: synthesis, characterization, and antitumor activity. J Biomed Nanotechnol,2013, 9:2007-2016.
[73]K. Miyata, R.J. Christie, K. Kataoka Polymeric micelles for nano-scale drug delivery. Reactive and Functional Polymers,2011,71:227-234.
[74]Z. Liu, N. Zhang pH-Sensitive polymeric micelles for programmable drug and gene delivery. Curr Pharm Des,2012,18:3442-3451.
[75]I.-K. Park, K. Singha, R.B. Arote, et al. pH-Responsive Polymers as Gene Carriers. Macromolecular Rapid Communications,2010,31:1122-1133.
[76]O. Veiseh, J.W. Gunn, M. Zhang Design and fabrication of magnetic nanoparticles for targeted drug delivery and imaging. Advanced Drug Delivery Reviews,2010,62:284-304.
[77]M. Kudo Current status of molecularly targeted therapy for hepatocellular carcinoma:clinical practice. Int J Clin Oncol,2010,15:242-255.
[78]A.J. Cole, V.C. Yang, A.E. David Cancer theranostics:the rise of targeted magnetic nanoparticles. Trends Biotechnol,2011,29:323-332.
[79]L. Brannon-Peppas, J.O. Blanchette Nanoparticle and targeted systems for cancer therapy. Advanced Drug Delivery Reviews,2012,64, Supplement: 206-212.
[80]N. Kamaly, Z. Xiao, P.M. Valencia, et al. Targeted polymeric therapeutic nanoparticles:design, development and clinical translation. Chem Soc Rev, 2012,41:2971-3010.
[81]F. Danhier, N. Lecouturier, B. Vroman, et al. Paclitaxel-loaded PEGylated PLGA-based nanoparticles:in vitro and in vivo evaluation. J Control Release, 2009,133:11-17.
[82]B. Zhang, X. Li, B. Yan Advances in HPLC detection--towards universal detection. Anal Bioanal Chem,2008,390:299-301.
[83]S. Hirsjarvi, C. Passirani, J.P. Benoit Passive and active tumour targeting with nanocarriers. Curr Drug Discov Technol,2011,8:188-196.
[84]L. Mu, M.M. Teo, H.Z. Ning, et al. Novel powder formulations for controlled delivery of poorly soluble anticancer drug:application and investigation of TPGS and PEG in spray-dried particulate system. J Control Release,2005,103: 565-575.
[85]R. Ghosh, K.L. Lipson, K.E. Sargent, et al. Transcriptional regulation of VEGF-A by the unfolded protein response pathway. PLoS One,2010,5:e9575.
[86]K. Na, S.A. Lee, S.H. Jung, et al. Gadolinium-based cancer therapeutic liposomes for chemotherapeutics and diagnostics. Colloids Surf B Biointerfaces, 2011,84:82-87.
[87]M.A. Oghabian, N.M. Farahbakhsh Potential Use of Nanoparticle Based Contrast Agents in MRI:A Molecular Imaging Perspective. Journal of Biomedical Nanotechnology,2010,6:203-213.
[88]H.P. Lesch, M.U. Kaikkonen, J.T. Pikkarainen, et al. Avidin-biotin technology in targeted therapy. Expert Opinion on Drug Delivery,2010,7:551-564.
[89]C.H. Huang, K. Nwe, A. Al Zaki, et al. Biodegradable polydisulfide dendrimer nanoclusters as MRI contrast agents. ACS Nano,2012,6:9416-9424.
[90]M. Botta, L. Tei Relaxivity Enhancement in Macromolecular and Nanosized GdⅢ-Based MRI Contrast Agents. European Journal of Inorganic Chemistry, 2012,2012:1945-1960.
[91]O. Algin, B. Turkbey Intrathecal gadolinium-enhanced MR cisternography:a comprehensive review. AJNR Am J Neuroradiol,2013,34:14-22.
[92]J. Kost, R. Langer Responsive polymeric delivery systems. Adv Drug Deliv Rev, 2001,46:125-148.
[93]S. Yu, G. Wu, X. Gu, et al. Magnetic and pH-sensitive nanoparticles for antitumor drug delivery. Colloids Surf B Biointerfaces,2013,103:15-22.
[94]S. Manchun, C.R. Dass, P. Sriamornsak Targeted therapy for cancer using pH-responsive nanocarrier systems. Life Sciences,2012,90:381-387.
[95]J.-Z. Du, X.-J. Du, C.-Q. Mao, et al. Tailor-Made Dual pH-Sensitive Polymer 鈥 揇 oxorubicin Nanoparticles for Efficient Anticancer Drug Delivery. Journal of the American Chemical Society,2011,133:17560-17563.
[96]N. Abed, P. Couvreur Nanocarriers for antibiotics:A promising solution to treat intracellular bacterial infections. International Journal of Antimicrobial Agents, 2014,
[97]X.Q. Wang, J.M. Fan, Y.O. Liu, et al. Bioavailability and pharmacokinetics of sorafenib suspension, nanoparticles and nanomatrix for oral administration to rat. Int J Pharm,2011,419:339-346.
[98]R.K. Ambasta, A. Sharma, P. Kumar Nanoparticle mediated targeting of VEGFR and cancer stem cells for cancer therapy. Vasc Cell,2011,3:26.
[99]X. Chen, S.S. Gambhir, J. Cheon Theranostic nanomedicine. Acc Chem Res, 2011,44:841.
[100]A. Rode, B. Bancel, P. Douek, et al. Small nodule detection in cirrhotic livers: evaluation with US, spiral CT, and MRI and correlation with pathologic examination of explanted liver. J Comput Assist Tomogr,2001,25:327-336.
[101]C. Wischke, S.P. Schwendeman Principles of encapsulating hydrophobic drugs in PLA/PLGA microparticles. Int J Pharm,2008,364:298-327.
[102]M. Rimann, T. Luhmann, M. Textor, et al. Characterization of PLL-g-PEG-DNA nanoparticles for the delivery of therapeutic DNA. Bioconjug Chem,2008,19: 548-557.
[103]R. Webster, E. Didier, P. Harris, et al. PEGylated Proteins:Evaluation of Their Safety in the Absence of Definitive Metabolism Studies. Drug Metabolism and Disposition,2007,35:9-16.
[1]VMaY C. Nanoparticles-a review. J Pharmaceut Res 2006; 5:561-73.
[2]Cho K, Wang X, Nie S, Chen Z G.Shin D M. Therapeutic nanoparticles for drug delivery in cancer. Clin Cancer Res 2008; 14:1310-6.
[3]Janib S M, Moses A S.Mackay J A. Imaging and drug delivery using theranostic nanoparticles. Adv Drug Deliv Rev 2010; 1052-63.
[4]Liu F, Park J Y, Zhang Y, Conwell C, Liu Y, Bathula S R, et al. Targeted cancer therapy with novel high drug-loading nanocrystals. J Pharm Sci 2010; 99:3542-51.
[5]ICHIKAWA Y F a H. Nanoparticles for cancer therapy and diagnosis. Adv Powder Technol 2006; 17:1-28.
[6]Zhang M Q, Sun C.Lee J S H. Magnetic nanoparticles in mr imaging and drug delivery. Adv Drug Deliv Rev 2008; 60:1252-65.
[7]Ozdemir V, Williams-Jones B, Glatt S J, Tsuang M T, Lohr J B.Reist C. Shifting emphasis from pharmacogenomics to theragnostics. Nat Biotechnol 2006; 24:942-6.
[8]Hudis C A. Trastuzumab--mechanism of action and use in clinical practice. N Engl J Med 2007; 357:39-51.
[9]Pene F, Courtine E, Cariou A.Mira J P. Toward theragnostics. Crit Care Med 2009; 37:S50-8.
[10]Bhojani M S, Van Dort M, Rehemtulla A.Ross B D. Targeted imaging and therapy of brain cancer using theranostic nanoparticles. Mol Pharmaceut 2010; 7:1921-9.
[11]Lammers T, Kiessling F, Hennink W E.Storm G. Nanotheranostics and image-guided drug delivery:Current concepts and future directions. Mol Pharmaceut 2010; 7:1899-912.
[12]Hong H, Zhang Y, Sun J.Cai W. Molecular imaging and therapy of cancer with radiolabeled nanoparticles. Nano Today 2009; 4:399-413.
[13]Lanza G M, Winter P M, Caruthers S D, Hughes M S, Hu G, Schmieder A H, et al. Theragnostics for tumor and plaque angiogenesis with perfluorocarbon nanoemulsions. Angiogenesis 2010;
[14]Weissleder R. Molecular imaging in cancer. Science 2006; 312:1168-71.
[15]Guo-Ping Yan LR P H. Magnetic resonance imaging contrast agents:Overview and perspective. Radiography 2007; 13:e5-e19.
[16]Caravan P. Strategies for increasing the sensitivity of gadolinium based mri contrast agents. Chem Soc Rev 2006; 35:512-23.
[17]Sharma P, Brown S C, Walter G, Santra S, Scott E, Ichikawa H, et al. Gd nanoparticulates:From magnetic resonance imaging to neutron capture therapy. Adv Powder Technol 2007; 18:663-98.
[18]Wang Y X, Hussain S M.Krestin G P. Superparamagnetic iron oxide contrast agents: Physicochemical characteristics and applications in mr imaging. Eur Radiol 2001; 11:2319-31.
[19]Bellin M F. Mr contrast agents, the old and the new. Eur J Radiol 2006; 60:314-23.
[20]Thorek D L, Chen A K, Czupryna J.Tsourkas A. Superparamagnetic iron oxide nanoparticle probes for molecular imaging. Ann Biomed Eng 2006; 34:23-38.
[21]Yang X Q, Grailer J J, Rowland I J, Javadi A, Hurley S A, Steeber D A, et al. Multifunctional spio/dox-loaded wormlike polymer vesicles for cancer therapy and mr imaging. Biomaterials 2010; 31:9065-73.
[22]Yang X Q, Grailer J J, Rowland I J, Javadi A, Hurley S A, Matson V Z, et al. Multifunctional stable and ph-responsive polymer vesicles formed by heterofunctional triblock copolymer for targeted anticancer drug delivery and ultrasensitive mr imaging. ACS Nano 2010; 4:6805-17.
[23]Na K, Lee S A, Jung S H.Shin B C. Gadolinium-based cancer therapeutic liposomes for chemotherapeutics and diagnostics. Colloids Surf B Biointerfaces 2011; 84:82-7.
[24]de Smet M, Langereis S, van den Bosch S.Grull H. Temperature-sensitive liposomes for doxorubicin delivery under mri guidance. J Control Release 2010; 143:120-7.
[25]Shubayev V 1, Pisanic T R.Jin S H. Magnetic nanoparticles for theragnostics. Adv Drug Deliv Rev 2009; 61:467-77.
[26]McCarthy J R.Weissleder R. Multifunctional magnetic nanoparticles for targeted imaging and therapy. Adv Drug Deliv Rev 2008; 60:1241-51.
[27]Yoo D, Lee J H, Shin T H.Cheon J. Theranostic magnetic nanoparticles. Acc Chem Res 2011; 44: 863-74.
[28]Arruebo M, Femandez-Pacheco R, Ibarra M R.Santamaria J. Magnetic nanoparticles for drug delivery. Nano Today 2007; 2:22-32.
[29]Bentzen S M. Theragnostic imaging for radiation oncology:Dose-painting by numbers. Lancet Oncol 2005; 6:112-7.
[30]Bentzen S M. Dose painting and theragnostic imaging:Towards the prescription, planning and delivery of biologically targeted dose distributions in external beam radiation oncology. Cancer Treat Res 2008; 139:41-62.
[31]Manus L M, Mastarone D J, Waters E A, Zhang X Q, Schultz-Sikma E A, MacRenaris K W, et al. Gd(ⅲ)-nanodiamond conjugates for mri contrast enhancement. Nano Letters 2010; 10:484-9.
[32]Cabella C, Crich S G, Corpillo D, Barge A, Ghirelli C, Bruno E, et al. Cellular labeling with gd(ⅲ) chelates:Only high thermodynamic stabilities prevent the cells acting as 'sponges' of gd3+ions. Contrast Media Mol Imaging 2006; 1:23-9.
[33]Morcos S K. Extracellular gadolinium contrast agents:Differences in stability. Eur J Radiol 2008; 66:175-9.
[34]Caravan P. Strategies for increasing the sensitivity of gadolinium based mri contrast agents. Chem Soc Rev 2006; 35:512-23.
[35]Bernini A, Venditti V, Spiga O, Ciutti A, Prischi F, Consonni R, et al. Nmr studies on the surface accessibility of the archaeal protein sso7d by using tempol and gd(iii)(dtpa-bma) as paramagnetic probes. Biophys Chem 2008; 137:71-5.
[36]Chen Z J, Yu D X, Wang S J, Zhang N, Ma C H.Lu Z J. Biocompatible nanocomplexes for molecular targeted mri contrast agent. Nanoscale Res Lett 2009; 4:618-26.
[37]Hu K W, Hsu K C.Yeh C S. Ph-dependent biodegradable silica nanotubes derived from gd(oh)(3) nanorods and their potential for oral drug delivery and mr imaging. Biomaterials 2010; 31: 6843-8.
[38]Chapman P. Nanotechnology in the pharmaceutical industry. Expert Opin Ther Pat 2005; 15: 249-51.
[39]Medina C, Santos-Martinez M J, Radomski A, Corrigan O I.Radomski M W. Nanoparticles: Pharmacological and toxicological significance. Brit J Pharmacol 2007; 150:552-8.
[40]Rinaudo M. Main properties and current applications of some polysaccharides as biomaterials. Polym Int 2008; 57:397-430.
[41]Yan G P, Xu W, Yang L A, Li L A, Liu F.Guo Q Z. Dextran gadolinium complexes as contrast agents for magnetic resonance imaging to sentinel lymph nodes. Pharmaceut Res 2010; 27: 1884-92.
[42]Kim I Y, Seo S J, Moon H S, Yoo M K, Park I Y, Kim B C, et al. Chitosan and its derivatives for tissue engineering applications. Biotechnol Adv 2008; 26:1-21.
[43]Ge Y, Zhang Y, He S, Nie F, Teng G.Gu N. Fluorescence modified chitosan-coated magnetic nanoparticles for high-efficient cellular imaging. Nanoscale Res Lett 2009; 4:287-95.
[44]Darras V, Nelea M, Winnik F M.Buschmann M D. Chitosan modified with gadolinium diethylenetriaminepentaacetic acid for magnetic resonance imaging of DNA/chitosan nanoparticles. Carbohyd Polym 2010; 80:1137-46.
[45]Poger D, Van Gunsteren W F.Mark A E. A new force field for simulating phosphatidylcholine bilayers. J Comput Chem 2010; 31:1117-25.
[46]Huang S L. Liposomes in ultrasonic drug and gene delivery. Adv Drug Deliv Rev 2008; 60: 1167-76.
[47]Spanoghe M, Lanens D, Dommisse R, Van der Linden A.Alderweireldt F. Proton relaxation enhancement by means of serum albumin and poly-1-lysine labeled with dtpa-gd3+:Relaxivities as a function of molecular weight and conjugation efficiency. Magn Reson Imaging 1992; 10: 913-7.
[48]Shiraishi K, Kawano K, Minowa T, Maitani Y.Yokoyama M. Preparation and in vivo imaging of peg-poly(l-lysine)-based polymeric micelle mri contrast agents. J Control Release 2009; 136: 14-20.
[49]Liu Y, Chen Z, Liu C, Yu D, Lu Z.Zhang N. Gadolinium-loaded polymeric nanoparticles modified with anti-vegf as multifunctional mri contrast agents for the diagnosis of liver cancer. Biomaterials 2011; 32:5167-76.
[50]Wijagkanalan W, Kawakami S.Hashida M. Designing dendrimers for drug delivery and imaging: Pharmacokinetic considerations. Pharmaceut Res 2011; 28:1500-19.
[51]Nwe K, Bryant L H, Jr..Brechbiel M W. Poly(amidoamine) dendrimer based mri contrast agents exhibiting enhanced relaxivities derived via metal preligation techniques. Bioconjug Chem 2010; 21:1014-7.
[52]Svenson S. Dendrimers as versatile platform in drug delivery applications. Eur J Pharm Biopharm 2009; 71:445-62.
[53]Dreis S, Rothweiler F, Michaelis M, Cinatl J, Jr., Kreuter J.Langer K. Preparation, characterisation and maintenance of drug efficacy of doxorubicin-loaded human serum albumin (hsa) nanoparticles. Int J Pharm 2007; 341:207-14.
[54]Schmiedl U, Ogan M, Paajanen H, Marotti M, Crooks L E, Brito A C, et al. Albumin labeled with gd-dtpa as an intravascular, blood pool-enhancing agent for mr imaging:Biodistribution and imaging studies. Radiology 1987; 162:205-10.
[55]Schmiedl U, Moseley M E, Ogan M D, Chew W M.Brasch R C. Comparison of initial biodistribution patterns of gd-dtpa and albumin-(gd-dtpa) using rapid spin echo mr imaging. J Comput Assist Tomogr 1987; 11:306-13.
[56]Aime S, Botta M.Terreno E. Gd(iii)-based contrast agents for mri. Adv Inorg Chem 2005; 57: 173-237.
[57]Nakamura E, Makino K, Okano T, Yamamoto T.Yokoyama M. A polymeric micelle mri contrast agent with changeable relaxivity. J Control Release 2006; 114:325-33.
[58]Ratzinger G, Agrawal P, Korner W, Lonkai J, Sanders H M, Terreno E, et al. Surface modification of plga nanospheres with gd-dtpa and gd-dota for high-relaxivity mri contrast agents. Biomaterials 2010; 31:8716-23.
[59]Chen Z, Yu D, Liu C, Yang X, Zhang N, Ma C, et al. Gadolinium-conjugated pla-peg nanoparticles as liver targeted molecular mri contrast agent. J Drug Target 2011; 19:657-65.
[60]Jeong S Y, Kim H J, Kwak B-K, Lee H-Y.Cho S H. Biocompatible polyhydroxyethylaspartamide-based micelles with gadolinium for mri contrast agents. Nanoscale Res Lett 2010; 5:1970-6.
[61]Hak S, Sanders H M, Agrawal P, Langereis S, Grull H, Keizer H M, et al. A high relaxivity gd(iii)dota-dspe-based liposomal contrast agent for magnetic resonance imaging. Eur J Pharm Biopharm 2009; 72:397-404.
[62]Nwe K, Bernardo M, Regino C A S, Williams M.Brechbiel M W. Comparison of mri properties between derivatized dtpa and dota gadolinium-dendrimer conjugates. Bioorgan Med Chem 2010; 18:5925-31.
[63]Zhang M Q, Veiseh O.Gunn J W. Design and fabrication of magnetic nanoparticles for targeted drug delivery and imaging. Adv Drug Deliv Rev 2010; 62:284-304.
[64]Veiseh O, Gunn J W.Zhang M Q. Design and fabrication of magnetic nanoparticles for targeted drug delivery and imaging. Adv Drug Deliv Rev 2010; 62:284-304.
[65]Fang J, Nakamura H.Maeda H. The epr effect:Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv Drug Deliv Rev 2011; 136-51.
[66]Li S D.Huang L. Pharmacokinetics and biodistribution of nanoparticles. Mol Pharm 2008; 5: 496-504.
[67]Liu D, Mori A.Huang L. Role of liposome size and res blockade in controlling biodistribution and tumor uptake of gml-containing liposomes. Biochim Biophys Acta 1992; 1104:95-101.
[68]Delgado C, Francis G E.Fisher D. The uses and properties of peg-linked proteins. Crit Rev Ther Drug Carrier Syst 1992; 9:249-304.
[69]Mok H, Palmer D J, Ng P.Barry M A. Evaluation of polyethylene glycol modification of first-generation and helper-dependent adenoviral vectors to reduce innate immune responses. Mol Ther 2005; 11:66-79.
[70]Blume G.Cevc G. Molecular mechanism of the lipid vesicle longevity in vivo. Biochim Biophys Acta 1993; 1146:157-68.
[71]Kumar R, Ohulchanskyy T Y, Turowski S G, Thompson M E, Seshadri M.Prasad P N. Combined magnetic resonance and optical imaging of head and neck tumor xenografts using gadolinium-labelled phosphorescent polymeric nanomicelles. Head Neck Oncol 2010; 2:35.
[72]Caruso F, Johnston A P R, Such G K.Ng S L. Challenges facing colloidal delivery systems:From synthesis to the clinic. Curr Opin Colloid In 2011; 16:171-81.
[73]Kozlowska D, Foran P, MacMahon P, Shelly M J, Eustace S.O'Kennedy R. Molecular and magnetic resonance imaging:The value of immunoliposomes. Adv Drug Deliv Rev 2009; 61: 1402-11.
[74]Saito Y, Oba N, Nishinakagawa S, Mizuguchi Y, Kojima T, Nomura K, et al. Identification of beta 2-microgloblin as a candidate for early diagnosis of imaging-invisible hepatocellular carcinoma in patient with liver cirrhosis. Oncol Rep 2010; 23:1325-30.
[75]Ke J H, Lin J J, Carey J R, Chen J S, Chen C Y.Wang L F. A specific tumor-targeting magnetofluorescent nanoprobe for dual-modality molecular imaging. Biomaterials 2010; 31: 1707-15.
[76]Wang K, Pruthodam S, Lee J Y, Na M H, Park H, Oh S J, et al. In vivo imaging of tumor apoptosis using histone hl-targeting peptide. J Control Release 2010;
[77]Zhang D, Feng X Y, Henning T D, Wen L, Lu W Y, Pan H, et al. Mr imaging of tumor angiogenesis using sterically stabilized gd-dtpa liposomes targeted to cd105. Eur J Radiol 2009; 70:180-9.
[78]Esposito G, Geninatti Crich S.Aime S. Efficient cellular labeling by cd44 receptor-mediated uptake of cationic liposomes functionalized with hyaluronic acid and loaded with mri contrast agents. ChemMedChem 2008; 3:1858-62.
[79]Leamon C P.Reddy J A. Folate-targeted chemotherapy. Adv Drug Deliv Rev 2004; 56:1127-41.
[80]Chen W T, Thirumalai D, Shih T T, Chen R C, Tu S Y, Lin C I, et al. Dynamic contrast-enhanced folate-receptor-targeted mr imaging using a gd-loaded peg-dendrimer-folate conjugate in a mouse xenograft tumor model. Mol Imaging Biol 2010; 12:145-54.
[81]Hu Z, Luo F, Pan Y, Hou C, Ren L, Chen J, et al. Arg-gly-asp (rgd) peptide conjugated poly(lactic acid)-poly(ethylene oxide) micelle for targeted drug delivery. J Biomed Mater Res A 2008; 85:797-807.
[82]Corti A, Curnis F, Arap W.Pasqualini R. The neovasculature homing motif ngr:More than meets the eye. Blood 2008; 112:2628-35.
[83]Li W, Su B, Meng S, Ju L, Yan L, Ding Y, et al. Rgd-targeted paramagnetic liposomes for early detection of tumor:In vitro and in vivo studies. Eur J Radiol 2011; 80:598-606.
[84]Couvreur P, Bildstein L.Dubernet C. Prodrug-based intracellular delivery of anticancer agents. Adv Drug Deliv Rev 2011; 63:3-23.
[85]Fay F.Scott C J. Antibody-targeted nanoparticles for cancer therapy. Immunotherapy 2011; 3: 381-94.
[86]Amiji M, Milane L.Duan Z F. Pharmacokinetics and biodistribution of lonidamine/paclitaxel loaded, egfr-targeted nanoparticles in an orthotopic animal model of multi-drug resistant breast cancer. Nanomedicine:NBM 2011; 7:435-44.
[87]Hun X.Zhang Z J. Anti-epidermal growth factor receptor (anti-egfr) antibody conjugated fluorescent nanoparticles probe for breast cancer imaging. Spectrochim Acta A 2009; 74:410-4.
[88]Yang L L, Mao H, Wang Y A, Cao Z H, Peng X H, Wang X X, et al. Single chain epidermal growth factor receptor antibody conjugated nanoparticles for in vivo tumor targeting and imaging. Small 2009; 5:235-43.
[89]Kreuter J, Ulbrich K, Hekmatara T.Herbert E. Transferrin- and transferrin-receptor-antibody-modified nanoparticles enable drug delivery across the blood-brain barrier (bbb). Eur J Pharm Biopharm 2009; 71:251-6.
[90]Ossipov D A. Nanostructured hyaluronic acid-based materials for active delivery to cancer. Expert Opin Drug Deliv 2010; 7:681-703.
[91]Buffa R, Betak J, Kettou S, Hermannova M, Pospisilova L.Velebny V. A novel dtpa cross-linking of hyaluronic acid and metal complexation thereof. Carbohydr Res 2011; 346: 1909-15.
[92]Kohane D S. Microparticles and nanoparticles for drug delivery. Biotechnol Bioeng 2007; 96: 203-9.
[93]Bhalgat C M, Mudshinge S R, Deore A B.Patil S. Nanoparticles:Emerging carriers for drug delivery. Saudi Pharm J 2011; 19:129-41.
[94]Greene M E. Nanoparticles deliver the goods. Nano Today 2006; 1:16-.
[95]Gregoriadis G. The carrier potential of liposomes in biology and medicine (first of two parts). N Engl J Med 1976; 295:704-10.
[96]Torchilin V P. Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov 2005; 4:145-60.
[97]Mody V V, Nounou M I.Bikram M. Novel nanomedicine-based mri contrast agents for gynecological malignancies. Adv Drug Deliv Rev 2009; 61:795-807.
[98]Unger E C, Winokur T, MacDougall P, Rosenblum J, Clair M, Gatenby R, et al. Hepatic metastases:Liposomal gd-dtpa-enhanced mr imaging. Radiology 1989; 171:81-5.
[99]Fritz T, Unger E, Wilson-Sanders S, Ahkong Q F.Tilcock C. Detailed toxicity studies of liposomal gadolinium-dtpa. Invest Radiol 1991; 26:960-8.
[100]Tilcock C, Unger E, Cullis P.MacDougall P. Liposomal gd-dtpa:Preparation and characterization of relaxivity. Radiology 1989; 171:77-80.
[101]Sibson N R, Blamire A M, Bernades-Silva M, Laurent S, Boutry S, Muller R N, et al. Mri detection of early endothelial activation in brain inflammation. Magn Reson Med 2004; 51: 248-52.
[102]Fossheim S L, Il'yasov K A, Hennig J.Bjornerud A. Thermosensitive paramagnetic liposomes for temperature control during mr imaging-guided hyperthermia:In vitro feasibility studies. Acad Radiol 2000; 7:1107-15.
[103]McDannold N, Fossheim S L, Rasmussen H, Martin H, Vykhodtseva N.Hynynen K. Heat-activated liposomal mr contrast agent:Initial in vivo results in rabbit liver and kidney. Radiology 2004; 230:743-52.
[104]Delli Castelli D, Dastru W, Terreno E, Cittadino E, Mainini F, Torres E, et al. In vivo mri multicontrast kinetic analysis of the uptake and intracellular trafficking of paramagnetically labeled liposomes. J Control Release 2010; 144:271-9.
[105]Andre J P, Toth E, Fischer H, Seelig A, Macke H R.Merbach A E. High relaxivity for monomeric gd(dota)-based mri contrast agents, thanks to micellar self-organization. Chem-Eur J 1999; 5: 2977-83.
[106]Terreno E, Sanino A, Carrera C, Castelli D D, Glovenzana G B, Lombardi A, et al. Determination of water permeability of paramagnetic liposomes of interest in mri field. J Inorg Biochem 2008; 102:1112-9.
[107]Koenig S H, Ahkong Q F, Brown R D,3rd, Lafleur M, Spiller M, Unger E, et al. Permeability of liposomal membranes to water:Results from the magnetic field dependence of t1 of solvent protons in suspensions of vesicles with entrapped paramagnetic ions. Magn Reson Med 1992; 23: 275-86.
[108]Ghaghada K, Hawley C, Kawaji K, Annapragada A.Mukundan S, Jr. T1 relaxivity of core-encapsulated gadolinium liposomal contrast agents--effect of liposome size and internal gadolinium concentration. Acad Radiol 2008; 15:1259-63.
[109]Kamaly N.Miller A D. Paramagnetic liposome nanoparticles for cellular and tumour imaging. Int JMol Sci 2010;11:1759-76.
[110]Kamaly N, Kalber T, Ahmad A, Oliver M H, So P W, Herlihy A H, et al. Bimodal paramagnetic and fluorescent liposomes for cellular and tumor magnetic resonance imaging. Bioconjug Chem 2008; 19:118-29.
[111]Weissig V V, Babich J.Torchilin V V. Long-circulating gadolinium-loaded liposomes:Potential use for magnetic resonance imaging of the blood pool. Colloids Surf B Biointerfaces 2000; 18: 293-9.
[112]Kielar F, Tei L, Terreno E.Botta M. Large relaxivity enhancement of paramagnetic lipid nanoparticles by restricting the local motions of the gd(iii) chelates. J Am Chem Soc 2010; 132: 7836-7.
[113]Tournier H, Hyacinthe R.Schneider M. Gadolinium-containing mixed micelle formulations:A new class of blood pool mri/mra contrast agents. Acad Radiol 2002; 9:20-8.
[114]Lattuada L.Lux G. Synthesis of gd-dtpa-cholesterol:A new lipophilic gadolinium complex as a potential mri contrast agent. Tetrahedron Lett 2003; 44:3893-5.
[115]Parac-Vogt T N, Kimpe K, Laurent S, Pierart C, Elst L V, Muller R N, et al. Paramagnetic liposomes containing amphiphilic bisamide derivatives of gd-dtpa with aromatic side chain groups as possible contrast agents for magnetic resonance imaging. Eur Biophys J 2006; 35: 136-44.
[116]Kimpe K, Parac-Vogt T N, Laurent S, Pierart C, Vander Elst L, Muller R N, et al. Potential mri contrast agents based on micellar incorporation of amphiphilic bis(alkylamide) derivatives of [(gd-dtpa)(h2o)](2-). Eur J Inorg Chem 2003; 3021-7.
[117]Anelli P L, Lattuada L, Gabellini M.Recanati P. Dota tris(phenylmethyl) ester:A new useful synthon for the synthesis of dota monoamides containing acid-labile bonds. Bioconjug Chem 2001; 12:1081-4.
[118]Laurent S, Vander Elst L, Thirifays C.Muller R N. Relaxivities of paramagnetic liposomes:On the importance of the chain type and the length of the amphiphilic complex. Eur Biophys J 2008; 37:1007-14.
[119]Georgiev G A, Sarker D K, Al-Hanbali O, Georgiev G D.Lalchev Z. Effects of poly (ethylene glycol) chains conformational transition on the properties of mixed dmpc/dmpe-peg thin liquid films and monolayers. Colloids Surf B Biointerfaces 2007; 59:184-93.
[120]Erdogan S, Medarova Z O, Roby A, Moore A.Torchilin V P. Enhanced tumor mr imaging with gadolinium-loaded polychelating polymer-containing tumor-targeted liposomes. J Magn Reson Imaging 2008; 27:574-80.
[121]Maruyama K. Intracellular targeting delivery of liposomal drugs to solid tumors based on epr effects. Adv Drug Deliv Rev 2010;
[122]Kullberg M, Owens J L.Mann K. Listeriolysin o enhances cytoplasmic delivery by her-2 targeting liposomes. J Drug Target 2010; 18:313-20.
[123]Zhang D, Feng X Y, Henning T D, Wen L, Lu W Y, Pan H, et al. Mr imaging of tumor angiogenesis using sterically stabilized gd-dtpa liposomes targeted to cd105. Eur J Radiol 2009; 70:180-9.
[124]Pan X, Wu G, Yang W, Barth R F, Tjarks W.Lee R J. Synthesis of cetuximab-immunoliposomes via a cholesterol-based membrane anchor for targeting of egfr. Bioconjug Chem 2007; 18: 101-8.
[125]Kamaly N, Kalber T, Thanou M, Bell J D.Miller A D. Folate receptor targeted bimodal liposomes for tumor magnetic resonance imaging. Bioconjug Chem 2009; 20:648-55.
[126]Lu Y.Ballauff M. "Smart" Nanoparticles:Preparation, characterization and applications. Polymer 2007; 48:1815-23.
[127]Terreno E, Figueiredo S, Moreira J N, Geraldes C F G C.Aime S. Supramolecular protamine/gd-loaded liposomes adducts as relaxometric protease responsive probes. Bioorg Med Chem 2011; 19:1131-5.
[128]Figueiredo S, Moreira J N, Geraldes C F, Aime S.Terreno E. Supramolecular protamine/gd-loaded liposomes adducts as relaxometric protease responsive probes. Bioorg Med Chem 2010;
[129]Terreno E, Boffa C, Menchise V, Fedeli F, Carrera C, Castelli D D, et al. Gadolinium-doped lipocest agents:A potential novel class of dual (1)h-mri probes. Chem Commun (Camb) 2011; 47:4667-9.
[130]Lokling K E, Fossheim S L, Skurtveit R, Bjornerud A.Klaveness J. Ph-sensitive paramagnetic liposomes as mri contrast agents:In vitro feasibility studies. Magn Reson Imaging 2001; 19: 731-8.
[131]Torres E, Mainini F, Napolitano R, Fedeli F, Cavalli R, Aime S, et al. Improved paramagnetic liposomes for mri visualization of ph triggered release. J Control Release 2011; 154:196-202.
[132]Gerasimov O V, Boomer J A, Qualls M M.Thompson D H. Cytosolic drug delivery using ph-and light-sensitive liposomes. Adv Drug Deliv Rev 1999; 38:317-38.
[133]Moghimi S M. Recent developments in polymeric nanoparticle engineering and their applications in experimental and clinical oncology. Anticancer Agents Med Chem 2006; 6: 553-61.
[134]Wischke C.Schwendeman S P. Principles of encapsulating hydrophobic drugs in pla/plga microparticles. Int J Pharm 2008; 364:298-327.
[135]Mainardes R M, Gremiao M P, Brunetti I L, da Fonseca L M.Khalil N M. Zidovudine-loaded pla and pla-peg blend nanoparticles:Influence of polymer type on phagocytic uptake by polymorphonuclear cells. J Pharm Sci 2009; 98:257-67.
[136]Shikata F, Tokumitsu H, Ichikawa H.Fukumori Y. In vitro cellular accumulation of gadolinium incorporated into chitosan nanoparticles designed for neutron-capture therapy of cancer. Eur J Pharm Biopharm 2002; 53:57-63.
[137]Fujimoto T, Ichikawa H, Akisue T, Fujita I, Kishimoto K, Hara H, et al. Accumulation of mri contrast agents in malignant fibrous histiocytoma for gadolinium neutron capture therapy. Appl Radiat Isot 2009; 67:S355-8.
[138]Kundu A, Peterlik H, Krssak M, Bytzek A K, Pashkunova-Martic I, Arion V B, et al. Strategies for the covalent conjugation of a bifunctional chelating agent to albumin:Synthesis and characterization of potential mri contrast agents. J Inorg Biochem 2011; 105:250-5.
[139]Tseng H R, Chen K J, Wolahan S M, Wang H, Hsu C H, Chang H W, et al. A small mri contrast agent library of gadolinium(iii)-encapsulated supramolecular nanoparticles for improved relaxivity and sensitivity. Biomaterials 2011; 32:2160-5.
[140]Lu Z R, Tan M Q, Wu X M, Jeong E K.Chen Q J. Peptide-targeted nanoglobular gd-dota monoamide conjugates for magnetic resonance cancer molecular imaging. Biomacromolecules 2010; 11:754-61.
[141]Liu J, Lee H.Allen C. Formulation of drugs in block copolymer micelles:Drug loading and release. Curr Pharm Des 2006; 12:4685-701.
[142]Kabalka G W, Davis M A, Holmberg E, Maruyama K.Huang L. Gadolinium-labeled liposomes containing amphiphilic gd-dtpa derivatives of varying chain length:Targeted mri contrast enhancement agents for the liver. Magn Reson Imaging 1991; 9:373-7.
[143]Schwendener R A, Wuthrich R, Duewell S, Wehrli E.von Schulthess G K. A pharmacokinetic and mri study of unilamellar gadolinium-, manganese-, and iron-dtpa-stearate liposomes as organ-specific contrast agents. Invest Radiol 1990; 25:922-32.
[144]Grogna M, Cloots R, Luxen A e, Jerome C.Detrembleur C. Polymer micelles decorated by gadolinium complexes as mri blood contrast agents:Design, synthesis and properties. Polym Chem 2010; 1:1485-90.
[145]Miyata K, Christie R J.Kataoka K. Polymeric micelles for nano-scale drug delivery. React Funct Polym 2011; 71:227-34.
[146]Shiraishi K, Kawano K, Maitani Y.Yokoyama M. Polyion complex micelle mri contrast agents from poly(ethylene glycol)-b-poly(l-lysine) block copolymers having gd-dota; preparations and their control of t(1)-relaxivities and blood circulation characteristics. J Control Release 2010; 148:160-7.
[147]Buhleier E, Wehner W.Vogtle F. "Cascade"- and "Nonskid-chain-like" Syntheses of molecular cavity topologies. Synthesis 1978; 2:155-8.
[148]Alper J. Rising chemical "Stars" Could play many roles. Science 1991; 251:1562-4.
[149]Rupp R, Rosenthal S L.Stanberry L R. Vivagel (tm) (spl7013 gel):A candidate dendrimer microbicide for the prevention of hiv and hsv infection. Int J Nanomed 2007; 2:561-6.
[150]Oliveira J M, Salgado A J, Sousa N, Mano J F.Reis R L. Dendrimers and derivatives as a potential therapeutic tool in regenerative medicine strategies-a review. Prog Polym Sci 2010; 35: 1163-94.
[151]Nanjwade B K, Bechra H M, Derkar G K, Manvi F V.Nanjwade V K. Dendrimers:Emerging polymers for drug-delivery systems. Eur J Pharm Sci 2009; 38:185-96.
[152]Caminade A M, Laurent R.Majoral J P. Characterization of dendrimers. Adv Drug Deliv Rev 2005; 57:2130-46.
[153]Wiener E C, Brechbiel M W, Brothers H, Magin R L, Gansow O A, Tomalia D A, et al. Dendrimer-based metal chelates:A new class of magnetic resonance imaging contrast agents. Magn Reson Med 1994; 31:1-8.
[154]Toth E E, Helm L, Merbach A E, Hedinger R, Hegetschweiler K.Janossy A. Structure and dynamics of a trinuclear gadolinium(iii) complex:The effect of intramolecular electron spin relaxation on its proton relaxivity(1). Inorg Chem 1998; 37:4104-13.
[155]Brechbiel M W, Nwe K, Xu H, Regino C A S, Bernardo M, Ileva L, et al. A new approach in the preparation of dendrimer-based bifunctional diethylenetriaminepentaacetic acid mr contrast agent derivatives. Bioconjugate Chem 2009; 20:1412-8.
[156]Swanson S D, Kukowska-Latallo J F, Patri A K, Chen C Y, Ge S, Cao Z Y, et al. Targeted gadolinium-loaded dendrimer nanoparticles for tumor-specific magnetic resonance contrast enhancement. International Journal of Nanomedicine 2008; 3:201-10.
[157]Zhu W, Okollie B, Bhujwalla Z M.Artemov D. Pamam dendrimer-based contrast agents for mr imaging of her-2/neu receptors by a three-step pretargeting approach. Magn Reson Med 2008; 59:679-85.
[158]Nwe K, Milenic D E, Ray G L, Kim Y S.Brechbiel M W. Preparation of cystamine core dendrimer and antibody-dendrimer conjugates for mri angiography. Mol Pharm 2012;
[159]Langereis S, de Lussanet Q G, van Genderen M H, Meijer E W, Beets-Tan R G, Griffioen A W, et al. Evaluation of gd(iii)dtpa-terminated poly(propylene imine) dendrimers as contrast agents for mr imaging. NMR Biomed 2006; 19:133-41.
[160]Huang R, Han L, Li J, Liu S, Shao K, Kuang Y, et al. Chlorotoxin-modified macromolecular contrast agent for mri tumor diagnosis. Biomaterials 2011; 32:5177-86.
[161]Gu Z W, Luo K, Liu G, He B, Wu Y, Gong Q Y, et al. Multifunctional gadolinium-based dendritic macromolecules as liver targeting imaging probes. Biomaterials 2011; 32:2575-85.
[162]Luo K, Liu G, She W, Wang Q, Wang G, He B, et al. Gadolinium-labeled peptide dendrimers with controlled structures as potential magnetic resonance imaging contrast agents. Biomaterials 2011; 32:7951-60.
[163]Slowing, Ⅱ, Vivero-Escoto J L, Wu C W.Lin V S. Mesoporous silica nanoparticles as controlled release drug delivery and gene transfection carriers. Adv Drug Deliv Rev 2008; 60:1278-88.
[164]Li S Z, Ma Y, Yue X L, Cao Z.Dai Z F. One-pot construction of doxorubicin conjugated magnetic silica nanoparticles. New J Chem 2009; 33:2414-8.
[165]Lin Y S, Hung Y, Su J K, Lee R, Chang C, Lin M L, et al. Gadolinium(iii)-incorporated nanosized mesoporous silica as potential magnetic resonance imaging contrast agents. J Phys Chem B 2004; 108:15608-11.
[166]Taylor K M L, Kim J S, Rieter W J, An H, Lin W L.Lin W B. Mesoporous silica nanospheres as highly efficient mri contrast agents. J Am Chem Soc 2008; 130:2154-5.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |