用于鼻咽癌高效靶向诊疗的多肽—脂质纳米探针的研制
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摘要
鼻咽癌是中国南方和东南亚等地域广泛流行的高度恶性肿瘤，具有发病部位隐蔽和易于发生远处转移的特点。远处转移是鼻咽癌治疗失败的主要原因之一。目前对于局部晚期鼻咽癌主要使用以顺铂为基础的联合化疗，但是有30%以上的患者由于发生远处转移而导致治疗失败，其5年总生存率仅为25%-30%。抗EGFR单克隆抗体Cetuximab联合化疗可以一定程度提高复发或转移性鼻咽癌患者的总生存率，但尚存在着人抗鼠抗体（HAMA）反应导致的显著毒副作用问题。与小分子化疗药物相比，基于纳米载体的药物靶向运输具有延长药物的体内循环周期、提高药物的利用率、增加药物的细胞内摄取能力等优点，并在一定程度上降低了药物的毒副作用。因此，研制高效的鼻咽癌靶向纳米药物，对转移性鼻咽癌的治疗具有重要的临床应用价值。本研究取得如下创新结果：
（1）发明了一种八价多肽纳米荧光探针，可用于靶向多肽的在体评价，由此鉴定了一条鼻咽癌高特异性的靶向多肽（TTP）。具体方法是，将靶向多肽基因序列偶联到四聚体远红色荧光蛋白（tfRFP）基因序列的碳、氮两端，通过tfRFP成熟后的四聚化效应自组装形成一种八价多肽纳米荧光探针Octa-FNP。在体荧光成像证实，它对鼻咽癌5-8F皮下肿瘤具有高特异性的靶向能力、增强的富集能力和高对比度的肿瘤显像能力，因此利用Octa-FNP可以快速灵敏地评价多肽的靶向能力。本文利用此方法鉴定出一条鼻咽癌高特异性的靶向多肽LTVSPWY（TTP），并通过对125I标记的Octa-FNP进行活体放射成像，同样发现其能够高效蓄积于肿瘤组织内；
（2）发明了一种新型的同时具有鼻咽癌协同靶向增强能力和杀伤能力的多肽R4F-TTP。具体方法是将鉴定的TTP多肽与两亲性螺旋多肽R4F亲水端进行偶联。荧光显微成像和流式细胞检测结果均证实，FITC标记的R4F-TTP被5-8F细胞摄取的量是FITC标记的TTP的3.1倍，是FITC标记的R4F的10.4倍。此结果表明R4F-TTP多肽对5-8F细胞确实具有协同增强的靶向能力。碘化丙啶（PI）染色结果证实，R4F-TTP对5-8F细胞还具有选择性杀伤能力。
（3）成功研制了一种对鼻咽癌5-8F肿瘤具有高选择性靶向能力和良好治疗效果的超小粒径纳米颗粒。透射电镜和纳米粒度仪结果显示，NP-TTP是一种直径约为11nm的球形纳米颗粒。流式细胞检测结果表明，NP-TTP被5-8F细胞摄取的量是纳米颗粒NP（不含多肽TTP）的20.5倍，是NP-scrTTP（scrTTP为TTP的随机序列多肽）的3.0倍。NP-TTP表现出明显增强的鼻咽癌细胞特异性摄取能力，提示多肽TTP被呈现在纳米颗粒的表面。整体荧光成像结果证实，近红外荧光染料DiR-BOA标记的NP-TTP能够高效蓄积于鼻咽癌5-8F肿瘤内，并有效地扩散到整个肿瘤组织中，DiR-BOA的荧光信号在肿瘤组织与肝、肾等正常脏器之间具有极高的对比度。通过尾静脉连续两次隔天给药，NP-TTP对5-8F肿瘤的生长抑制率为88±7%，对5-8F-mRFP转移性肿瘤也具有明显的抑制效果。NP-TTP对肿瘤生长的这种抑制作用，被证明与其诱导细胞凋亡和自噬体形成密切相关。当NP-TTP同步装载姜黄素后，表现出更强的抑制鼻咽癌5-8F-mRFP肿瘤转移的能力，明显延长了实验小鼠的生存期。
综上所述，本文基于四聚体荧光蛋白发明了一种八价多肽纳米荧光探针，鉴定了一条鼻咽癌高特异性的靶向多肽TTP。将TTP与两亲性螺旋多肽R4F偶联所形成的杂交多肽R4F-TTP，不仅具有协同增强鼻咽癌靶向摄取和选择性杀伤的能力，还能控制脂质纳米颗粒形成及其功能。利用R4F-TTP形成的脂质纳米颗粒，具有鼻咽癌高对比度靶向成像的能力和极低毒副作用的靶向治疗效果。本研究为靶向和治疗性多肽的在体评价、肿瘤的靶向成像和诊断以及多策略治疗提供了新方法。
Nasopharyngeal carcinoma (NPC) is an epidemic malignant cancer in SouthernChina and Southeast Asia with hidden location and early distant metastasis, which resultsto its treatment failure as one of the main reasons. Cisplatin-based combinationchemotherapy remains the main treatment for locoregional advanced NPC, but over30%of patients fail with local recurrent or distant metastases in the treatment and their5-yearsurvival rate is just25%-30%. Anti-epidermal growth factor receptor (EGFR) monoclonalantibody cetuximab combined with chemotherapy improves the overall survival ofmetastatic NPC patients to some extent but still with side effects induced by humananti-mouse antibody (HAMA) response. Compared with small-molecule chemothera-peutic agents, nanocarrier-based drugs can extend the half-time of drugs in the blood,improve drugs utilization and increase intracellular concentration of drugs but with lowside effects. Thus, it is valuable in clinical applications for developing nanodrugs targetedNPC with high efficiency to treat metastatic NPC. The innovation results in this thesis canbe summarized as follows.
1) We develop an octavalent peptide fluorescent nanoprobe (Octa-FNP) which canbe used to evaluate peptides in vivo and utilize it to identify a NPC-targeting peptide TTP.This was accomplished by combining a tetrameric far-red fluorescent protein (tfRFP) as ascaffold with a tumor-targeting peptide to engineer an Octa-FNP. Whole-body imaging invivo demonstrated Octa-FNP could specifically target5-8F subcutaneous tumor withenhanced tumor accumulation and high-contrast tumor imaging which was valuable forassessing the targeting capability of peptides. We used the methods to identify aNPC-targeting peptide LTVSPWY (TTP), which could high efficiently accumulate in thetumor tissue when radioimaging with125I-labeled Octa-FNP.
2) We creat a novel NPC-targeting peptide R4F-TTP with synergistic enhancementand selective killing. It was designed by conjugating a tandem NPC-targeted peptide(LTVSPWY) with an amphipathic-helical peptide R4F. Confocal imaging and FACSanalysis demonstrated the uptake of R4F-TTP by5-8F cells after incubated24h is3.1-fold of TTP,10.4-fold of R4F, indicating R4F-TTP exhibit a synergistic effect on enhancing the targeting to5-8F cells. Propidium iodide (PI) staining further demonstratedthe selective killing tumor cells of R4F-TTP.
3) We develop a ultra-small nanocarrier for5-8F tumors with high-specific targetingand significant therapeutic effects. Both transmission electron microscopy (TEM) anddynamic light scattering (DLS) revealed NP-TTP with an average size of11nm andspherical structure. FACS analysis demonstrated the uptake of NP-TTP by5-8F cells afterincubated3h is20.5-fold of TTP,3.0-fold of R4F-scrTTP (scrTTP is the scramble peptideof TTP). The enhanced specific uptake of NP-TTP by5-8F cells suggested that targetingpeptide TTP was presented on the surface of the NP-TTP. Whole-body imagingdemonstrated NP-TTP loaded with near infrared fluorescent dyes DiR-BOA could beefficiently accumulated in the5-8F-mRFP tumor and diffused into entire tumor tissue,which resulted in extremely high contrast between the tumor tissue and normal tissues,such as liver and kidney. When administered twice every other day by post-injection,NP-TTP achieved88±7%inhibition rate in subcutaneous growth of5-8F tumors andsignificant higher survival rate when compared with PBS. The inhibition of tumor growthwas demonstrated to be related with the induction of apoptosis and autophagy formationby NP-TTP. When synchronized with curcumin, NP-TTP showed a strong preventiveeffect on5-8F metastasis.
In sumarry, we invented an octavalent peptide fluorescent nanoprobe based ontetrameric far-red fluorescent protein and used it to identify a target-specific peptide TTPfor NPC. Conjugating the TTP peptide with an amphipathic-helical peptide R4F createda novel NPC-targeting peptide R4F-TTP, which not only synergistically enhance thetarget-specific cellular upatke by5-8F cells and their selective killing, but only can controlthe formation of lipid nanoparticles and their function. The novel lipid nanoparticle couldachieve high-contrast imaging in vivo and therapeutic effects for5-8F tumors. This studyprovides new methods for the evaluation in vivo of therapeutic and targeted peptides,tumor-targeted imaging for diagnosis and multi-targeted therapies for cancer treatment.
（1）发明了一种八价多肽纳米荧光探针，可用于靶向多肽的在体评价，由此鉴定了一条鼻咽癌高特异性的靶向多肽（TTP）。具体方法是，将靶向多肽基因序列偶联到四聚体远红色荧光蛋白（tfRFP）基因序列的碳、氮两端，通过tfRFP成熟后的四聚化效应自组装形成一种八价多肽纳米荧光探针Octa-FNP。在体荧光成像证实，它对鼻咽癌5-8F皮下肿瘤具有高特异性的靶向能力、增强的富集能力和高对比度的肿瘤显像能力，因此利用Octa-FNP可以快速灵敏地评价多肽的靶向能力。本文利用此方法鉴定出一条鼻咽癌高特异性的靶向多肽LTVSPWY（TTP），并通过对125I标记的Octa-FNP进行活体放射成像，同样发现其能够高效蓄积于肿瘤组织内；
（2）发明了一种新型的同时具有鼻咽癌协同靶向增强能力和杀伤能力的多肽R4F-TTP。具体方法是将鉴定的TTP多肽与两亲性螺旋多肽R4F亲水端进行偶联。荧光显微成像和流式细胞检测结果均证实，FITC标记的R4F-TTP被5-8F细胞摄取的量是FITC标记的TTP的3.1倍，是FITC标记的R4F的10.4倍。此结果表明R4F-TTP多肽对5-8F细胞确实具有协同增强的靶向能力。碘化丙啶（PI）染色结果证实，R4F-TTP对5-8F细胞还具有选择性杀伤能力。
（3）成功研制了一种对鼻咽癌5-8F肿瘤具有高选择性靶向能力和良好治疗效果的超小粒径纳米颗粒。透射电镜和纳米粒度仪结果显示，NP-TTP是一种直径约为11nm的球形纳米颗粒。流式细胞检测结果表明，NP-TTP被5-8F细胞摄取的量是纳米颗粒NP（不含多肽TTP）的20.5倍，是NP-scrTTP（scrTTP为TTP的随机序列多肽）的3.0倍。NP-TTP表现出明显增强的鼻咽癌细胞特异性摄取能力，提示多肽TTP被呈现在纳米颗粒的表面。整体荧光成像结果证实，近红外荧光染料DiR-BOA标记的NP-TTP能够高效蓄积于鼻咽癌5-8F肿瘤内，并有效地扩散到整个肿瘤组织中，DiR-BOA的荧光信号在肿瘤组织与肝、肾等正常脏器之间具有极高的对比度。通过尾静脉连续两次隔天给药，NP-TTP对5-8F肿瘤的生长抑制率为88±7%，对5-8F-mRFP转移性肿瘤也具有明显的抑制效果。NP-TTP对肿瘤生长的这种抑制作用，被证明与其诱导细胞凋亡和自噬体形成密切相关。当NP-TTP同步装载姜黄素后，表现出更强的抑制鼻咽癌5-8F-mRFP肿瘤转移的能力，明显延长了实验小鼠的生存期。
综上所述，本文基于四聚体荧光蛋白发明了一种八价多肽纳米荧光探针，鉴定了一条鼻咽癌高特异性的靶向多肽TTP。将TTP与两亲性螺旋多肽R4F偶联所形成的杂交多肽R4F-TTP，不仅具有协同增强鼻咽癌靶向摄取和选择性杀伤的能力，还能控制脂质纳米颗粒形成及其功能。利用R4F-TTP形成的脂质纳米颗粒，具有鼻咽癌高对比度靶向成像的能力和极低毒副作用的靶向治疗效果。本研究为靶向和治疗性多肽的在体评价、肿瘤的靶向成像和诊断以及多策略治疗提供了新方法。
Nasopharyngeal carcinoma (NPC) is an epidemic malignant cancer in SouthernChina and Southeast Asia with hidden location and early distant metastasis, which resultsto its treatment failure as one of the main reasons. Cisplatin-based combinationchemotherapy remains the main treatment for locoregional advanced NPC, but over30%of patients fail with local recurrent or distant metastases in the treatment and their5-yearsurvival rate is just25%-30%. Anti-epidermal growth factor receptor (EGFR) monoclonalantibody cetuximab combined with chemotherapy improves the overall survival ofmetastatic NPC patients to some extent but still with side effects induced by humananti-mouse antibody (HAMA) response. Compared with small-molecule chemothera-peutic agents, nanocarrier-based drugs can extend the half-time of drugs in the blood,improve drugs utilization and increase intracellular concentration of drugs but with lowside effects. Thus, it is valuable in clinical applications for developing nanodrugs targetedNPC with high efficiency to treat metastatic NPC. The innovation results in this thesis canbe summarized as follows.
1) We develop an octavalent peptide fluorescent nanoprobe (Octa-FNP) which canbe used to evaluate peptides in vivo and utilize it to identify a NPC-targeting peptide TTP.This was accomplished by combining a tetrameric far-red fluorescent protein (tfRFP) as ascaffold with a tumor-targeting peptide to engineer an Octa-FNP. Whole-body imaging invivo demonstrated Octa-FNP could specifically target5-8F subcutaneous tumor withenhanced tumor accumulation and high-contrast tumor imaging which was valuable forassessing the targeting capability of peptides. We used the methods to identify aNPC-targeting peptide LTVSPWY (TTP), which could high efficiently accumulate in thetumor tissue when radioimaging with125I-labeled Octa-FNP.
2) We creat a novel NPC-targeting peptide R4F-TTP with synergistic enhancementand selective killing. It was designed by conjugating a tandem NPC-targeted peptide(LTVSPWY) with an amphipathic-helical peptide R4F. Confocal imaging and FACSanalysis demonstrated the uptake of R4F-TTP by5-8F cells after incubated24h is3.1-fold of TTP,10.4-fold of R4F, indicating R4F-TTP exhibit a synergistic effect on enhancing the targeting to5-8F cells. Propidium iodide (PI) staining further demonstratedthe selective killing tumor cells of R4F-TTP.
3) We develop a ultra-small nanocarrier for5-8F tumors with high-specific targetingand significant therapeutic effects. Both transmission electron microscopy (TEM) anddynamic light scattering (DLS) revealed NP-TTP with an average size of11nm andspherical structure. FACS analysis demonstrated the uptake of NP-TTP by5-8F cells afterincubated3h is20.5-fold of TTP,3.0-fold of R4F-scrTTP (scrTTP is the scramble peptideof TTP). The enhanced specific uptake of NP-TTP by5-8F cells suggested that targetingpeptide TTP was presented on the surface of the NP-TTP. Whole-body imagingdemonstrated NP-TTP loaded with near infrared fluorescent dyes DiR-BOA could beefficiently accumulated in the5-8F-mRFP tumor and diffused into entire tumor tissue,which resulted in extremely high contrast between the tumor tissue and normal tissues,such as liver and kidney. When administered twice every other day by post-injection,NP-TTP achieved88±7%inhibition rate in subcutaneous growth of5-8F tumors andsignificant higher survival rate when compared with PBS. The inhibition of tumor growthwas demonstrated to be related with the induction of apoptosis and autophagy formationby NP-TTP. When synchronized with curcumin, NP-TTP showed a strong preventiveeffect on5-8F metastasis.
In sumarry, we invented an octavalent peptide fluorescent nanoprobe based ontetrameric far-red fluorescent protein and used it to identify a target-specific peptide TTPfor NPC. Conjugating the TTP peptide with an amphipathic-helical peptide R4F createda novel NPC-targeting peptide R4F-TTP, which not only synergistically enhance thetarget-specific cellular upatke by5-8F cells and their selective killing, but only can controlthe formation of lipid nanoparticles and their function. The novel lipid nanoparticle couldachieve high-contrast imaging in vivo and therapeutic effects for5-8F tumors. This studyprovides new methods for the evaluation in vivo of therapeutic and targeted peptides,tumor-targeted imaging for diagnosis and multi-targeted therapies for cancer treatment.
引文
[1] Ma BB, Chan AT. Systemic treatment strategies and therapeutic monitoring foradvanced nasopharyngeal carcinoma. Expert Rev Anticancer Ther,2006,6(3):383-394.
[2] Tao Q, Chan AT. Nasopharyngeal carcinoma: molecular pathogenesis andtherapeutic developments. Expert Rev Mol Med,2007,9(12):1-24.
[3] Razak AR, Siu LL, Liu FF, et al. Nasopharyngeal carcinoma: the next challenges.Eur J Cancer,2010,46(11):1967-1978.
[4] Geara FB, Sanguineti G, Tucker SL, et al. Carcinoma of the nasopharynx treated byradiotherapy alone: determinants of distant metastasis and survival. RadiotherOncol,1997,43(1):53-61.
[5] King AD, Vlantis AC, Bhatia KSS, et al. Primary Nasopharyngeal Carcinoma:Diagnostic Accuracy of MR Imaging versus that of Endoscopy and EndoscopicBiopsy. Radiology,2011,258(2):531-537.
[6] Wen YH, Wen WP, Chen HX, et al. Endoscopic nasopharyngectomy for salvage innasopharyngeal carcinoma: a novel anatomic orientation. Laryngoscope,2010,120(7):1298-1302.
[7] Abdel Khalek Abdel Razek A, King A. MRI and CT of nasopharyngeal carcinoma.AJR Am J Roentgenol,2012,198(1):11-18.
[8] Manavis J, Sivridis L, Koukourakis MI. Nasopharyngeal carcinoma: the impact ofCT-scan and of MRI on staging, radiotherapy treatment planning, and outcome ofthe disease. Clin Imaging,2005,29(2):128-133.
[9] Suarez C, Rodrigo JP, Rinaldo A, et al. Current treatment options for recurrentnasopharyngeal cancer. Eur Arch Otorhinolaryngol,2010,267(12):1811-1824.
[10] Chan ATC. Nasopharyngeal carcinoma. Ann Oncol,2010,21(7):308-312.
[11] Ng SH, Chan SC, Yen TC, et al. Staging of untreated nasopharyngeal carcinomawith PET/CT: comparison with conventional imaging work-up. Eur J Nucl MedMol Imaging,2009,36(3):538-538.
[12] Baujat B, Audry H, Bourhis J, et al. Chemotherapy in locally advancednasopharyngeal carcinoma: an individual patient data meta-analysis of eightrandomized trials and1753patients. Int J Radiat Oncol Biol Phys,2006,64(1):47-56.
[13] Xiao WW, Huang SM, Han F, et al. Local control, survival, and late toxicities oflocally advanced nasopharyngeal carcinoma treated by simultaneous modulatedaccelerated radiotherapy combined with cisplatin concurrent chemotherapy:long-term results of a phase2study. Cancer,2011,117(9):1874-1883.
[14] Hui EP, Leung SF, Au JS, et al. Lung metastasis alone in nasopharyngealcarcinoma: a relatively favorable prognostic group. Cancer,2004,101(2):300-306.
[15] Chen MY, Wen WP, Guo X, et al. Endoscopic nasopharyngectomy for locallyrecurrent nasopharyngeal carcinoma. Laryngoscope,2009,119(3):516-522.
[16] Leemans CR, Braakhuis BJM, Brakenhoff RH. The molecular biology of head andneck cancer. Nat Rev Cancer,2011,11(1):9-22.
[17] Bensouda Y, Kaikani W, Ahbeddou N, et al. Treatment for metastaticnasopharyngeal carcinoma. Eur Ann Otorhinolaryngol Head Neck Dis,2011,128(2):79-85.
[18] Bei JX, Li Y, Jia WH, et al. A genome-wide association study of nasopharyngealcarcinoma identifies three new susceptibility loci. Nat Genet,2010,42(7):599-603.
[19] Wai Pak M, To KF, Lee JC, et al. In vivo real-time diagnosis of nasopharyngealcarcinoma in situ by contact rhinoscopy. Head Neck,2005,27(11):1008-1013.
[20] Pathmanathan R, Prasad U, Sadler R, et al. Clonal proliferations of cells infectedwith Epstein-Barr virus in preinvasive lesions related to nasopharyngeal carcinoma.N Engl J Med,1995,333(11):693-698.
[21] Cao SM, Liu Z, Jia WH, et al. Fluctuations of epstein-barr virus serologicalantibodies and risk for nasopharyngeal carcinoma: a prospective screening studywith a20-year follow-up. PLoS One,2011,6(4): e19100.
[22] Xu LY, Pan JJ, Wu JX, et al. Factors associated with overall survival in1706patients with nasopharyngeal carcinoma: Significance of intensive neoadjuvantchemotherapy and radiation break. Radiother Oncol,2010,96(1):94-99.
[23] Chan YW, Chow VL, Wei WI. Quality of life of patients after salvagenasopharyngectomy for recurrent nasopharyngeal carcinoma. Cancer,2012,118(15):3710-3718.
[24] Ma BBY, Poon TCW, To KF, et al. Prognostic significance of tumor angiogenesis,Ki67, p53oncoprotein, epidermal growth factor receptor and HER2receptorprotein expression in undifferentiated nasopharyngeal carcinoma-A prospectivestudy. Head Neck,2003,25(10):864-872.
[25] Wykosky J, Fenton T, Furnari F, et al. Therapeutic targeting of epidermal growthfactor receptor in human cancer: successes and limitations. Chin J Cancer,2011,30(1):5-12.
[26] Naji F, Attaleb M, Laantri N, et al. Identification of G2607A mutation in EGFRgene with a significative rate in Moroccan patients with nasopharyngeal carcinoma.Cell Mol Biol,2010,56(15): OL1442-1446.
[27] Schrama D, Reisfeld RA, Becker JC. Antibody targeted drugs as cancertherapeutics. Nat Rev Drug Discov,2006,5(2):147-159.
[28] Adams GP, Weiner LM. Monoclonal antibody therapy of cancer. Nat Biotechnol,2005,23(9):1147-1157.
[29] Chan ATC, Hsu MM, Goh BC, et al. Multicenter, phase II study of cetuximab incombination with carboplatin in patients with recurrent or metastaticnasopharyngeal carcinoma. J Clin Oncol,2005,23(15):3568-3576.
[30] Ma BB, Kam MK, Leung SF, et al. A phase II study of concurrentcetuximab-cisplatin and intensity-modulated radiotherapy in locoregionallyadvanced nasopharyngeal carcinoma. Ann Oncol,2012,23(5):1287-1292.
[31] Chua DTT, Wei WI, Wong MP, et al. Phase II study of gefitinib for the treatment ofrecurrent and metastatic nasopharyngeal carcinoma. Head Neck,2008,30(7):863-867.
[32] Krishna SM, James S, Balaram P. Expression of VEGF as prognosticator in primarynasopharyngeal cancer and its relation to EBV status. Virus Res,2006,115(1):85-90.
[33] Li YH, Hu CF, Shao Q, et al. Elevated expressions of survivin and VEGF proteinare strong independent predictors of survival in advanced nasopharyngealcarcinoma. J Transl Med,2008,6(1):1-11.
[34] Stevenson D, Charalambous C, Wilson JB. Epstein-Barr virus latent membraneprotein1(CAO) up-regulates VEGF and TGF alpha concomitant with hyperlasia,with subsequent up-regulation of p16and MMP9. Cancer Res,2005,65(19):8826-8835.
[35] O'Neil JD, Owen TJ, Wood VHJ, et al. Epstein-Barr virus-encoded EBNA1modulates the AP-1transcription factor pathway in nasopharyngeal carcinoma cellsand enhances angiogenesis in vitro. J Gen Virol,2008,89(11):2833-2842.
[36] Lee NY, Zhang Q, Pfister DG, et al. Addition of bevacizumab to standardchemoradiation for locoregionally advanced nasopharyngeal carcinoma (RTOG0615): a phase2multi-institutional trial. Lancet Oncol,2012,13(2):172-180.
[37] Salama JK, Haraf DJ, Stenson KM, et al. A randomized phase II study of5-fluorouracil, hydroxyurea, and twice-daily radiotherapy compared withbevacizumab plus5-fluorouracil, hydroxyurea, and twice-daily radiotherapy forintermediate-stage and T4N0-1head and neck cancers. Ann Oncol,2011,22(10):2304-2309.
[38] Elser C, Siu LL, Winquist E, et al. Phase II trial of sorafenib in patients withrecurrent or metastatic squamous cell carcinoma of the head and neck ornasopharyngeal carcinoma. J Clin Oncol,2007,25(24):3766-3773.
[39] Tan KB, Putti TC. Cyclooxygenase2expression in nasopharyngeal carcinoma:immunohistochemical findings and potential implications. J Clin Pathol,2005,58(5):535-538.
[40] Soo R, Putti T, Tao Q, et al. Overexpression of cyclooxygenase-2innasopharyngeal carcinoma and association with epidermal growth factor receptorexpression. Arch Otolaryngol,2005,131(2):147-152.
[41] Liu DB, Hu GY, Long GX, et al. Celecoxib induces apoptosis and cell-cycle arrestin nasopharyngeal carcinoma cell lines via inhibition of STAT3phosphorylation.Acta Pharmacol Sin,2012,33(5):682-690.
[42] Soo RA, Wu J, Aggarwal A, et al. Celecoxib reduces microvessel density inpatients treated with nasopharyngeal carcinoma and induces changes in geneexpression. Ann Oncol,2006,17(11):1625-1630.
[43] Pan J, Tang T, Xu L, et al. Prognostic significance of expression ofcyclooxygenase-2, vascular endothelial growth factor, and epidermal growth factorreceptor in nasopharyngeal carcinoma. Head Neck,2012.
[44] Allen TM. Ligand-targeted therapeutics in anticancer therapy. Nat Rev Cancer,2002,2(10):750-763.
[45] Nelson AL, Dhimolea E, Reichert JM. Development trends for human monoclonalantibody therapeutics. Nat Rev Drug Discov,2010,9(10):767-774.
[46] Dasgupta P, Sun J, Wang S, et al. Disruption of the Rb--Raf-1interaction inhibitstumor growth and angiogenesis. Mol Cell Biol,2004,24(21):9527-9541.
[47] Jia WD, Xu GL, Xu RN, et al. Octreotide acts as an antitumor angiogenesiscompound and suppresses tumor growth in nude mice bearing human hepatocellularcarcinoma xenografts. J Cancer Res Clin Oncol,2003,129(6):327-334.
[48] Kondo E, Seto M, Yoshikawa K, et al. Highly efficient delivery of p16antitumorpeptide into aggressive leukemia/lymphoma cells using a novel transporter system.Mol Cancer Ther,2004,3(12):1623-1630.
[49] Florio T, Morini M, Villa V, et al. Somatostatin inhibits tumor angiogenesis andgrowth via somatostatin receptor-3-mediated regulation of endothelial nitric oxidesynthase and mitogen-activated protein kinase activities. Endocrinology,2003,144(4):1574-1584.
[50] Alba A, Lopez-Abarrategui C, Otero-Gonzalez AJ. Host defense peptides: Analternative as antiinfective and immunomodulatory therapeutics. Biopolymers,2012,98(4):251-267.
[51] Hancock RE, Sahl HG. Antimicrobial and host-defense peptides as newanti-infective therapeutic strategies. Nat Biotechnol,2006,24(12):1551-1557.
[52] Fjell CD, Hiss JA, Hancock RE, et al. Designing antimicrobial peptides: formfollows function. Nat Rev Drug Discov,2012,11(1):37-51.
[53] Pasupuleti M, Schmidtchen A, Malmsten M. Antimicrobial peptides: keycomponents of the innate immune system. Crit Rev Biotechnol,2012,32(2):143-171.
[54] Dawson MJ, Scott RW. New horizons for host defense peptides and lantibiotics.Curr Opin Pharmacol,2012,12(5):545-550.
[55] Franzman MR, Burnell KK, Dehkordi-Vakil FH, et al. Targeted antimicrobialactivity of a specific IgG-SMAP28conjugate against Porphyromonas gingivalis in amixed culture. Int J Antimicrob Agents,2009,33(1):14-20.
[56] Eckert R, He J, Yarbrough DK, et al. Targeted killing of Streptococcus mutans by apheromone-guided "smart" antimicrobial peptide. Antimicrob Agents Ch,2006,50(11):3651-3657.
[57] Yount NY, Yeaman MR. Emerging themes and therapeutic prospects foranti-infective peptides. Annu Rev Pharmacol Toxicol,2012,52(1):337-360.
[58] Zasloff M. Antimicrobial peptides of multicellular organisms. Nature,2002,415(6870):389-395.
[59] Agemy L, Friedmann-Morvinski D, Kotamraju VR, et al. Targeted nanoparticleenhanced proapoptotic peptide as potential therapy for glioblastoma. Proc NatlAcad Sci U S A,2011,108(42):17450-17455.
[60] Devocelle M. Targeted antimicrobial peptides. Front Immunol,2012,(3):309.
[61] Okarvi SM. Peptide-based radiopharmaceuticals: future tools for diagnosticimaging of cancers and other diseases. Med Res Rev,2004,24(3):357-397.
[62] Ahrens VM, Bellmann-Sickert K, Beck-Sickinger AG. Peptides and peptideconjugates: therapeutics on the upward path. Future Med Chem,2012,4(12):1567-1586.
[63] Han Z, Fu A, Wang H, et al. Noninvasive assessment of cancer response to therapy.Nat Med,2008,14(3):343-349.
[64] Morris MC, Depollier J, Mery J, et al. A peptide carrier for the delivery ofbiologically active proteins into mammalian cells. Nat Biotechnol,2001,19(12):1173-1176.
[65] Pasqualini R, Koivunen E, Ruoslahti E. Alpha v integrins as receptors for tumortargeting by circulating ligands. Nat Biotechnol,1997,15(6):542-546.
[66] Arap W, Pasqualini R, Ruoslahti E. Cancer treatment by targeted drug delivery totumor vasculature in a mouse model. Science,1998,279(5349):377-380.
[67] Laakkonen P, Akerman ME, Biliran H, et al. Antitumor activity of a homingpeptide that targets tumor lymphatics and tumor cells. Proc Natl Acad Sci U S A,2004,101(25):9381-9386.
[68] Ullman CG, Frigotto L, Cooley RN. In vitro methods for peptide display and theirapplications. Brief Funct Genomic,2011,10(3):125-134.
[69] Wu HC, Chang DK. Peptide-mediated liposomal drug delivery system targetingtumor blood vessels in anticancer therapy. J Oncol,2010,(2010):723798.
[70] Szardenings M. Phage display of random peptide libraries: Applications, limits, andpotential. J Recept Sig Transd,2003,23(4):307-349.
[71] Molek P, Strukelj B, Bratkovic T. Peptide Phage Display as a Tool for DrugDiscovery: Targeting Membrane Receptors. Molecules,2011,16(1):857-887.
[72] Tu XG, Zhuang JT, Wang WW, et al. Screening and identification of a renalcarcinoma specific peptide from a phage display peptide library. J Exp Clin CancRes,2012,31(13):105-106.
[73] Shadidi M, Sioud M. Identification of novel carrier peptides for the specificdelivery of therapeutics into cancer cells. FASEB J,2003,17(2):256-258.
[74] Mammen M, Choi SK, Whitesides GM. Polyvalent interactions in biologicalsystems: Implications for design and use of multivalent ligands and inhibitors.Angew Chem Int Edit,1998,37(20):2755-2794.
[75] Jiang W, Kim BY, Rutka JT, et al. Nanoparticle-mediated cellular response issize-dependent. Nat Nanotechnol,2008,3(3):145-150.
[76] Cho K, Wang X, Nie S, et al. Therapeutic nanoparticles for drug delivery in cancer.Clin Cancer Res,2008,14(5):1310-1316.
[77] Peer D, Karp JM, Hong S, et al. Nanocarriers as an emerging platform for cancertherapy. Nat Nanotechnol,2007,2(12):751-760.
[78] Davis ME, Chen ZG, Shin DM. Nanoparticle therapeutics: an emerging treatmentmodality for cancer. Nat Rev Drug Discov,2008,7(9):771-782.
[79] Zhang L, Gu FX, Chan JM, et al. Nanoparticles in medicine: therapeuticapplications and developments. Clin Pharmacol Ther,2008,83(5):761-769.
[80] Alexis F, Pridgen EM, Langer R, et al. Nanoparticle technologies for cancer therapy.Handb Exp Pharmacol,2010,(197):55-86.
[81] Lammers T, Hennink WE, Storm G. Tumour-targeted nanomedicines: principlesand practice. Br J Cancer,2008,99(3):392-397.
[82] Egusquiaguirre SP, Igartua M, Hernandez RM, et al. Nanoparticle delivery systemsfor cancer therapy: advances in clinical and preclinical research. Clin Transl Oncol,2012,14(2):83-93.
[83] Petros RA, DeSimone JM. Strategies in the design of nanoparticles for therapeuticapplications. Nat Rev Drug Discov,2010,9(8):615-627.
[84] Hrkach J, Von Hoff D, Mukkaram Ali M, et al. Preclinical development and clinicaltranslation of a PSMA-targeted docetaxel nanoparticle with a differentiatedpharmacological profile. Sci Transl Med,2012,4(128):128ra139.
[85] MacKay JA, Chen M, McDaniel JR, et al. Self-assembling chimericpolypeptide-doxorubicin conjugate nanoparticles that abolish tumours after a singleinjection. Nat Mater,2009,8(12):993-999.
[86] Choi HS, Liu W, Misra P, et al. Renal clearance of quantum dots. Nat Biotechnol,2007,25(10):1165-1170.
[87] Nomura T, Koreeda N, Yamashita F, et al. Effect of particle size and charge on thedisposition of lipid carriers after intratumoral injection into tissue-isolated tumors.Pharm Res,1998,15(1):128-132.
[88] Cabral H, Matsumoto Y, Mizuno K, et al. Accumulation of sub-100nm polymericmicelles in poorly permeable tumours depends on size. Nat Nanotechnol,2011,6(12):815-823.
[89] Pluen A, Boucher Y, Ramanujan S, et al. Role of tumor-host interactions ininterstitial diffusion of macromolecules: cranial vs. subcutaneous tumors. Proc NatlAcad Sci U S A,2001,98(8):4628-4633.
[90] Alexandrakis G, Brown EB, Tong RT, et al. Two-photon fluorescence correlationmicroscopy reveals the two-phase nature of transport in tumors. Nat Med,2004,10(2):203-207.
[91] Ramanujan S, Pluen A, McKee TD, et al. Diffusion and convection in collagen gels:implications for transport in the tumor interstitium. Biophys J,2002,83(3):1650-1660.
[92] Scott JE. Extracellular matrix, supramolecular organisation and shape. J Anat,1995,187(2):259-269.
[93] Rothenfluh DA, Bermudez H, O'Neil CP, et al. Biofunctional polymer nanoparticlesfor intra-articular targeting and retention in cartilage. Nat Mater,2008,7(3):248-254.
[94] Jain RK, Stylianopoulos T. Delivering nanomedicine to solid tumors. Nat Rev ClinOncol,2010,7(11):653-664.
[95] Geng Y, Dalhaimer P, Cai S, et al. Shape effects of filaments versus sphericalparticles in flow and drug delivery. Nat Nanotechnol,2007,2(4):249-255.
[96] Cho EC, Zhang Q, Xia Y. The effect of sedimentation and diffusion on cellularuptake of gold nanoparticles. Nat Nanotechnol,2011,6(6):385-391.
[97] Barua S, Yoo JW, Kolhar P, et al. Particle shape enhances specificity ofantibody-displaying nanoparticles. Proc Natl Acad Sci U S A,2013,110(9):3270-3275.
[98] Zhao D, Sun XC, Tong JL, et al. A novel multifunctional nanocompositeC225-conjugated Fe3O4/Ag enhances the sensitivity of nasopharyngeal carcinomacells to radiotherapy. Acta Bioch Bioph Sin,2012,44(8):678-684.
[99] Lee TY, Wu HC, Tseng YL, et al. A novel peptide specifically binding tonasopharyngeal carcinoma for targeted drug delivery. Cancer Res,2004,64(21):8002-8008.
[100] Chen YC, Min CN, Wu HC, et al. In vitro evaluation of the L-peptide modifiedmagnetic lipid nanoparticles as targeted magnetic resonance imaging contrast agentfor the nasopharyngeal cancer. J Biomater Appl,2012, Epub ahead of print.
[101] Wasan KM, Brocks DR, Lee SD, et al. Impact of lipoproteins on the biologicalactivity and disposition of hydrophobic drugs: implications for drug discovery. NatRev Drug Discov,2008,7(1):84-99.
[102] Acton S, Rigotti A, Landschulz KT, et al. Identification of scavenger receptorSR-BI as a high density lipoprotein receptor. Science,1996,271(5248):518-520.
[103] Mooberry LK, Nair M, Paranjape S, et al. Receptor mediated uptake of paclitaxelfrom a synthetic high density lipoprotein nanocarrier. J Drug Target,2010,18(1):53-58.
[104] Cormode DP, Skajaa T, van Schooneveld MM, et al. Nanocrystal CoreHigh-Density Lipoproteins: A Multimodality Contrast Agent Platform. Nano Lett,2008,8(11):3715-3723.
[105] Nykiforuk CL, Shen Y, Murray EW, et al. Expression and recovery of biologicallyactive recombinant Apolipoprotein AI(Milano) from transgenic safflower(Carthamus tinctorius) seeds. Plant Biotechnol J,2011,9(2):250-263.
[106] Zhang Z, Cao W, Jin H, et al. Biomimetic nanocarrier for direct cytosolic drugdelivery. Angew Chem Int Ed Engl,2009,48(48):9171-9175.
[107] Zhang Z, Chen J, Ding L, et al. HDL-mimicking peptide-lipid nanoparticles withimproved tumor targeting. Small,2010,6(3):430-437.
[108] Yang M, Chen J, Cao WG, et al. Attenuation of nontargeted cell-kill using ahigh-density lipoprotein-mimicking peptide phospholipid nanoscaffold.Nanomedicine,2011,6(4):631-641.
[109] Cao W, Ng KK, Corbin I, et al. Synthesis and evaluation of a stablebacteriochlorophyll-analog and its incorporation into high-density lipoproteinnanoparticles for tumor imaging. Bioconjug Chem,2009,20(11):2023-2031.
[110] Ng KK, Lovell JF, Zheng G. Lipoprotein-Inspired Nanoparticles for CancerTheranostics. Accounts Chem Res,2011,44(10):1105-1113.
[111] Pande J, Szewczyk MM, Grover AK. Phage display: Concept, innovations,applications and future. Biotechnol Adv,2010,28(6):849-858.
[112] Uchiyama F, Tanaka Y, Minari Y, et al. Designing scaffolds of peptides for phagedisplay libraries. J Biosci Bioeng,2005,99(5):448-456.
[113] Borghouts C, Kunz C, Groner B. Current strategies for the development ofpeptide-based anti-cancer therapeutics. J Pept Sci,2005,11(11):713-726.
[114] Cyranka-Czaja A, Otlewski J. A novel, stable, helical scaffold as an alternativebinder-construction of phage display libraries. Acta Biochim Pol,2012,59(3):383-390.
[115] Rizzo MA, Davidson MW, Piston DW. Fluorescent protein tracking and detection:applications using fluorescent proteins in living cells. Cold Spring Harb Protoc,2009,2009(12): pdb top64.
[116] Fradkov AF, Chen Y, Ding L, et al. Novel fluorescent protein from Discosomacoral and its mutants possesses a unique far-red fluorescence. Febs Lett,2000,479(3):127-130.
[117] Shcherbo D, Merzlyak EM, Chepurnykh TV, et al. Bright far-red fluorescentprotein for whole-body imaging. Nat Methods,2007,4(9):741-746.
[118] Shcherbo D, Murphy CS, Ermakova GV, et al. Far-red fluorescent tags for proteinimaging in living tissues. Biochem J,2009,418(3):567-574.
[119] Lin MZ, McKeown MR, Ng HL, et al. Autofluorescent proteins with excitation inthe optical window for intravital imaging in mammals. Chem Biol,2009,16(11):1169-1179.
[120] Kredel S, Nienhaus K, Oswald F, et al. Optimized and far-red-emitting variants offluorescent protein eqFP611. Chem Biol,2008,15(3):224-233.
[121] Morozova KS, Piatkevich KD, Gould TJ, et al. Far-red fluorescent protein excitablewith red lasers for flow cytometry and superresolution STED nanoscopy. Biophys J,2010,99(2): L13-15.
[122] Shu X, Royant A, Lin MZ, et al. Mammalian expression of infrared fluorescentproteins engineered from a bacterial phytochrome. Science,2009,324(5928):804-807.
[123] Shcherbo D, Shemiakina, II, Ryabova AV, et al. Near-infrared fluorescent proteins.Nat Methods,2010,7(10):827-829.
[124] Filonov GS, Piatkevich KD, Ting LM, et al. Bright and stable near-infraredfluorescent protein for in vivo imaging. Nat Biotechnol,2011,29(8):757-761.
[125] Lecoq J, Schnitzer MJ. An infrared fluorescent protein for deeper imaging. NatBiotechnol,2011,29(8):715-716.
[126] Jiang W, Kim BYS, Rutka JT, et al. Nanoparticle-mediated cellular response issize-dependent. Nat Nanotechnol,2008,3(3):145-150.
[127] Kelloff GJ, Hoffman JM, Johnson B, et al. Progress and promise of FDG-PETimaging for cancer patient management and oncologic drug development. ClinCancer Res,2005,11(8):2785-2808.
[128] Chen K, Chen X. Positron emission tomography imaging of cancer biology: currentstatus and future prospects. Semin Oncol,2011,38(1):70-86.
[129] Khalil MM, Tremoleda JL, Bayomy TB, et al. Molecular SPECT Imaging: AnOverview. Int J Mol Imaging,2011,796025-796015.
[130] Cai W, Olafsen T, Zhang X, et al. PET imaging of colorectal cancer inxenograft-bearing mice by use of an18F-labeled T84.66anti-carcinoembryonicantigen diabody. J Nucl Med,2007,48(2):304-310.
[131] Wu AM, Senter PD. Arming antibodies: prospects and challenges forimmunoconjugates. Nat Biotechnol,2005,23(9):1137-1146.
[132] Okarvi SM. Peptide-based radiopharmaceuticals and cytotoxic conjugates: potentialtools against cancer. Cancer Treat Rev,2008,34(1):13-26.
[133] Wu AM, Yazaki PJ, Tsai S, et al. High-resolution microPET imaging ofcarcinoembryonic antigen-positive xenografts by using a copper-64-labeledengineered antibody fragment. Proc Natl Acad Sci U S A,2000,97(15):8495-8500.
[134] Zhang R, Xiong C, Huang M, et al. Peptide-conjugated polymeric micellarnanoparticles for Dual SPECT and optical imaging of EphB4receptors in prostatecancer xenografts. Biomaterials,2011,32(25):5872-5879.
[135] Shi J, Wang L, Kim YS, et al. Improving tumor uptake and excretion kinetics of99mTc-labeled cyclic arginine-glycine-aspartic (RGD) dimers with triglycinelinkers. J Med Chem,2008,51(24):7980-7990.
[136] Harris TD, Kalogeropoulos S, Nguyen T, et al. Structure-activity relationships of111In-and99mTc-labeled quinolin-4-one peptidomimetics as ligands for thevitronectin receptor: potential tumor imaging agents. Bioconjug Chem,2006,17(5):1294-1313.
[137] Jiang L, Kimura RH, Miao Z, et al. Evaluation of a (64)Cu-labeled cystine-knotpeptide based on agouti-related protein for PET of tumors expressing alphavbeta3integrin. J Nucl Med,2010,51(2):251-258.
[138] Xu Q, BAO L, LIN Y, et al. Self-assembled quantum dots on Au and the interfacefluorescence. J. Innov. Opt. Health Sci.,2010,3(4):315-320.
[139] Mammen MC, S.-K.; Whitesides, G. M.,. Polyvalent Interactions in BiologicalSystems: Implications for Design and Use of Multivalent Ligands and Inhibitors.Angew Chem Int Ed Engl,1998,37(20):2754-2794.
[140] Fani M, Mueller A, Tamma ML, et al. Radiolabeled bicyclic somatostatin-basedanalogs: a novel class of potential radiotracers for SPECT/PET of neuroendocrinetumors. J Nucl Med,2010,51(11):1771-1779.
[141] Chen K, Conti PS. Target-specific delivery of peptide-based probes for PETimaging. Adv Drug Deliv Rev,2010,62(11):1005-1022.
[142] Liu Z, Shi J, Jia B, et al. Two Y-labeled multimeric RGD peptides RGD4and3PRGD2for integrin targeted radionuclide therapy. Mol Pharm,2011,8(2):591-599.
[143] Choi CW, Lang L, Lee JT, et al. Biodistribution of18F-and125I-labeled anti-Tacdisulfide-stabilized Fv fragments in nude mice with interleukin2alphareceptor-positive tumor xenografts. Cancer Res,1995,55(22):5323-5329.
[144] Haubner R, Wester HJ, Reuning U, et al. Radiolabeled alpha(v)beta(3) integrinantagonists: A new class of tracers for tumor targeting. J Nucl Med,1999,40(6):1061-1071.
[145] Garkavij M, Tennvall J, Ohlsson T, et al. Comparison of125I-and (111)In-labeledmonoclonal antibody BR96for tumor targeting in combination with extracorporealimmunoadsorption. Clin Cancer Res,1999,5(10):3059s-3064s.
[146] Orlova A, Nilsson FY, Wikman M, et al. Comparative in vivo evaluation oftechnetium and iodine labels on an anti-HER2affibody for single-photon imagingof HER2expression in tumors. J Nucl Med,2006,47(3):512-519.
[147] Quadri SM, Lai J, Mohammadpour H, et al. Assessment of radiolabeled stabilizedF(ab')2fragments of monoclonal antiferritin in nude mouse model. J Nucl Med,1993,34(12):2152-2159.
[148] Sheikholvaezin A, Eriksson D, Ahlstrom KR, et al. Tumor radioimmunolocalizationin nude mice by mono-and divalent-single-chain Fv antiplacental alkalinephosphatase antibodies. Cancer Biother Radiopharm,2007,22(1):64-72.
[149] Olafsen T, Wu AM. Antibody vectors for imaging. Semin Nucl Med,2010,40(3):167-181.
[150] Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of curcumin: preclinicaland clinical studies. Anticancer Res,2003,23(1):363-398.
[151] Kuttan R, Bhanumathy P, Nirmala K, et al. Potential anticancer activity of turmeric(Curcuma longa). Cancer Lett,1985,29(2):197-202.
[152] Anand P, Kunnumakkara AB, Newman RA, et al. Bioavailability of curcumin:problems and promises. Mol Pharm,2007,4(6):807-818.
[153] Anand P, Nair HB, Sung B, et al. Design of curcumin-loaded PLGA nanoparticlesformulation with enhanced cellular uptake, and increased bioactivity in vitro andsuperior bioavailability in vivo. Biochem Pharmacol,2010,79(3):330-338.
[154] Lin YT, Wang LF, Hsu YC. Curcuminoids suppress the growth of pharynx andnasopharyngeal carcinoma cells through induced apoptosis. J Agric Food Chem,2009,57(9):3765-3770.
[155] Bisht S, Feldmann G, Soni S, et al. Polymeric nanoparticle-encapsulated curcumin("nanocurcumin"): a novel strategy for human cancer therapy. J Nanobiotechnology,2007,5(17):3.
[156] Sanvicens N, Marco MP. Multifunctional nanoparticles-properties and prospectsfor their use in human medicine. Trends Biotechnol,2008,26(8):425-433.
[157] Ferrari M. Cancer nanotechnology: opportunities and challenges. Nat Rev Cancer,2005,5(3):161-171.
[2] Tao Q, Chan AT. Nasopharyngeal carcinoma: molecular pathogenesis andtherapeutic developments. Expert Rev Mol Med,2007,9(12):1-24.
[3] Razak AR, Siu LL, Liu FF, et al. Nasopharyngeal carcinoma: the next challenges.Eur J Cancer,2010,46(11):1967-1978.
[4] Geara FB, Sanguineti G, Tucker SL, et al. Carcinoma of the nasopharynx treated byradiotherapy alone: determinants of distant metastasis and survival. RadiotherOncol,1997,43(1):53-61.
[5] King AD, Vlantis AC, Bhatia KSS, et al. Primary Nasopharyngeal Carcinoma:Diagnostic Accuracy of MR Imaging versus that of Endoscopy and EndoscopicBiopsy. Radiology,2011,258(2):531-537.
[6] Wen YH, Wen WP, Chen HX, et al. Endoscopic nasopharyngectomy for salvage innasopharyngeal carcinoma: a novel anatomic orientation. Laryngoscope,2010,120(7):1298-1302.
[7] Abdel Khalek Abdel Razek A, King A. MRI and CT of nasopharyngeal carcinoma.AJR Am J Roentgenol,2012,198(1):11-18.
[8] Manavis J, Sivridis L, Koukourakis MI. Nasopharyngeal carcinoma: the impact ofCT-scan and of MRI on staging, radiotherapy treatment planning, and outcome ofthe disease. Clin Imaging,2005,29(2):128-133.
[9] Suarez C, Rodrigo JP, Rinaldo A, et al. Current treatment options for recurrentnasopharyngeal cancer. Eur Arch Otorhinolaryngol,2010,267(12):1811-1824.
[10] Chan ATC. Nasopharyngeal carcinoma. Ann Oncol,2010,21(7):308-312.
[11] Ng SH, Chan SC, Yen TC, et al. Staging of untreated nasopharyngeal carcinomawith PET/CT: comparison with conventional imaging work-up. Eur J Nucl MedMol Imaging,2009,36(3):538-538.
[12] Baujat B, Audry H, Bourhis J, et al. Chemotherapy in locally advancednasopharyngeal carcinoma: an individual patient data meta-analysis of eightrandomized trials and1753patients. Int J Radiat Oncol Biol Phys,2006,64(1):47-56.
[13] Xiao WW, Huang SM, Han F, et al. Local control, survival, and late toxicities oflocally advanced nasopharyngeal carcinoma treated by simultaneous modulatedaccelerated radiotherapy combined with cisplatin concurrent chemotherapy:long-term results of a phase2study. Cancer,2011,117(9):1874-1883.
[14] Hui EP, Leung SF, Au JS, et al. Lung metastasis alone in nasopharyngealcarcinoma: a relatively favorable prognostic group. Cancer,2004,101(2):300-306.
[15] Chen MY, Wen WP, Guo X, et al. Endoscopic nasopharyngectomy for locallyrecurrent nasopharyngeal carcinoma. Laryngoscope,2009,119(3):516-522.
[16] Leemans CR, Braakhuis BJM, Brakenhoff RH. The molecular biology of head andneck cancer. Nat Rev Cancer,2011,11(1):9-22.
[17] Bensouda Y, Kaikani W, Ahbeddou N, et al. Treatment for metastaticnasopharyngeal carcinoma. Eur Ann Otorhinolaryngol Head Neck Dis,2011,128(2):79-85.
[18] Bei JX, Li Y, Jia WH, et al. A genome-wide association study of nasopharyngealcarcinoma identifies three new susceptibility loci. Nat Genet,2010,42(7):599-603.
[19] Wai Pak M, To KF, Lee JC, et al. In vivo real-time diagnosis of nasopharyngealcarcinoma in situ by contact rhinoscopy. Head Neck,2005,27(11):1008-1013.
[20] Pathmanathan R, Prasad U, Sadler R, et al. Clonal proliferations of cells infectedwith Epstein-Barr virus in preinvasive lesions related to nasopharyngeal carcinoma.N Engl J Med,1995,333(11):693-698.
[21] Cao SM, Liu Z, Jia WH, et al. Fluctuations of epstein-barr virus serologicalantibodies and risk for nasopharyngeal carcinoma: a prospective screening studywith a20-year follow-up. PLoS One,2011,6(4): e19100.
[22] Xu LY, Pan JJ, Wu JX, et al. Factors associated with overall survival in1706patients with nasopharyngeal carcinoma: Significance of intensive neoadjuvantchemotherapy and radiation break. Radiother Oncol,2010,96(1):94-99.
[23] Chan YW, Chow VL, Wei WI. Quality of life of patients after salvagenasopharyngectomy for recurrent nasopharyngeal carcinoma. Cancer,2012,118(15):3710-3718.
[24] Ma BBY, Poon TCW, To KF, et al. Prognostic significance of tumor angiogenesis,Ki67, p53oncoprotein, epidermal growth factor receptor and HER2receptorprotein expression in undifferentiated nasopharyngeal carcinoma-A prospectivestudy. Head Neck,2003,25(10):864-872.
[25] Wykosky J, Fenton T, Furnari F, et al. Therapeutic targeting of epidermal growthfactor receptor in human cancer: successes and limitations. Chin J Cancer,2011,30(1):5-12.
[26] Naji F, Attaleb M, Laantri N, et al. Identification of G2607A mutation in EGFRgene with a significative rate in Moroccan patients with nasopharyngeal carcinoma.Cell Mol Biol,2010,56(15): OL1442-1446.
[27] Schrama D, Reisfeld RA, Becker JC. Antibody targeted drugs as cancertherapeutics. Nat Rev Drug Discov,2006,5(2):147-159.
[28] Adams GP, Weiner LM. Monoclonal antibody therapy of cancer. Nat Biotechnol,2005,23(9):1147-1157.
[29] Chan ATC, Hsu MM, Goh BC, et al. Multicenter, phase II study of cetuximab incombination with carboplatin in patients with recurrent or metastaticnasopharyngeal carcinoma. J Clin Oncol,2005,23(15):3568-3576.
[30] Ma BB, Kam MK, Leung SF, et al. A phase II study of concurrentcetuximab-cisplatin and intensity-modulated radiotherapy in locoregionallyadvanced nasopharyngeal carcinoma. Ann Oncol,2012,23(5):1287-1292.
[31] Chua DTT, Wei WI, Wong MP, et al. Phase II study of gefitinib for the treatment ofrecurrent and metastatic nasopharyngeal carcinoma. Head Neck,2008,30(7):863-867.
[32] Krishna SM, James S, Balaram P. Expression of VEGF as prognosticator in primarynasopharyngeal cancer and its relation to EBV status. Virus Res,2006,115(1):85-90.
[33] Li YH, Hu CF, Shao Q, et al. Elevated expressions of survivin and VEGF proteinare strong independent predictors of survival in advanced nasopharyngealcarcinoma. J Transl Med,2008,6(1):1-11.
[34] Stevenson D, Charalambous C, Wilson JB. Epstein-Barr virus latent membraneprotein1(CAO) up-regulates VEGF and TGF alpha concomitant with hyperlasia,with subsequent up-regulation of p16and MMP9. Cancer Res,2005,65(19):8826-8835.
[35] O'Neil JD, Owen TJ, Wood VHJ, et al. Epstein-Barr virus-encoded EBNA1modulates the AP-1transcription factor pathway in nasopharyngeal carcinoma cellsand enhances angiogenesis in vitro. J Gen Virol,2008,89(11):2833-2842.
[36] Lee NY, Zhang Q, Pfister DG, et al. Addition of bevacizumab to standardchemoradiation for locoregionally advanced nasopharyngeal carcinoma (RTOG0615): a phase2multi-institutional trial. Lancet Oncol,2012,13(2):172-180.
[37] Salama JK, Haraf DJ, Stenson KM, et al. A randomized phase II study of5-fluorouracil, hydroxyurea, and twice-daily radiotherapy compared withbevacizumab plus5-fluorouracil, hydroxyurea, and twice-daily radiotherapy forintermediate-stage and T4N0-1head and neck cancers. Ann Oncol,2011,22(10):2304-2309.
[38] Elser C, Siu LL, Winquist E, et al. Phase II trial of sorafenib in patients withrecurrent or metastatic squamous cell carcinoma of the head and neck ornasopharyngeal carcinoma. J Clin Oncol,2007,25(24):3766-3773.
[39] Tan KB, Putti TC. Cyclooxygenase2expression in nasopharyngeal carcinoma:immunohistochemical findings and potential implications. J Clin Pathol,2005,58(5):535-538.
[40] Soo R, Putti T, Tao Q, et al. Overexpression of cyclooxygenase-2innasopharyngeal carcinoma and association with epidermal growth factor receptorexpression. Arch Otolaryngol,2005,131(2):147-152.
[41] Liu DB, Hu GY, Long GX, et al. Celecoxib induces apoptosis and cell-cycle arrestin nasopharyngeal carcinoma cell lines via inhibition of STAT3phosphorylation.Acta Pharmacol Sin,2012,33(5):682-690.
[42] Soo RA, Wu J, Aggarwal A, et al. Celecoxib reduces microvessel density inpatients treated with nasopharyngeal carcinoma and induces changes in geneexpression. Ann Oncol,2006,17(11):1625-1630.
[43] Pan J, Tang T, Xu L, et al. Prognostic significance of expression ofcyclooxygenase-2, vascular endothelial growth factor, and epidermal growth factorreceptor in nasopharyngeal carcinoma. Head Neck,2012.
[44] Allen TM. Ligand-targeted therapeutics in anticancer therapy. Nat Rev Cancer,2002,2(10):750-763.
[45] Nelson AL, Dhimolea E, Reichert JM. Development trends for human monoclonalantibody therapeutics. Nat Rev Drug Discov,2010,9(10):767-774.
[46] Dasgupta P, Sun J, Wang S, et al. Disruption of the Rb--Raf-1interaction inhibitstumor growth and angiogenesis. Mol Cell Biol,2004,24(21):9527-9541.
[47] Jia WD, Xu GL, Xu RN, et al. Octreotide acts as an antitumor angiogenesiscompound and suppresses tumor growth in nude mice bearing human hepatocellularcarcinoma xenografts. J Cancer Res Clin Oncol,2003,129(6):327-334.
[48] Kondo E, Seto M, Yoshikawa K, et al. Highly efficient delivery of p16antitumorpeptide into aggressive leukemia/lymphoma cells using a novel transporter system.Mol Cancer Ther,2004,3(12):1623-1630.
[49] Florio T, Morini M, Villa V, et al. Somatostatin inhibits tumor angiogenesis andgrowth via somatostatin receptor-3-mediated regulation of endothelial nitric oxidesynthase and mitogen-activated protein kinase activities. Endocrinology,2003,144(4):1574-1584.
[50] Alba A, Lopez-Abarrategui C, Otero-Gonzalez AJ. Host defense peptides: Analternative as antiinfective and immunomodulatory therapeutics. Biopolymers,2012,98(4):251-267.
[51] Hancock RE, Sahl HG. Antimicrobial and host-defense peptides as newanti-infective therapeutic strategies. Nat Biotechnol,2006,24(12):1551-1557.
[52] Fjell CD, Hiss JA, Hancock RE, et al. Designing antimicrobial peptides: formfollows function. Nat Rev Drug Discov,2012,11(1):37-51.
[53] Pasupuleti M, Schmidtchen A, Malmsten M. Antimicrobial peptides: keycomponents of the innate immune system. Crit Rev Biotechnol,2012,32(2):143-171.
[54] Dawson MJ, Scott RW. New horizons for host defense peptides and lantibiotics.Curr Opin Pharmacol,2012,12(5):545-550.
[55] Franzman MR, Burnell KK, Dehkordi-Vakil FH, et al. Targeted antimicrobialactivity of a specific IgG-SMAP28conjugate against Porphyromonas gingivalis in amixed culture. Int J Antimicrob Agents,2009,33(1):14-20.
[56] Eckert R, He J, Yarbrough DK, et al. Targeted killing of Streptococcus mutans by apheromone-guided "smart" antimicrobial peptide. Antimicrob Agents Ch,2006,50(11):3651-3657.
[57] Yount NY, Yeaman MR. Emerging themes and therapeutic prospects foranti-infective peptides. Annu Rev Pharmacol Toxicol,2012,52(1):337-360.
[58] Zasloff M. Antimicrobial peptides of multicellular organisms. Nature,2002,415(6870):389-395.
[59] Agemy L, Friedmann-Morvinski D, Kotamraju VR, et al. Targeted nanoparticleenhanced proapoptotic peptide as potential therapy for glioblastoma. Proc NatlAcad Sci U S A,2011,108(42):17450-17455.
[60] Devocelle M. Targeted antimicrobial peptides. Front Immunol,2012,(3):309.
[61] Okarvi SM. Peptide-based radiopharmaceuticals: future tools for diagnosticimaging of cancers and other diseases. Med Res Rev,2004,24(3):357-397.
[62] Ahrens VM, Bellmann-Sickert K, Beck-Sickinger AG. Peptides and peptideconjugates: therapeutics on the upward path. Future Med Chem,2012,4(12):1567-1586.
[63] Han Z, Fu A, Wang H, et al. Noninvasive assessment of cancer response to therapy.Nat Med,2008,14(3):343-349.
[64] Morris MC, Depollier J, Mery J, et al. A peptide carrier for the delivery ofbiologically active proteins into mammalian cells. Nat Biotechnol,2001,19(12):1173-1176.
[65] Pasqualini R, Koivunen E, Ruoslahti E. Alpha v integrins as receptors for tumortargeting by circulating ligands. Nat Biotechnol,1997,15(6):542-546.
[66] Arap W, Pasqualini R, Ruoslahti E. Cancer treatment by targeted drug delivery totumor vasculature in a mouse model. Science,1998,279(5349):377-380.
[67] Laakkonen P, Akerman ME, Biliran H, et al. Antitumor activity of a homingpeptide that targets tumor lymphatics and tumor cells. Proc Natl Acad Sci U S A,2004,101(25):9381-9386.
[68] Ullman CG, Frigotto L, Cooley RN. In vitro methods for peptide display and theirapplications. Brief Funct Genomic,2011,10(3):125-134.
[69] Wu HC, Chang DK. Peptide-mediated liposomal drug delivery system targetingtumor blood vessels in anticancer therapy. J Oncol,2010,(2010):723798.
[70] Szardenings M. Phage display of random peptide libraries: Applications, limits, andpotential. J Recept Sig Transd,2003,23(4):307-349.
[71] Molek P, Strukelj B, Bratkovic T. Peptide Phage Display as a Tool for DrugDiscovery: Targeting Membrane Receptors. Molecules,2011,16(1):857-887.
[72] Tu XG, Zhuang JT, Wang WW, et al. Screening and identification of a renalcarcinoma specific peptide from a phage display peptide library. J Exp Clin CancRes,2012,31(13):105-106.
[73] Shadidi M, Sioud M. Identification of novel carrier peptides for the specificdelivery of therapeutics into cancer cells. FASEB J,2003,17(2):256-258.
[74] Mammen M, Choi SK, Whitesides GM. Polyvalent interactions in biologicalsystems: Implications for design and use of multivalent ligands and inhibitors.Angew Chem Int Edit,1998,37(20):2755-2794.
[75] Jiang W, Kim BY, Rutka JT, et al. Nanoparticle-mediated cellular response issize-dependent. Nat Nanotechnol,2008,3(3):145-150.
[76] Cho K, Wang X, Nie S, et al. Therapeutic nanoparticles for drug delivery in cancer.Clin Cancer Res,2008,14(5):1310-1316.
[77] Peer D, Karp JM, Hong S, et al. Nanocarriers as an emerging platform for cancertherapy. Nat Nanotechnol,2007,2(12):751-760.
[78] Davis ME, Chen ZG, Shin DM. Nanoparticle therapeutics: an emerging treatmentmodality for cancer. Nat Rev Drug Discov,2008,7(9):771-782.
[79] Zhang L, Gu FX, Chan JM, et al. Nanoparticles in medicine: therapeuticapplications and developments. Clin Pharmacol Ther,2008,83(5):761-769.
[80] Alexis F, Pridgen EM, Langer R, et al. Nanoparticle technologies for cancer therapy.Handb Exp Pharmacol,2010,(197):55-86.
[81] Lammers T, Hennink WE, Storm G. Tumour-targeted nanomedicines: principlesand practice. Br J Cancer,2008,99(3):392-397.
[82] Egusquiaguirre SP, Igartua M, Hernandez RM, et al. Nanoparticle delivery systemsfor cancer therapy: advances in clinical and preclinical research. Clin Transl Oncol,2012,14(2):83-93.
[83] Petros RA, DeSimone JM. Strategies in the design of nanoparticles for therapeuticapplications. Nat Rev Drug Discov,2010,9(8):615-627.
[84] Hrkach J, Von Hoff D, Mukkaram Ali M, et al. Preclinical development and clinicaltranslation of a PSMA-targeted docetaxel nanoparticle with a differentiatedpharmacological profile. Sci Transl Med,2012,4(128):128ra139.
[85] MacKay JA, Chen M, McDaniel JR, et al. Self-assembling chimericpolypeptide-doxorubicin conjugate nanoparticles that abolish tumours after a singleinjection. Nat Mater,2009,8(12):993-999.
[86] Choi HS, Liu W, Misra P, et al. Renal clearance of quantum dots. Nat Biotechnol,2007,25(10):1165-1170.
[87] Nomura T, Koreeda N, Yamashita F, et al. Effect of particle size and charge on thedisposition of lipid carriers after intratumoral injection into tissue-isolated tumors.Pharm Res,1998,15(1):128-132.
[88] Cabral H, Matsumoto Y, Mizuno K, et al. Accumulation of sub-100nm polymericmicelles in poorly permeable tumours depends on size. Nat Nanotechnol,2011,6(12):815-823.
[89] Pluen A, Boucher Y, Ramanujan S, et al. Role of tumor-host interactions ininterstitial diffusion of macromolecules: cranial vs. subcutaneous tumors. Proc NatlAcad Sci U S A,2001,98(8):4628-4633.
[90] Alexandrakis G, Brown EB, Tong RT, et al. Two-photon fluorescence correlationmicroscopy reveals the two-phase nature of transport in tumors. Nat Med,2004,10(2):203-207.
[91] Ramanujan S, Pluen A, McKee TD, et al. Diffusion and convection in collagen gels:implications for transport in the tumor interstitium. Biophys J,2002,83(3):1650-1660.
[92] Scott JE. Extracellular matrix, supramolecular organisation and shape. J Anat,1995,187(2):259-269.
[93] Rothenfluh DA, Bermudez H, O'Neil CP, et al. Biofunctional polymer nanoparticlesfor intra-articular targeting and retention in cartilage. Nat Mater,2008,7(3):248-254.
[94] Jain RK, Stylianopoulos T. Delivering nanomedicine to solid tumors. Nat Rev ClinOncol,2010,7(11):653-664.
[95] Geng Y, Dalhaimer P, Cai S, et al. Shape effects of filaments versus sphericalparticles in flow and drug delivery. Nat Nanotechnol,2007,2(4):249-255.
[96] Cho EC, Zhang Q, Xia Y. The effect of sedimentation and diffusion on cellularuptake of gold nanoparticles. Nat Nanotechnol,2011,6(6):385-391.
[97] Barua S, Yoo JW, Kolhar P, et al. Particle shape enhances specificity ofantibody-displaying nanoparticles. Proc Natl Acad Sci U S A,2013,110(9):3270-3275.
[98] Zhao D, Sun XC, Tong JL, et al. A novel multifunctional nanocompositeC225-conjugated Fe3O4/Ag enhances the sensitivity of nasopharyngeal carcinomacells to radiotherapy. Acta Bioch Bioph Sin,2012,44(8):678-684.
[99] Lee TY, Wu HC, Tseng YL, et al. A novel peptide specifically binding tonasopharyngeal carcinoma for targeted drug delivery. Cancer Res,2004,64(21):8002-8008.
[100] Chen YC, Min CN, Wu HC, et al. In vitro evaluation of the L-peptide modifiedmagnetic lipid nanoparticles as targeted magnetic resonance imaging contrast agentfor the nasopharyngeal cancer. J Biomater Appl,2012, Epub ahead of print.
[101] Wasan KM, Brocks DR, Lee SD, et al. Impact of lipoproteins on the biologicalactivity and disposition of hydrophobic drugs: implications for drug discovery. NatRev Drug Discov,2008,7(1):84-99.
[102] Acton S, Rigotti A, Landschulz KT, et al. Identification of scavenger receptorSR-BI as a high density lipoprotein receptor. Science,1996,271(5248):518-520.
[103] Mooberry LK, Nair M, Paranjape S, et al. Receptor mediated uptake of paclitaxelfrom a synthetic high density lipoprotein nanocarrier. J Drug Target,2010,18(1):53-58.
[104] Cormode DP, Skajaa T, van Schooneveld MM, et al. Nanocrystal CoreHigh-Density Lipoproteins: A Multimodality Contrast Agent Platform. Nano Lett,2008,8(11):3715-3723.
[105] Nykiforuk CL, Shen Y, Murray EW, et al. Expression and recovery of biologicallyactive recombinant Apolipoprotein AI(Milano) from transgenic safflower(Carthamus tinctorius) seeds. Plant Biotechnol J,2011,9(2):250-263.
[106] Zhang Z, Cao W, Jin H, et al. Biomimetic nanocarrier for direct cytosolic drugdelivery. Angew Chem Int Ed Engl,2009,48(48):9171-9175.
[107] Zhang Z, Chen J, Ding L, et al. HDL-mimicking peptide-lipid nanoparticles withimproved tumor targeting. Small,2010,6(3):430-437.
[108] Yang M, Chen J, Cao WG, et al. Attenuation of nontargeted cell-kill using ahigh-density lipoprotein-mimicking peptide phospholipid nanoscaffold.Nanomedicine,2011,6(4):631-641.
[109] Cao W, Ng KK, Corbin I, et al. Synthesis and evaluation of a stablebacteriochlorophyll-analog and its incorporation into high-density lipoproteinnanoparticles for tumor imaging. Bioconjug Chem,2009,20(11):2023-2031.
[110] Ng KK, Lovell JF, Zheng G. Lipoprotein-Inspired Nanoparticles for CancerTheranostics. Accounts Chem Res,2011,44(10):1105-1113.
[111] Pande J, Szewczyk MM, Grover AK. Phage display: Concept, innovations,applications and future. Biotechnol Adv,2010,28(6):849-858.
[112] Uchiyama F, Tanaka Y, Minari Y, et al. Designing scaffolds of peptides for phagedisplay libraries. J Biosci Bioeng,2005,99(5):448-456.
[113] Borghouts C, Kunz C, Groner B. Current strategies for the development ofpeptide-based anti-cancer therapeutics. J Pept Sci,2005,11(11):713-726.
[114] Cyranka-Czaja A, Otlewski J. A novel, stable, helical scaffold as an alternativebinder-construction of phage display libraries. Acta Biochim Pol,2012,59(3):383-390.
[115] Rizzo MA, Davidson MW, Piston DW. Fluorescent protein tracking and detection:applications using fluorescent proteins in living cells. Cold Spring Harb Protoc,2009,2009(12): pdb top64.
[116] Fradkov AF, Chen Y, Ding L, et al. Novel fluorescent protein from Discosomacoral and its mutants possesses a unique far-red fluorescence. Febs Lett,2000,479(3):127-130.
[117] Shcherbo D, Merzlyak EM, Chepurnykh TV, et al. Bright far-red fluorescentprotein for whole-body imaging. Nat Methods,2007,4(9):741-746.
[118] Shcherbo D, Murphy CS, Ermakova GV, et al. Far-red fluorescent tags for proteinimaging in living tissues. Biochem J,2009,418(3):567-574.
[119] Lin MZ, McKeown MR, Ng HL, et al. Autofluorescent proteins with excitation inthe optical window for intravital imaging in mammals. Chem Biol,2009,16(11):1169-1179.
[120] Kredel S, Nienhaus K, Oswald F, et al. Optimized and far-red-emitting variants offluorescent protein eqFP611. Chem Biol,2008,15(3):224-233.
[121] Morozova KS, Piatkevich KD, Gould TJ, et al. Far-red fluorescent protein excitablewith red lasers for flow cytometry and superresolution STED nanoscopy. Biophys J,2010,99(2): L13-15.
[122] Shu X, Royant A, Lin MZ, et al. Mammalian expression of infrared fluorescentproteins engineered from a bacterial phytochrome. Science,2009,324(5928):804-807.
[123] Shcherbo D, Shemiakina, II, Ryabova AV, et al. Near-infrared fluorescent proteins.Nat Methods,2010,7(10):827-829.
[124] Filonov GS, Piatkevich KD, Ting LM, et al. Bright and stable near-infraredfluorescent protein for in vivo imaging. Nat Biotechnol,2011,29(8):757-761.
[125] Lecoq J, Schnitzer MJ. An infrared fluorescent protein for deeper imaging. NatBiotechnol,2011,29(8):715-716.
[126] Jiang W, Kim BYS, Rutka JT, et al. Nanoparticle-mediated cellular response issize-dependent. Nat Nanotechnol,2008,3(3):145-150.
[127] Kelloff GJ, Hoffman JM, Johnson B, et al. Progress and promise of FDG-PETimaging for cancer patient management and oncologic drug development. ClinCancer Res,2005,11(8):2785-2808.
[128] Chen K, Chen X. Positron emission tomography imaging of cancer biology: currentstatus and future prospects. Semin Oncol,2011,38(1):70-86.
[129] Khalil MM, Tremoleda JL, Bayomy TB, et al. Molecular SPECT Imaging: AnOverview. Int J Mol Imaging,2011,796025-796015.
[130] Cai W, Olafsen T, Zhang X, et al. PET imaging of colorectal cancer inxenograft-bearing mice by use of an18F-labeled T84.66anti-carcinoembryonicantigen diabody. J Nucl Med,2007,48(2):304-310.
[131] Wu AM, Senter PD. Arming antibodies: prospects and challenges forimmunoconjugates. Nat Biotechnol,2005,23(9):1137-1146.
[132] Okarvi SM. Peptide-based radiopharmaceuticals and cytotoxic conjugates: potentialtools against cancer. Cancer Treat Rev,2008,34(1):13-26.
[133] Wu AM, Yazaki PJ, Tsai S, et al. High-resolution microPET imaging ofcarcinoembryonic antigen-positive xenografts by using a copper-64-labeledengineered antibody fragment. Proc Natl Acad Sci U S A,2000,97(15):8495-8500.
[134] Zhang R, Xiong C, Huang M, et al. Peptide-conjugated polymeric micellarnanoparticles for Dual SPECT and optical imaging of EphB4receptors in prostatecancer xenografts. Biomaterials,2011,32(25):5872-5879.
[135] Shi J, Wang L, Kim YS, et al. Improving tumor uptake and excretion kinetics of99mTc-labeled cyclic arginine-glycine-aspartic (RGD) dimers with triglycinelinkers. J Med Chem,2008,51(24):7980-7990.
[136] Harris TD, Kalogeropoulos S, Nguyen T, et al. Structure-activity relationships of111In-and99mTc-labeled quinolin-4-one peptidomimetics as ligands for thevitronectin receptor: potential tumor imaging agents. Bioconjug Chem,2006,17(5):1294-1313.
[137] Jiang L, Kimura RH, Miao Z, et al. Evaluation of a (64)Cu-labeled cystine-knotpeptide based on agouti-related protein for PET of tumors expressing alphavbeta3integrin. J Nucl Med,2010,51(2):251-258.
[138] Xu Q, BAO L, LIN Y, et al. Self-assembled quantum dots on Au and the interfacefluorescence. J. Innov. Opt. Health Sci.,2010,3(4):315-320.
[139] Mammen MC, S.-K.; Whitesides, G. M.,. Polyvalent Interactions in BiologicalSystems: Implications for Design and Use of Multivalent Ligands and Inhibitors.Angew Chem Int Ed Engl,1998,37(20):2754-2794.
[140] Fani M, Mueller A, Tamma ML, et al. Radiolabeled bicyclic somatostatin-basedanalogs: a novel class of potential radiotracers for SPECT/PET of neuroendocrinetumors. J Nucl Med,2010,51(11):1771-1779.
[141] Chen K, Conti PS. Target-specific delivery of peptide-based probes for PETimaging. Adv Drug Deliv Rev,2010,62(11):1005-1022.
[142] Liu Z, Shi J, Jia B, et al. Two Y-labeled multimeric RGD peptides RGD4and3PRGD2for integrin targeted radionuclide therapy. Mol Pharm,2011,8(2):591-599.
[143] Choi CW, Lang L, Lee JT, et al. Biodistribution of18F-and125I-labeled anti-Tacdisulfide-stabilized Fv fragments in nude mice with interleukin2alphareceptor-positive tumor xenografts. Cancer Res,1995,55(22):5323-5329.
[144] Haubner R, Wester HJ, Reuning U, et al. Radiolabeled alpha(v)beta(3) integrinantagonists: A new class of tracers for tumor targeting. J Nucl Med,1999,40(6):1061-1071.
[145] Garkavij M, Tennvall J, Ohlsson T, et al. Comparison of125I-and (111)In-labeledmonoclonal antibody BR96for tumor targeting in combination with extracorporealimmunoadsorption. Clin Cancer Res,1999,5(10):3059s-3064s.
[146] Orlova A, Nilsson FY, Wikman M, et al. Comparative in vivo evaluation oftechnetium and iodine labels on an anti-HER2affibody for single-photon imagingof HER2expression in tumors. J Nucl Med,2006,47(3):512-519.
[147] Quadri SM, Lai J, Mohammadpour H, et al. Assessment of radiolabeled stabilizedF(ab')2fragments of monoclonal antiferritin in nude mouse model. J Nucl Med,1993,34(12):2152-2159.
[148] Sheikholvaezin A, Eriksson D, Ahlstrom KR, et al. Tumor radioimmunolocalizationin nude mice by mono-and divalent-single-chain Fv antiplacental alkalinephosphatase antibodies. Cancer Biother Radiopharm,2007,22(1):64-72.
[149] Olafsen T, Wu AM. Antibody vectors for imaging. Semin Nucl Med,2010,40(3):167-181.
[150] Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of curcumin: preclinicaland clinical studies. Anticancer Res,2003,23(1):363-398.
[151] Kuttan R, Bhanumathy P, Nirmala K, et al. Potential anticancer activity of turmeric(Curcuma longa). Cancer Lett,1985,29(2):197-202.
[152] Anand P, Kunnumakkara AB, Newman RA, et al. Bioavailability of curcumin:problems and promises. Mol Pharm,2007,4(6):807-818.
[153] Anand P, Nair HB, Sung B, et al. Design of curcumin-loaded PLGA nanoparticlesformulation with enhanced cellular uptake, and increased bioactivity in vitro andsuperior bioavailability in vivo. Biochem Pharmacol,2010,79(3):330-338.
[154] Lin YT, Wang LF, Hsu YC. Curcuminoids suppress the growth of pharynx andnasopharyngeal carcinoma cells through induced apoptosis. J Agric Food Chem,2009,57(9):3765-3770.
[155] Bisht S, Feldmann G, Soni S, et al. Polymeric nanoparticle-encapsulated curcumin("nanocurcumin"): a novel strategy for human cancer therapy. J Nanobiotechnology,2007,5(17):3.
[156] Sanvicens N, Marco MP. Multifunctional nanoparticles-properties and prospectsfor their use in human medicine. Trends Biotechnol,2008,26(8):425-433.
[157] Ferrari M. Cancer nanotechnology: opportunities and challenges. Nat Rev Cancer,2005,5(3):161-171.