多功能PAMAM/金纳米复合材料的制备、表征及其在生物CT成像中的应用
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摘要
分子影像学是一类先进的医学成像技术,可以用于检测并且定量测量体外、体内的生物学和细胞水平活动。分子影像学的一个重要分支是X-射线断层扫描技术(CT成像),该技术由于较高的空间分辨率和密度被广泛地用于临床成像。作为生物学体系中CT成像的重要组成部分,如何设计合适的具有良好生物相容性、更长成像时间、更高成像灵敏度和特异性的造影剂是非常重要的。相对于传统的含碘(I)造影剂而言,金纳米粒子(Au NPs)具有的一些优势使得其被作为分子探针用于CT成像的趋势在逐渐增长。树状大分子是一类高度支化、单分散、可合成的大分子,具有精确的组成结构。由于临床使用的含碘CT造影剂(如Omnipaque)成像时间短、高浓度时具有肾脏毒性且无特异性,所以本论文将树状大分子和Au NPs的优点结合起来,系统地研究了树状大分子/Au纳米复合材料的制备、稳定性、生物相容性和X-射线衰减系数,并评估了此类纳米复合材料作为造影剂在CT成像中应用的可行性。
本论文选用第五代聚酰胺-胺(Polyamidoamine,PAMAM)树状大分子(G5.NH2)作为模板制备树状大分子包裹的Au NPs (Au DENPs),并对G5.NH2的末端氨基进行乙酰化修饰以中和材料的表面电势。通过调节Au和G5.NH2的摩尔比,制备了直径在2-4nm的[(Au0)50-G5.NHAc]DENP。通过SPC-A1细胞(一种人肺癌细胞)的苏木精-曙红(HE)染色和MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)实验证实[(Au0)50-G5.NHAc] DENPs在一定浓度范围内无细胞毒性。同时,通过瘤内注射和腹腔注射的方式,考察了[(Au0)50-G5.NHAc] DENPs对SPC-A1肿瘤的荷瘤鼠肿瘤部位的CT成像效果。以上实验证实,此类乙酰化的AuDENPs在肿瘤细胞的CT成像中具有巨大的潜力。
为了改进所制备的Au DENPs的性能,利用聚乙二醇(PEG)对G5.NH2进行了修饰。首先,将PEG通过化学键合的方式修饰连接在G5.NH2的末端胺基上制备了G5.NH2-mPEG。随后,以此G5.NH2-mPEG为模板制备Au DENPs,并将末端氨基乙酰化即制备得到了PEG化的Au DENPs。PEG的修饰,提高了Au DENPs中Au的上载量,且通过调节Au/G5.NH2的摩尔比,此类PEG化的Au DENPs的尺寸分布在较窄的空间(2-4nm)。制备得到的PEG化的Au DENPs是水溶性的,且在pH=5-8和温度范围为4-50℃具有良好的稳定性,且当材料浓度达到50μM时,仍无明显的细胞毒性。通过对PEG化的Au DENPs的X-射线衰减系数的测定发现,在相同的Au和I浓度时,PEG化的Au DENPs较Omnipaque(传统的临床诊断用的含碘造CT影剂)具有更高的X-射线衰减系数。由于药代动力学的研究证明PEG化的Au DENPs具有较长的血液半衰期,故此类PEG化的Au DENPs不仅可以用于老鼠的血池造影成像,同时可以有效地用于SPC-A1移植瘤荷瘤鼠肿瘤部位的CT成像。这些结果均证实此类PEG化的Au DENPs有望被作为具有良好生物相容性的CT造影剂用于多重生物体系尤其是癌症的CT成像诊断。
目前,开发多功能对肿瘤组织靶向高效CT成像的纳米探针仍然是研发工作的一大挑战。在上述研究工作的基础上,进一步以PEG作为中间体合成并表征了叶酸(FA)修饰的PEG化的Au DENPs,并将此种造影剂用于活体荷瘤鼠肿瘤部位的CT成像。在此,依次利用两种不同的PEG(FA-PEG-COOH和mPEG-COOH)修饰在G5.NH2的表面,并以此化合物作为模板合成Au DENPs,随后对G5.NH2末端剩余的氨基进行乙酰化处理即可制备得到FA修饰的PEG化的Au DENPs。制备得到的多功能化的AuDENPs通过不同的检测手段进行了表征。通过细胞活性实验、流式细胞术检测细胞周期实验、溶血实验分别验证了所制备材料的细胞毒性和血液相容性。所制备的多功能的Au DENPs在不同pH和温度范围、不同溶剂中均具有良好的胶体稳定性,且在给定的浓度范围内具有良好的细胞相容性和血液相容性。在相同的Au和I浓度时,所制备的FA修饰的PEG化的Au DENPs较Omnipaque具有更高的X-射线衰减系数。更重要的是,此类FA修饰的PEG化的Au DENPs可以实现对高叶酸受体的癌细胞的体外靶向CT成像,同时实现对活体移植瘤荷瘤鼠肿瘤部位的靶向CT成像。以上的结果证实,此类FA修饰的PEG化的Au DENPs有望被作为造影剂用于肿瘤组织的靶向CT成像。
研究新型CT造影剂的另一个方向是如何将多种造影元素有效地结合起来。因此,我们设计利用含碘(I)造影剂泛影酸(Diatrizoic acid,DTA)修饰的G5.NH2作为稳定剂,通过温和的反应方法制备树状大分子稳定的Au NPs (Au DSNPs),并将此类造影剂用于增强CT成像的效果。首先,通过EDC将DTA修饰在G5.NH2上,并以此化合物为模板在室温且无外加还原剂的条件下,通过自还原的方法将氯金酸的水溶液还原成Au NPs,随后将G5.NH2剩余的末端氨基乙酰化中和电势,即可得到平均直径为6nm的DTA修饰的Au DSNPs ([(Au0)50-G5.NHAc-DTA] DSNPs),通过不同的方法对所制备的[(Au0)50-G5.NHAc-DTA] DSNPs进行了表征。结果证实,所制备的Au DSNPs在不同pH和温度范围内具有良好的胶体稳定性。体外溶血实验、细胞毒性实验、流式细胞检测分析和细胞形貌的观察均表明制备的Au DSNPs在材料浓度达到3μm时,仍具有良好的血液相容性和细胞相容性。在相同的Au和I浓度时,[(Au0)50-G5.NHAc-DTA] DSNPs较仅含Au的[(Au0)50-G5.NHAc] DENPs和仅含I的Omnipaque而言,具有更高的X-射线衰减系数。同时,制备的DTA修饰的Au DSNPs可以用于体外癌细胞和活体小鼠的血管CT成像,且较单一的含Au的[(Au0)50-G5.NHAc] DENPs和含I的Omnipaque在相同的Au和I浓度时,具有更好的CT成像效果。同时含有Au和I两种造影元素的DTA修饰的Au DSNPs可以增强X-射线衰减系数和检测的灵敏度,因而被用于多种生物体系的CT成像。
在以上Au DENPs研究工作的基础上,进一步将DTA、异硫氰酸酯荧光素(FITC)和FA依次通过共价键修饰在[(Au0)5o-G5.NH2] DENPs的表面并对剩余氨基乙酰化以降低材料的表面电势从而制备得到了平均粒径为2.6nm的DTA修饰的多功能化的Au DENPs。通过溶血性实验、细胞形貌观察和细胞毒性实验证实,所制备的材料在给定的浓度范围内(3000nm),具有良好的血液相容性和细胞相容性。且所制备的材料,较单一的含金造影剂([(Au0)50-G5.NHAc] DENPs)而言,在相同Au摩尔浓度时,具有更高的X-射线衰减系数。所制备的DTA修饰的多功能化的Au DENPs可以实现对具有高叶酸受体表达的SKO细胞(一种具有高叶酸受体表达的人卵巢癌细胞)体外靶向CT成像,同时实现对活体移植瘤荷瘤鼠肿瘤部位的靶向CT成像。以上的结果证实,此类FA修饰的含有DTA的多功能化的AuDENPs有望被作为造影剂用于肿瘤组织的靶向CT成像。
总之,PAMAM/Au纳米复合材料由于具有良好的X-射线衰减系数,在CT成像领域具有巨大的应用潜质。
Molecular imaging (MI) is an advanced technology in the field of medical imaging that has the ability to detect and to quantitatively measure the function of biological and cellular events in vitro and in vivo. As one of the important MI technologies, computed tomography (CT) is a reliable and widely used clinical imaging technique with high spatial and density resolution. The key component in CT imaging of biological systems is to design suitable contrast agents that have good biocompatibility, longer imaging time, and desirable imaging sensitivity and specificity. The utilization of gold nanoparticles (Au NPs) has seen an increasing potential as molecular probes for X-ray CT imaging, as they offer several advantages over conventional iodine-based agents. Dendrimers are a family of highly branched, monodispersed, synthetic macromolecules with well defined structural composition and architecture. Due to the drawbacks of clinically used iodine-based CT contrast agents (e.g., Omnipaque) such as short imaging time, renal toxicity at a high concentration, and non-specificity, the advantage of dendrimers and Au NPs were combined to systematically study the preparation, stability, biocompatibility, and X-ray attenuation characteristics of dendrimer/Au-based nanocomposites to testify their feasibility as contrast agents for CT imaging in this thesis.
In this thesis, amine-terminated generation5polyarnidoamine (PAMAM) dendrimers (G5.NH2) were used as templates to prepared dendrimer-entrapped Au NPs (Au DENPs) followed by acetylation to neutralize the positive surface charge of the particles. By varying the molar ratio of gold salt/G5dendrimer, the acetylated Au DENPs ([(Au0)50-G5.NHAc] DENPs) with a size range of2-4nm can be prepared. The cell viability of acetylated Au DENPs were tested by hematoxylin and eosin staining and MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay of a human lung adencarcinoma cell line (SPC-A1cells), and confirmed that the [(Au0)5o-G5.NHAc] DENPs have no cell toxicity at a certain concentration. Meanwhile, the xenograft SPC-A1tumor model can be imaged after both intratumoral and intraperitoneal administration of the particles. Findings from this study suggest that the developed acetylated Au DENPs have a great potential to be used for CT imaging of cancer cells.
Surface modification for G5.NH2was then carried out by polyethylene glycol (PEG) to improve the properties of Au DENPs. Firstly, PEG monomethyl ether was connected with the terminal amino group of G5.NH2by chemical bonding to get G5.NH2-mPEG. Then, G5.NH2-mPEG dendrimers were used as templates to synthesize Au DENPs, followed by acetylation of the remaining dendrimer terminal amines to generate PEGylated Au DENPs. The partial PEGylation modification of dendrimer terminal amines allows high loading of Au within the dendrimer interior, and consequently by simply varying the Au/dendrimer molar ratio, the size of the PEGylated Au DENPs can be controlled at a range of2-4nm with a narrow size distribution. The formed PEGylated Au DENPs are water-dispersible, stable in a pH range of5-8and a temperature range of4-50℃, and non-cytotoxic at a concentration as high as50u.M. X-ray absorption coefficient measurements show that the X-ray attenuation of the PEGylated Au DENPs is much higher than that of Omnipaque (a kind of traditional CT imaging contrast agent based on iodine used for clinical diagnosis) with I (iodine) concentration similar to Au. With the sufficiently long half-decay time demonstrated by pharmacokinetics studies for blood, the PEGylated Au DENPs enabled not only X-ray CT blood pool imaging of mice and rats after intravenous injection of the particles, but also effective CT imaging of a xenograft SPC-A1tumor model in nude mice. These findings suggest that the designed PEGylated Au DENPs can be used as a promising contrast agent with enhanced biocompatibility for CT imaging of various biological systems, especially in cancer diagnosis.
At the moment, development of multifunctional nanoprobes with a targeting capability for efficient CT imaging of tumors still remains a great challenge. Herein, based on the previous research, folic acid (FA)-modified PEGylated Au DENPs were synthesized and characterized via a facile polyethylene glycol (PEG) linking strategy for in vivo targeted tumor computed tomography (CT) imaging applications. For this study, G5.NH2sequentially modified by two types of PEG moieties (PEG monomethyl ether with one end of carboxyl group (mPEG-COOH), and FA-modified PEG with one end of carboxyl groups (FA-PEG-COOH)) were used as templates to synthesize Au NPs within the dendrimer interiors, followed by acetylation of the remaining dendrimer terminal amines. The formed multifunctional Au DENPs were characterized via different techniques. Cell viability assay, flow cytometric analysis of the cell cycles, and hemolysis assay were used to assess the cytotoxicity and hemocompatibility of the particles. We show that the formed multifunctional Au DENPs are stable at different pH and temperature conditions and in different aqueous media, cytocompatible and hemocompatible in the given Au concentration range, and display much higher x-ray attenuation intensity than Omnipaque (an iodine-based CT contrast agent) under similar concentration of the active element (Au or iodine). Moreover, the developed FA-modified PEGylated Au DENPs enable targeted CT imaging of the model cancer cells with high FA receptor expression in vitro and the corresponding xenografted tumor model in vivo. These findings suggest that the designed FA-modified PEGylated Au DENPs may be used as a promising contrast agent for targeted CT imaging of tumors.
Another direction for CT imaging is to design novel CT contrast agents which contains more than one radiodense element. Therefore, we designed a facile approach to forming dendrimer-stabilized gold nanoparticles (Au DSNPs) through the use of G5.NH2modified by diatrizoic acid (G5.NH2-DTA) as stabilizers for enhanced computed tomography (CT) imaging applications. G5.NH2dendrimers were first conjugated with DTA via EDC chemistry to get G5.NH2-DTA conjugates, which were subsequently used as templates for the synthesis of Au NPs via reduction of HAuCl4in aqueous solution without additional reducing agents at room temperature. Followed by an acetylation reaction to neutralize the dendrimer remaining terminal amines, DTA-modified Au DSNPs with a mean size of6nm were formed. The formed DTA-containing [(Au0)50-G5.NHAc-DTA] DSNPs were characterized via different techniques. We show that the Au DSNPs are colloid stable in aqueous solution under different pH and temperature conditions. In vitro hemolytic assay, cytotoxicity assay, flow cytometry analysis, and cell morphology observation reveal that the formed Au DSNPs have good hemocompatibility and non-cytotoxic at a concentration up to3.0μM. X-ray absorption coefficient measurements show that the DTA-containing Au DSNPs have enhanced attenuation intensity, much higher than that of [(Au0)50-G5.NHAc] DENPs without DTA or Omnipaque at the same molar concentration of the active element (Au or I). The formed DTA-containing Au DSNPs can be used for CT imaging of cancer cells in vitro as well as for blood pool CT imaging of mice in vivo with significantly improved signal enhancement. With the two radiodense elements of Au and iodine incorporated within one particle, the formed DTA-containing Au DSNPs may be applicable for CT imaging of various biological systems with enhanced X-ray attenuation property and detection sensitivity.
Based on the above research about Au DENPs, DTA, fluorescein isothiocyanate (FITC), and FA were further ordinal modified onto the surface of [(Au0)50-G5.NH2] DENPs by covalent bond, followed by acetylation to neutralize the positive surface charge of the particles, and DTA-modified multifunctional Au DENPs with a mean size of2.6nm were formed. In vitro hemolytic assay, cell morphology observation, and cytotoxicity assay reveal that the formed Au DENPs have good hemocompatibility and non-cytotoxic at a concentration up to3000nM. X-ray absorption coefficient measurements show that the DTA-containing multifunctional Au DENPs have enhanced attenuation intensity, much higher than that of [(Au0)50-G5.NHAc] DENPs without DTA at the same molar concentration of Au. Moreover, the developed FA-modified DTA-containing multifunctional Au DENPs enable targeted CT imaging of the model SKO cells with high FA receptor expression in vitro and the corresponding xenografted tumor model in vivo. These findings suggest that the designed FA-modified DTA-containing multifunctional Au DENPs may be used as a promising contrast agent for targeted CT imaging of tumors.
In summary, this PAMAM/Au system with well X-ray attenuation will find various applications in CT imaging area.
本论文选用第五代聚酰胺-胺(Polyamidoamine,PAMAM)树状大分子(G5.NH2)作为模板制备树状大分子包裹的Au NPs (Au DENPs),并对G5.NH2的末端氨基进行乙酰化修饰以中和材料的表面电势。通过调节Au和G5.NH2的摩尔比,制备了直径在2-4nm的[(Au0)50-G5.NHAc]DENP。通过SPC-A1细胞(一种人肺癌细胞)的苏木精-曙红(HE)染色和MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)实验证实[(Au0)50-G5.NHAc] DENPs在一定浓度范围内无细胞毒性。同时,通过瘤内注射和腹腔注射的方式,考察了[(Au0)50-G5.NHAc] DENPs对SPC-A1肿瘤的荷瘤鼠肿瘤部位的CT成像效果。以上实验证实,此类乙酰化的AuDENPs在肿瘤细胞的CT成像中具有巨大的潜力。
为了改进所制备的Au DENPs的性能,利用聚乙二醇(PEG)对G5.NH2进行了修饰。首先,将PEG通过化学键合的方式修饰连接在G5.NH2的末端胺基上制备了G5.NH2-mPEG。随后,以此G5.NH2-mPEG为模板制备Au DENPs,并将末端氨基乙酰化即制备得到了PEG化的Au DENPs。PEG的修饰,提高了Au DENPs中Au的上载量,且通过调节Au/G5.NH2的摩尔比,此类PEG化的Au DENPs的尺寸分布在较窄的空间(2-4nm)。制备得到的PEG化的Au DENPs是水溶性的,且在pH=5-8和温度范围为4-50℃具有良好的稳定性,且当材料浓度达到50μM时,仍无明显的细胞毒性。通过对PEG化的Au DENPs的X-射线衰减系数的测定发现,在相同的Au和I浓度时,PEG化的Au DENPs较Omnipaque(传统的临床诊断用的含碘造CT影剂)具有更高的X-射线衰减系数。由于药代动力学的研究证明PEG化的Au DENPs具有较长的血液半衰期,故此类PEG化的Au DENPs不仅可以用于老鼠的血池造影成像,同时可以有效地用于SPC-A1移植瘤荷瘤鼠肿瘤部位的CT成像。这些结果均证实此类PEG化的Au DENPs有望被作为具有良好生物相容性的CT造影剂用于多重生物体系尤其是癌症的CT成像诊断。
目前,开发多功能对肿瘤组织靶向高效CT成像的纳米探针仍然是研发工作的一大挑战。在上述研究工作的基础上,进一步以PEG作为中间体合成并表征了叶酸(FA)修饰的PEG化的Au DENPs,并将此种造影剂用于活体荷瘤鼠肿瘤部位的CT成像。在此,依次利用两种不同的PEG(FA-PEG-COOH和mPEG-COOH)修饰在G5.NH2的表面,并以此化合物作为模板合成Au DENPs,随后对G5.NH2末端剩余的氨基进行乙酰化处理即可制备得到FA修饰的PEG化的Au DENPs。制备得到的多功能化的AuDENPs通过不同的检测手段进行了表征。通过细胞活性实验、流式细胞术检测细胞周期实验、溶血实验分别验证了所制备材料的细胞毒性和血液相容性。所制备的多功能的Au DENPs在不同pH和温度范围、不同溶剂中均具有良好的胶体稳定性,且在给定的浓度范围内具有良好的细胞相容性和血液相容性。在相同的Au和I浓度时,所制备的FA修饰的PEG化的Au DENPs较Omnipaque具有更高的X-射线衰减系数。更重要的是,此类FA修饰的PEG化的Au DENPs可以实现对高叶酸受体的癌细胞的体外靶向CT成像,同时实现对活体移植瘤荷瘤鼠肿瘤部位的靶向CT成像。以上的结果证实,此类FA修饰的PEG化的Au DENPs有望被作为造影剂用于肿瘤组织的靶向CT成像。
研究新型CT造影剂的另一个方向是如何将多种造影元素有效地结合起来。因此,我们设计利用含碘(I)造影剂泛影酸(Diatrizoic acid,DTA)修饰的G5.NH2作为稳定剂,通过温和的反应方法制备树状大分子稳定的Au NPs (Au DSNPs),并将此类造影剂用于增强CT成像的效果。首先,通过EDC将DTA修饰在G5.NH2上,并以此化合物为模板在室温且无外加还原剂的条件下,通过自还原的方法将氯金酸的水溶液还原成Au NPs,随后将G5.NH2剩余的末端氨基乙酰化中和电势,即可得到平均直径为6nm的DTA修饰的Au DSNPs ([(Au0)50-G5.NHAc-DTA] DSNPs),通过不同的方法对所制备的[(Au0)50-G5.NHAc-DTA] DSNPs进行了表征。结果证实,所制备的Au DSNPs在不同pH和温度范围内具有良好的胶体稳定性。体外溶血实验、细胞毒性实验、流式细胞检测分析和细胞形貌的观察均表明制备的Au DSNPs在材料浓度达到3μm时,仍具有良好的血液相容性和细胞相容性。在相同的Au和I浓度时,[(Au0)50-G5.NHAc-DTA] DSNPs较仅含Au的[(Au0)50-G5.NHAc] DENPs和仅含I的Omnipaque而言,具有更高的X-射线衰减系数。同时,制备的DTA修饰的Au DSNPs可以用于体外癌细胞和活体小鼠的血管CT成像,且较单一的含Au的[(Au0)50-G5.NHAc] DENPs和含I的Omnipaque在相同的Au和I浓度时,具有更好的CT成像效果。同时含有Au和I两种造影元素的DTA修饰的Au DSNPs可以增强X-射线衰减系数和检测的灵敏度,因而被用于多种生物体系的CT成像。
在以上Au DENPs研究工作的基础上,进一步将DTA、异硫氰酸酯荧光素(FITC)和FA依次通过共价键修饰在[(Au0)5o-G5.NH2] DENPs的表面并对剩余氨基乙酰化以降低材料的表面电势从而制备得到了平均粒径为2.6nm的DTA修饰的多功能化的Au DENPs。通过溶血性实验、细胞形貌观察和细胞毒性实验证实,所制备的材料在给定的浓度范围内(3000nm),具有良好的血液相容性和细胞相容性。且所制备的材料,较单一的含金造影剂([(Au0)50-G5.NHAc] DENPs)而言,在相同Au摩尔浓度时,具有更高的X-射线衰减系数。所制备的DTA修饰的多功能化的Au DENPs可以实现对具有高叶酸受体表达的SKO细胞(一种具有高叶酸受体表达的人卵巢癌细胞)体外靶向CT成像,同时实现对活体移植瘤荷瘤鼠肿瘤部位的靶向CT成像。以上的结果证实,此类FA修饰的含有DTA的多功能化的AuDENPs有望被作为造影剂用于肿瘤组织的靶向CT成像。
总之,PAMAM/Au纳米复合材料由于具有良好的X-射线衰减系数,在CT成像领域具有巨大的应用潜质。
Molecular imaging (MI) is an advanced technology in the field of medical imaging that has the ability to detect and to quantitatively measure the function of biological and cellular events in vitro and in vivo. As one of the important MI technologies, computed tomography (CT) is a reliable and widely used clinical imaging technique with high spatial and density resolution. The key component in CT imaging of biological systems is to design suitable contrast agents that have good biocompatibility, longer imaging time, and desirable imaging sensitivity and specificity. The utilization of gold nanoparticles (Au NPs) has seen an increasing potential as molecular probes for X-ray CT imaging, as they offer several advantages over conventional iodine-based agents. Dendrimers are a family of highly branched, monodispersed, synthetic macromolecules with well defined structural composition and architecture. Due to the drawbacks of clinically used iodine-based CT contrast agents (e.g., Omnipaque) such as short imaging time, renal toxicity at a high concentration, and non-specificity, the advantage of dendrimers and Au NPs were combined to systematically study the preparation, stability, biocompatibility, and X-ray attenuation characteristics of dendrimer/Au-based nanocomposites to testify their feasibility as contrast agents for CT imaging in this thesis.
In this thesis, amine-terminated generation5polyarnidoamine (PAMAM) dendrimers (G5.NH2) were used as templates to prepared dendrimer-entrapped Au NPs (Au DENPs) followed by acetylation to neutralize the positive surface charge of the particles. By varying the molar ratio of gold salt/G5dendrimer, the acetylated Au DENPs ([(Au0)50-G5.NHAc] DENPs) with a size range of2-4nm can be prepared. The cell viability of acetylated Au DENPs were tested by hematoxylin and eosin staining and MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay of a human lung adencarcinoma cell line (SPC-A1cells), and confirmed that the [(Au0)5o-G5.NHAc] DENPs have no cell toxicity at a certain concentration. Meanwhile, the xenograft SPC-A1tumor model can be imaged after both intratumoral and intraperitoneal administration of the particles. Findings from this study suggest that the developed acetylated Au DENPs have a great potential to be used for CT imaging of cancer cells.
Surface modification for G5.NH2was then carried out by polyethylene glycol (PEG) to improve the properties of Au DENPs. Firstly, PEG monomethyl ether was connected with the terminal amino group of G5.NH2by chemical bonding to get G5.NH2-mPEG. Then, G5.NH2-mPEG dendrimers were used as templates to synthesize Au DENPs, followed by acetylation of the remaining dendrimer terminal amines to generate PEGylated Au DENPs. The partial PEGylation modification of dendrimer terminal amines allows high loading of Au within the dendrimer interior, and consequently by simply varying the Au/dendrimer molar ratio, the size of the PEGylated Au DENPs can be controlled at a range of2-4nm with a narrow size distribution. The formed PEGylated Au DENPs are water-dispersible, stable in a pH range of5-8and a temperature range of4-50℃, and non-cytotoxic at a concentration as high as50u.M. X-ray absorption coefficient measurements show that the X-ray attenuation of the PEGylated Au DENPs is much higher than that of Omnipaque (a kind of traditional CT imaging contrast agent based on iodine used for clinical diagnosis) with I (iodine) concentration similar to Au. With the sufficiently long half-decay time demonstrated by pharmacokinetics studies for blood, the PEGylated Au DENPs enabled not only X-ray CT blood pool imaging of mice and rats after intravenous injection of the particles, but also effective CT imaging of a xenograft SPC-A1tumor model in nude mice. These findings suggest that the designed PEGylated Au DENPs can be used as a promising contrast agent with enhanced biocompatibility for CT imaging of various biological systems, especially in cancer diagnosis.
At the moment, development of multifunctional nanoprobes with a targeting capability for efficient CT imaging of tumors still remains a great challenge. Herein, based on the previous research, folic acid (FA)-modified PEGylated Au DENPs were synthesized and characterized via a facile polyethylene glycol (PEG) linking strategy for in vivo targeted tumor computed tomography (CT) imaging applications. For this study, G5.NH2sequentially modified by two types of PEG moieties (PEG monomethyl ether with one end of carboxyl group (mPEG-COOH), and FA-modified PEG with one end of carboxyl groups (FA-PEG-COOH)) were used as templates to synthesize Au NPs within the dendrimer interiors, followed by acetylation of the remaining dendrimer terminal amines. The formed multifunctional Au DENPs were characterized via different techniques. Cell viability assay, flow cytometric analysis of the cell cycles, and hemolysis assay were used to assess the cytotoxicity and hemocompatibility of the particles. We show that the formed multifunctional Au DENPs are stable at different pH and temperature conditions and in different aqueous media, cytocompatible and hemocompatible in the given Au concentration range, and display much higher x-ray attenuation intensity than Omnipaque (an iodine-based CT contrast agent) under similar concentration of the active element (Au or iodine). Moreover, the developed FA-modified PEGylated Au DENPs enable targeted CT imaging of the model cancer cells with high FA receptor expression in vitro and the corresponding xenografted tumor model in vivo. These findings suggest that the designed FA-modified PEGylated Au DENPs may be used as a promising contrast agent for targeted CT imaging of tumors.
Another direction for CT imaging is to design novel CT contrast agents which contains more than one radiodense element. Therefore, we designed a facile approach to forming dendrimer-stabilized gold nanoparticles (Au DSNPs) through the use of G5.NH2modified by diatrizoic acid (G5.NH2-DTA) as stabilizers for enhanced computed tomography (CT) imaging applications. G5.NH2dendrimers were first conjugated with DTA via EDC chemistry to get G5.NH2-DTA conjugates, which were subsequently used as templates for the synthesis of Au NPs via reduction of HAuCl4in aqueous solution without additional reducing agents at room temperature. Followed by an acetylation reaction to neutralize the dendrimer remaining terminal amines, DTA-modified Au DSNPs with a mean size of6nm were formed. The formed DTA-containing [(Au0)50-G5.NHAc-DTA] DSNPs were characterized via different techniques. We show that the Au DSNPs are colloid stable in aqueous solution under different pH and temperature conditions. In vitro hemolytic assay, cytotoxicity assay, flow cytometry analysis, and cell morphology observation reveal that the formed Au DSNPs have good hemocompatibility and non-cytotoxic at a concentration up to3.0μM. X-ray absorption coefficient measurements show that the DTA-containing Au DSNPs have enhanced attenuation intensity, much higher than that of [(Au0)50-G5.NHAc] DENPs without DTA or Omnipaque at the same molar concentration of the active element (Au or I). The formed DTA-containing Au DSNPs can be used for CT imaging of cancer cells in vitro as well as for blood pool CT imaging of mice in vivo with significantly improved signal enhancement. With the two radiodense elements of Au and iodine incorporated within one particle, the formed DTA-containing Au DSNPs may be applicable for CT imaging of various biological systems with enhanced X-ray attenuation property and detection sensitivity.
Based on the above research about Au DENPs, DTA, fluorescein isothiocyanate (FITC), and FA were further ordinal modified onto the surface of [(Au0)50-G5.NH2] DENPs by covalent bond, followed by acetylation to neutralize the positive surface charge of the particles, and DTA-modified multifunctional Au DENPs with a mean size of2.6nm were formed. In vitro hemolytic assay, cell morphology observation, and cytotoxicity assay reveal that the formed Au DENPs have good hemocompatibility and non-cytotoxic at a concentration up to3000nM. X-ray absorption coefficient measurements show that the DTA-containing multifunctional Au DENPs have enhanced attenuation intensity, much higher than that of [(Au0)50-G5.NHAc] DENPs without DTA at the same molar concentration of Au. Moreover, the developed FA-modified DTA-containing multifunctional Au DENPs enable targeted CT imaging of the model SKO cells with high FA receptor expression in vitro and the corresponding xenografted tumor model in vivo. These findings suggest that the designed FA-modified DTA-containing multifunctional Au DENPs may be used as a promising contrast agent for targeted CT imaging of tumors.
In summary, this PAMAM/Au system with well X-ray attenuation will find various applications in CT imaging area.
引文
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