基于Tie2的抗肿瘤及新生血管靶向药物输送系统研究
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摘要
肿瘤是一类严重威胁人类生命的恶性疾病，其原因在于人体自身细胞因为受到各种内在与外界因素的影响，失去正常的生长调节而造成增殖失控。常规的治疗手段包括手术切除，放射治疗，化学治疗，介入治疗，生物治疗等等。但是由于常规的治疗手段缺乏特异性，在杀伤肿瘤组织的同时也作用于正常组织细胞，造成极大的毒副作用，因此肿瘤特异的靶向药物输送尤显重要。
由长循环脂质体系统载化疗药物被研究多年，由于其能够通过EPR效应被动靶向肿瘤组织，减少毒副作用，同时能够在循环系统中保护药物不被降解，延长体内循环时间，因而得到人们的重视。在此基础上，如果能够通过肿瘤上特异性标志物的识别，实现脂质体的肿瘤主动靶向，将能够进一步的提高化疗药物的疗效。
Tie2蛋白是一种受体酪氨酸激酶，其在肿瘤诱导的血管新生过程中起着重要的作用。Tie2蛋白在肿瘤新生血管内皮细胞中表达水平会大大提高，同时Tie2还被部分肿瘤细胞所表达。因此，我们以Tie2为靶点，设计肿瘤靶向的脂质体药物输送系统。
靶向药物输送系统的关键在于肿瘤特异性标记物的靶向配体的筛选，由于小分子多肽具有多样性高，免疫原性低，制备简单，成本低廉，结构稳定等多种优点，我们选择了采用噬菌体固相筛选技术，Autodock对接评估计算机辅助药物设计技术以及天然配体Angiopoietin-2受体结合结构域结构分析等多种手段，筛选出能够与Tie2蛋白特异性结合的候选多肽配体PH1及An1，并利用表面等离子共振技术，验证了其与Tie2蛋白的结合能力，并计算亲和常数。
为了验证多肽引导脂质体药物输送系统靶向分布的潜力，我们通过连接剂SPDP，利用巯基与马来酰亚胺基的特异性反应，将多肽偶联到DSPE-PEG的聚乙二醇末端，并利用高效液相色谱分析连接产物。我们利用后插入技术，将PH1-PEG-DSPE胶束溶液与脂质体（HSPC:Chol:DSPE-PEG=2:1:0.1）共孵育，制备靶向脂质体。
在体外细胞试验中，通过细胞ELISA技术，激光共聚焦显微镜技术以及流式细胞术，利用对照多肽PH2, GE11偶联的脂质体以及普通长循环脂质体作为对照，我们发现PH1偶联的脂质体能够靶向Tie2蛋白高表达的肿瘤细胞以及血管内皮细胞，而对Tie2阴性表达细胞结合较低。利用PH1偶联载化疗药物顺铂的长循环脂质体，可以大大的特异性提高顺铂脂质体对Tie2阳性细胞的毒杀作用。除了化疗药物输送系统，我们还针对PH1靶向的基因输送系统进行了研究，通过PH1偶联修饰以及局部超声促进基因转染，达到靶向基因输送的目的，在体外细胞试验中得到一定的效果。
与体外系统相比，体内环境远远复杂，多肽与受体的结合受到一系列生理及病理因素的影响。我们将荧光分子Cy5.5偶联于多肽An1以及PH1靶向脂质体，利用小动物活体光学成像技术考察了多肽PH1与An1在体内的靶向行为。我们发现两多肽能够明显的提高肿瘤组织的荧光分布。通过硫酸铵梯度法，我们将广谱化疗药物阿霉素包封进靶向脂质体，PH1的修饰能够提高阿霉素在肿瘤部位的有效浓度，提高了对肿瘤生长的抑制作用。
Tumor is one of the lethalest diseases in the world. Due to variousinternal or external risk factors, cells lost the growth regulation and propagatewithout control. Routine strategies, including surgery, radiotherapy,chemotherapy, interventional therapy and biological therapy, lack of enoughspecificity and lead to seriously toxic and side effect. It’s extremely importantto develop an effective tumor targeting drug delivery system.
Long circulation liposomal drug delivery system can passively target totumor and reduce the distribution in other tissues due to enhanced permeationand retention (EPR) effect. At the meanwhile, drug can be protected from theenzymatic degradation and promoting long circulation time. Moreover, theeffect of the liposomal therapeutics may farther increase because of the active targeting effect. It can be achieved by the specific ligand conjugation andtumor biomarker recognition.
Tie2is identified as a receptor tyrosine kinase and plays essential rolesin tumor induced angiogenesis. It is mainly expressed on endothelial cells aswell as some tumor cells. It will be upregulated during tumor angiogenesis.Therefore, we designed a liposomal drug delivery system of which bindingability to Tie2protein is increased.
The key component of targeting drug delivery system is the screening ofligands of tumor specific marker. Because of the advantages including lessimmunogenicity, easy manipulation, lower cost and more stable bioactivity,peptide ligands were chosen as targeting molecule. Direct coating phagedisplay method, computer-aided drug design technology and natural ligandbinding domain mimics analysis were combined to screen Tie2ligand.Finally, we found two peptides PH1and An1could specifically bind to Tie2protein. We use surface plasmon resonance (SPR) technology to calculate theaffinity constant.
To estimate the potential of peptides using in targeting liposomal drugdelivery system, we use SPDP linker to ligate the peptides to the hydrophilicdistal end of DSPE-PEG lipid and measure the ligation efficiency. Finally, weuse post-insertion method for the preparation of peptide modified liposome. We mixed the peptide-lipid micelle with pre-made blank liposome solution（HSPC:Chol:DSPE-PEG=2:1:0.1）and incubated at60℃for1hour.
During the in vitro experiments, cell ELISA, laser confocal microscopeand FACS were used to analyze the specific binding ability of our targetingDDS to Tie2positive cells. Peptide PH2and GE11conjugated liposome andconventional long circulation liposome were chosen as negative controls. Wefound that PH1conjugated liposome can bind to Tie2positive tumor cells(SPC-A-1, H1299) and vessel endothelial cell (HUVEC), but not Tie2negative cell (SMMC-7721). The specific cytotoxicity of cis-platin liposomewhich conjugated to PH1peptide was greatly improved. Beside, we also dosome research on peptide targeting gene delivery system and ultrasoundsonoporation mediated transfection.
Compared to in vitro system, in vivo environment is much morecomplex. The physiological barriers, non-specific ineractions and internalMPS system may interfere the targeting effect. We labled the peptide An1andPH1conjugated liposome with fluorescent dye Cy5.5, injected via tail vein,and analyzed the fluorescence distribution using eXplore Optix live animalfluorescence imaging system. Compared to control group, An1peptide andPH1-liposome indeed concentrated at the tumor and retained longer time.Furthermore, we encapsulated doxorubicin in the liposome using ammonium sulphate gradient method. PH1conjugation increased the drug concentrationof the tumor site and enhanced the inhibition of the growth of tumor.
由长循环脂质体系统载化疗药物被研究多年，由于其能够通过EPR效应被动靶向肿瘤组织，减少毒副作用，同时能够在循环系统中保护药物不被降解，延长体内循环时间，因而得到人们的重视。在此基础上，如果能够通过肿瘤上特异性标志物的识别，实现脂质体的肿瘤主动靶向，将能够进一步的提高化疗药物的疗效。
Tie2蛋白是一种受体酪氨酸激酶，其在肿瘤诱导的血管新生过程中起着重要的作用。Tie2蛋白在肿瘤新生血管内皮细胞中表达水平会大大提高，同时Tie2还被部分肿瘤细胞所表达。因此，我们以Tie2为靶点，设计肿瘤靶向的脂质体药物输送系统。
靶向药物输送系统的关键在于肿瘤特异性标记物的靶向配体的筛选，由于小分子多肽具有多样性高，免疫原性低，制备简单，成本低廉，结构稳定等多种优点，我们选择了采用噬菌体固相筛选技术，Autodock对接评估计算机辅助药物设计技术以及天然配体Angiopoietin-2受体结合结构域结构分析等多种手段，筛选出能够与Tie2蛋白特异性结合的候选多肽配体PH1及An1，并利用表面等离子共振技术，验证了其与Tie2蛋白的结合能力，并计算亲和常数。
为了验证多肽引导脂质体药物输送系统靶向分布的潜力，我们通过连接剂SPDP，利用巯基与马来酰亚胺基的特异性反应，将多肽偶联到DSPE-PEG的聚乙二醇末端，并利用高效液相色谱分析连接产物。我们利用后插入技术，将PH1-PEG-DSPE胶束溶液与脂质体（HSPC:Chol:DSPE-PEG=2:1:0.1）共孵育，制备靶向脂质体。
在体外细胞试验中，通过细胞ELISA技术，激光共聚焦显微镜技术以及流式细胞术，利用对照多肽PH2, GE11偶联的脂质体以及普通长循环脂质体作为对照，我们发现PH1偶联的脂质体能够靶向Tie2蛋白高表达的肿瘤细胞以及血管内皮细胞，而对Tie2阴性表达细胞结合较低。利用PH1偶联载化疗药物顺铂的长循环脂质体，可以大大的特异性提高顺铂脂质体对Tie2阳性细胞的毒杀作用。除了化疗药物输送系统，我们还针对PH1靶向的基因输送系统进行了研究，通过PH1偶联修饰以及局部超声促进基因转染，达到靶向基因输送的目的，在体外细胞试验中得到一定的效果。
与体外系统相比，体内环境远远复杂，多肽与受体的结合受到一系列生理及病理因素的影响。我们将荧光分子Cy5.5偶联于多肽An1以及PH1靶向脂质体，利用小动物活体光学成像技术考察了多肽PH1与An1在体内的靶向行为。我们发现两多肽能够明显的提高肿瘤组织的荧光分布。通过硫酸铵梯度法，我们将广谱化疗药物阿霉素包封进靶向脂质体，PH1的修饰能够提高阿霉素在肿瘤部位的有效浓度，提高了对肿瘤生长的抑制作用。
Tumor is one of the lethalest diseases in the world. Due to variousinternal or external risk factors, cells lost the growth regulation and propagatewithout control. Routine strategies, including surgery, radiotherapy,chemotherapy, interventional therapy and biological therapy, lack of enoughspecificity and lead to seriously toxic and side effect. It’s extremely importantto develop an effective tumor targeting drug delivery system.
Long circulation liposomal drug delivery system can passively target totumor and reduce the distribution in other tissues due to enhanced permeationand retention (EPR) effect. At the meanwhile, drug can be protected from theenzymatic degradation and promoting long circulation time. Moreover, theeffect of the liposomal therapeutics may farther increase because of the active targeting effect. It can be achieved by the specific ligand conjugation andtumor biomarker recognition.
Tie2is identified as a receptor tyrosine kinase and plays essential rolesin tumor induced angiogenesis. It is mainly expressed on endothelial cells aswell as some tumor cells. It will be upregulated during tumor angiogenesis.Therefore, we designed a liposomal drug delivery system of which bindingability to Tie2protein is increased.
The key component of targeting drug delivery system is the screening ofligands of tumor specific marker. Because of the advantages including lessimmunogenicity, easy manipulation, lower cost and more stable bioactivity,peptide ligands were chosen as targeting molecule. Direct coating phagedisplay method, computer-aided drug design technology and natural ligandbinding domain mimics analysis were combined to screen Tie2ligand.Finally, we found two peptides PH1and An1could specifically bind to Tie2protein. We use surface plasmon resonance (SPR) technology to calculate theaffinity constant.
To estimate the potential of peptides using in targeting liposomal drugdelivery system, we use SPDP linker to ligate the peptides to the hydrophilicdistal end of DSPE-PEG lipid and measure the ligation efficiency. Finally, weuse post-insertion method for the preparation of peptide modified liposome. We mixed the peptide-lipid micelle with pre-made blank liposome solution（HSPC:Chol:DSPE-PEG=2:1:0.1）and incubated at60℃for1hour.
During the in vitro experiments, cell ELISA, laser confocal microscopeand FACS were used to analyze the specific binding ability of our targetingDDS to Tie2positive cells. Peptide PH2and GE11conjugated liposome andconventional long circulation liposome were chosen as negative controls. Wefound that PH1conjugated liposome can bind to Tie2positive tumor cells(SPC-A-1, H1299) and vessel endothelial cell (HUVEC), but not Tie2negative cell (SMMC-7721). The specific cytotoxicity of cis-platin liposomewhich conjugated to PH1peptide was greatly improved. Beside, we also dosome research on peptide targeting gene delivery system and ultrasoundsonoporation mediated transfection.
Compared to in vitro system, in vivo environment is much morecomplex. The physiological barriers, non-specific ineractions and internalMPS system may interfere the targeting effect. We labled the peptide An1andPH1conjugated liposome with fluorescent dye Cy5.5, injected via tail vein,and analyzed the fluorescence distribution using eXplore Optix live animalfluorescence imaging system. Compared to control group, An1peptide andPH1-liposome indeed concentrated at the tumor and retained longer time.Furthermore, we encapsulated doxorubicin in the liposome using ammonium sulphate gradient method. PH1conjugation increased the drug concentrationof the tumor site and enhanced the inhibition of the growth of tumor.
引文
1. Losordo, D.W., Angiogenesis: An Integrative Approach from Science to Medicine. N Engl J Med,
2008.359(23): p.2505-a-2506.
2. Folkman, J., Tumor angiogenesis: therapeutic implications. N Engl J Med,1971.285(21): p.1182-1186.
3. Schindl, M., Schoppmann, S.F., Samonigg, H., et al., Overexpression of hypoxia-inducible factor1alpha is associated with an unfavorable prognosis in lymph node-positive breast cancer. ClinCancer Res,2002.8(6): p.1831-1837.
4.刘泽隆,范红霞and王淑芳,对vasculogenesis和angiogenesis中文翻译的探讨.中国科技术语,2007(04): p.53-54+52.
5. Risau, W., Mechanisms of angiogenesis. Nature,1997.386(6626): p.671-674.
6. Hendrix, M.J., Seftor, E.A., Hess, A.R., et al., Vasculogenic mimicry and tumour-cell plasticity:lessons from melanoma. Nat Rev Cancer,2003.3(6): p.411-421.
7. Seftor, E.A., Meltzer, P.S., Schatteman, G.C., et al., Expression of multiple molecular phenotypesby aggressive melanoma tumor cells: role in vasculogenic mimicry. Crit Rev Oncol Hematol,2002.44(1): p.17-27.
8. Furuya, M., Yonemitsu, Y. and Aoki, I., III. Angiogenesis: complexity of tumor vasculature andmicroenvironment. Curr Pharm Des,2009.15(16): p.1854-1867.
9. Witmer, A.N., Vrensen, G.F., Van Noorden, C.J., et al., Vascular endothelial growth factors andangiogenesis in eye disease. Prog Retin Eye Res,2003.22(1): p.1-29.
10. Gariano, R.F. and Gardner, T.W., Retinal angiogenesis in development and disease. Nature,2005.438(7070): p.960-966.
11. Haddrill, M. and Slonim, C. Age-Related Macular Degeneration. Availablefrom: http://www.allaboutvision.com/conditions/amd.htm.
12. Michaelson, I.C., The mode of development of the vascular system of the retina, with someobservations on its significance for certain retinal diseases. Trans Ophthalmol Soc UK,1948.65: p.
4.
13. Wise, G.N., Factors influencing retinal new vessel formation. Am J Ophthalmol,1961.52: p.637-650.
14. Aiello, L.P., Avery, R.L., Arrigg, P.G., et al., Vascular endothelial growth factor in ocular fluid ofpatients with diabetic retinopathy and other retinal disorders. N Engl J Med,1994.331(22): p.1480-1487.
15. Kliffen, M., Sharma, H.S., Mooy, C.M., et al., Increased expression of angiogenic growth factors inage-related maculopathy. Br J Ophthalmol,1997.81(2): p.154-162.
16. Funatsu, H., Yamashita, H., Shimizu, E., et al., Relationship between vascular endothelial growthfactor and interleukin-6in diabetic retinopathy. Retina,2001.21(5): p.469-477.
17. Watanabe, D., Suzuma, K., Suzuma, I., et al., Vitreous levels of angiopoietin2and vascularendothelial growth factor in patients with proliferative diabetic retinopathy. Am J Ophthalmol,2005.139(3): p.476-481.
18. Watanabe, D., Suzuma, K., Matsui, S., et al., Erythropoietin as a retinal angiogenic factor inproliferative diabetic retinopathy. N Engl J Med,2005.353(8): p.782-792.
19. Tolentino, M.J., Current molecular understanding and future treatment strategies for pathologicocular neovascularization. Curr Mol Med,2009.9(8): p.973-981.
20. Yoshida, T.,[Molecular mechanism of choroidal neovascularization in age-related maculardegeneration]. Nippon Ganka Gakkai Zasshi,2007.111(11): p.881-891.
21. Hanahan, D. and Folkman, J., Patterns and emerging mechanisms of the angiogenic switch duringtumorigenesis. Cell,1996.86(3): p.353-364.
22. Kerbel, R.S., Tumor angiogenesis: past, present and the near future. Carcinogenesis,2000.21(3): p.505-515.
23. Foekens, J.A., Peters, H.A., Grebenchtchikov, N., et al., High tumor levels of vascular endothelialgrowth factor predict poor response to systemic therapy in advanced breast cancer. Cancer Res,
2001.61(14): p.5407-5414.
24. Nakopoulou, L., Stefanaki, K., Panayotopoulou, E., et al., Expression of the vascular endothelialgrowth factor receptor-2/Flk-1in breast carcinomas: correlation with proliferation. Hum Pathol,
2002.33(9): p.863-870.
25. Banerjee, S., Dowsett, M., Ashworth, A., et al., Mechanisms of disease: angiogenesis and themanagement of breast cancer. Nat Clin Pract Oncol,2007.4(9): p.536-550.
26. Nowak, D.G., Woolard, J., Amin, E.M., et al., Expression of pro-and anti-angiogenic isoforms ofVEGF is differentially regulated by splicing and growth factors. J Cell Sci,2008.121(Pt20): p.3487-3495.
27. Woolard, J., Wang, W.Y., Bevan, H.S., et al., VEGF165b, an inhibitory vascular endothelial growthfactor splice variant: mechanism of action, in vivo effect on angiogenesis and endogenous proteinexpression. Cancer Res,2004.64(21): p.7822-7835.
28. Bates, D.O., Cui, T.G., Doughty, J.M., et al., VEGF165b, an inhibitory splice variant of vascularendothelial growth factor, is down-regulated in renal cell carcinoma. Cancer Res,2002.62(14): p.4123-4131.
29. Varey, A.H., Rennel, E.S., Qiu, Y., et al., VEGF165b, an antiangiogenic VEGF-A isoform, bindsand inhibits bevacizumab treatment in experimental colorectal carcinoma: balance of pro-andantiangiogenic VEGF-A isoforms has implications for therapy. Br J Cancer,2008.98(8): p.1366-1379.
30. Soker, S., Takashima, S., Miao, H.Q., et al., Neuropilin-1is expressed by endothelial and tumorcells as an isoform-specific receptor for vascular endothelial growth factor. Cell,1998.92(6): p.735-745.
31. Pan, Q., Chathery, Y., Wu, Y., et al., Neuropilin-1binds to VEGF121and regulates endothelial cellmigration and sprouting. J Biol Chem,2007.282(33): p.24049-24056.
32. Partanen, J., Armstrong, E., Makela, T.P., et al., A novel endothelial cell surface receptor tyrosinekinase with extracellular epidermal growth factor homology domains. Mol Cell Biol,1992.12(4): p.1698-1707.
33. Ziegler, S.F., Bird, T.A., Schneringer, J.A., et al., Molecular cloning and characterization of a novelreceptor protein tyrosine kinase from human placenta. Oncogene,1993.8(3): p.663-670.
34. Marron, M.B., Hughes, D.P., Edge, M.D., et al., Evidence for heterotypic interaction between thereceptor tyrosine kinases TIE-1and TIE-2. J Biol Chem,2000.275(50): p.39741-39746.
35. Thomas, M. and Augustin, H.G., The role of the Angiopoietins in vascular morphogenesis.Angiogenesis,2009.12(2): p.125-137.
36. Eklund, L. and Olsen, B.R., Tie receptors and their angiopoietin ligands are context-dependentregulators of vascular remodeling. Exp Cell Res,2006.312(5): p.630-641.
37. Fiedler, U., Scharpfenecker, M., Koidl, S., et al., The Tie-2ligand angiopoietin-2is stored in andrapidly released upon stimulation from endothelial cell Weibel-Palade bodies. Blood,2004.103(11):p.4150-4156.
38. Kim, I., Kim, J.H., Moon, S.O., et al., Angiopoietin-2at high concentration can enhance endothelialcell survival through the phosphatidylinositol3'-kinase/Akt signal transduction pathway. Oncogene,
2000.19(39): p.4549-4552.
39. Lin, P., Buxton, J.A., Acheson, A., et al., Antiangiogenic gene therapy targeting theendothelium-specific receptor tyrosine kinase Tie2. Proc Natl Acad Sci U S A,1998.95(15): p.8829-8834.
40. Raikwar, S.P., Temm, C.J., Raikwar, N.S., et al., Adenoviral vectors expressing humanendostatin-angiostatin and soluble Tie2: enhanced suppression of tumor growth and antiangiogeniceffects in a prostate tumor model. Mol Ther,2005.12(6): p.1091-1100.
41. Hayes, A.J., Huang, W.Q., Mallah, J., et al., Angiopoietin-1and its receptor Tie-2participate in theregulation of capillary-like tubule formation and survival of endothelial cells. Microvasc Res,1999.58(3): p.224-237.
42. Santel, A., Aleku, M., Keil, O., et al., A novel siRNA-lipoplex technology for RNA interference inthe mouse vascular endothelium. Gene Ther,2006.13(16): p.1222-1234.
43. Niu, Q., Perruzzi, C., Voskas, D., et al., Inhibition of Tie-2signaling induces endothelial cellapoptosis, decreases Akt signaling, and induces endothelial cell expression of the endogenousanti-angiogenic molecule, thrombospondin-1. Cancer Biol Ther,2004.3(4): p.402-405.
44. Tournaire, R., Simon, M.P., le Noble, F., et al., A short synthetic peptide inhibits signal transduction,migration and angiogenesis mediated by Tie2receptor. EMBO Rep,2004.5(3): p.262-267.
45. Popkov, M., Jendreyko, N., McGavern, D.B., et al., Targeting tumor angiogenesis withadenovirus-delivered anti-Tie-2intrabody. Cancer Res,2005.65(3): p.972-981.
46. Suzuki, Y., Komi, Y., Ashino, H., et al., Retinoic acid controls blood vessel formation bymodulating endothelial and mural cell interaction via suppression of Tie2signaling in vascularprogenitor cells. Blood,2004.104(1): p.166-169.
47. Johnson, N.W., Semones, M., Adams, J.L., et al., Optimization of triarylimidazoles for Tie2:influence of conformation on potency. Bioorg Med Chem Lett,2007.17(20): p.5514-5517.
48. Fiedler, U. and Augustin, H.G., Angiopoietins: a link between angiogenesis and inflammation.Trends Immunol,2006.27(12): p.552-558.
49. Matsumura, Y. and Maeda, H., A new concept for macromolecular therapeutics in cancerchemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agentsmancs. Cancer Res,1986.46(12Pt1): p.6387-6392.
50. Maeda, H., Tumor-Selective Delivery of Macromolecular Drugs via the EPR Effect: Backgroundand Future Prospects. Bioconjug Chem,2010.
51. Greish, K., Enhanced permeability and retention of macromolecular drugs in solid tumors: a royalgate for targeted anticancer nanomedicines. J Drug Target,2007.15(7-8): p.457-464.
52. Duncan R. and T-N., S., Tumour targeting by enhanced permeability and retention (EPR) effect.Ann. Oncol.,1998.9(Suppl.2).
53. Yuan, F., Dellian, M., Fukumura, D., et al., Vascular permeability in a human tumor xenograft:molecular size dependence and cutoff size. Cancer Res,1995.55(17): p.3752-3756.
54. Ishida, O., Maruyama, K., Sasaki, K., et al., Size-dependent extravasation and interstitiallocalization of polyethyleneglycol liposomes in solid tumor-bearing mice. Int J Pharm,1999.190(1): p.49-56.
55. Iyer, A.K., Khaled, G., Fang, J., et al., Exploiting the enhanced permeability and retention effect fortumor targeting. Drug Discov Today,2006.11(17-18): p.812-818.
56. Fahr, A., van Hoogevest, P., May, S., et al., Transfer of lipophilic drugs between liposomalmembranes and biological interfaces: consequences for drug delivery. Eur J Pharm Sci,2005.26(3-4): p.251-265.
57. Scott, L.J. and Goa, K.L., Verteporfin. Drugs Aging,2000.16(2): p.139-146; discussion147-138.
58. Browder, T., Butterfield, C.E., Kraling, B.M., et al., Antiangiogenic scheduling of chemotherapyimproves efficacy against experimental drug-resistant cancer. Cancer Res,2000.60(7): p.1878-1886.
59. Kerbel, R.S. and Kamen, B.A., The anti-angiogenic basis of metronomic chemotherapy. Nat RevCancer,2004.4(6): p.423-436.
60. Andre, N., Padovani, L. and Verschuur, A., Metronomic chemotherapy: Back to the future! DrugNews Perspect,2010.23(2): p.143-151.
61. Wong, N.S., Buckman, R.A., Clemons, M., et al., Phase I/II trial of metronomic chemotherapy withdaily dalteparin and cyclophosphamide, twice-weekly methotrexate, and daily prednisone astherapy for metastatic breast cancer using vascular endothelial growth factor and soluble vascularendothelial growth factor receptor levels as markers of response. J Clin Oncol,2010.28(5): p.723-730.
62. Tonini, G., Schiavon, G., Silletta, M., et al., Antiangiogenic properties of metronomicchemotherapy in breast cancer. Future Oncol,2007.3(2): p.183-190.
63. Hanahan, D., Bergers, G. and Bergsland, E., Less is more, regularly: metronomic dosing ofcytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest,2000.105(8): p.1045-1047.
64.侯继院,沈方臻and安永恒,低剂量节律化疗——抗肿瘤血管生成的新思路.国际肿瘤学杂志,2007.34(9): p.4.
65. Bocci, G., Francia, G., Man, S., et al., Thrombospondin1, a mediator of the antiangiogenic effectsof low-dose metronomic chemotherapy. Proc Natl Acad Sci U S A,2003.100(22): p.12917-12922.
66. Hamano, Y., Sugimoto, H., Soubasakos, M.A., et al., Thrombospondin-1associated with tumormicroenvironment contributes to low-dose cyclophosphamide-mediated endothelial cell apoptosisand tumor growth suppression. Cancer Res,2004.64(5): p.1570-1574.
67.王云,杜伟and李醒亚,以抗血管生成为基础的节律化疗研究进展.现代肿瘤医学,2007.15(10): p.3.
68. Mutsaers, A.J., Metronomic chemotherapy. Top Companion Anim Med,2009.24(3): p.137-143.
69. Bocci, G., Nicolaou, K.C. and Kerbel, R.S., Protracted low-dose effects on human endothelial cellproliferation and survival in vitro reveal a selective antiangiogenic window for variouschemotherapeutic drugs. Cancer Res,2002.62(23): p.6938-6943.
70. Emmenegger, U., Man, S., Shaked, Y., et al., A comparative analysis of low-dose metronomiccyclophosphamide reveals absent or low-grade toxicity on tissues highly sensitive to the toxiceffects of maximum tolerated dose regimens. Cancer Res,2004.64(11): p.3994-4000.
71. Wang, J., Lou, P., Lesniewski, R., et al., Paclitaxel at ultra low concentrations inhibits angiogenesiswithout affecting cellular microtubule assembly. Anticancer Drugs,2003.14(1): p.13-19.
72. Hashimoto, K., Man, S., Xu, P., et al., Potent preclinical impact of metronomic low-dose oraltopotecan combined with the antiangiogenic drug pazopanib for the treatment of ovarian cancer.Mol Cancer Ther,2010.9(4): p.996-1006.
73. Tang, T.C., Man, S., Lee, C.R., et al., Impact of metronomic UFT/cyclophosphamide chemotherapyand antiangiogenic drug assessed in a new preclinical model of locally advanced orthotopichepatocellular carcinoma. Neoplasia,2010.12(3): p.264-274.
74. Daenen, L.G., Shaked, Y., Man, S., et al., Low-dose metronomic cyclophosphamide combined withvascular disrupting therapy induces potent antitumor activity in preclinical human tumor xenograftmodels. Mol Cancer Ther,2009.8(10): p.2872-2881.
75. Clarke, J.L., Iwamoto, F.M., Sul, J., et al., Randomized phase II trial of chemoradiotherapyfollowed by either dose-dense or metronomic temozolomide for newly diagnosed glioblastoma. JClin Oncol,2009.27(23): p.3861-3867.
76. Glode, L.M., Barqawi, A., Crighton, F., et al., Metronomic therapy with cyclophosphamide anddexamethasone for prostate carcinoma. Cancer,2003.98(8): p.1643-1648.
77. El Bary, N.A., Hashem, T., Metwally, H., et al., A phase II study of high-dose celecoxib andmetronomic 'low-dose' cyclophosphamide and methotrexate in patients with relapsed and refractorylymphoma. Hematol Oncol Stem Cell Ther,2010.3(1): p.13-18.
78. Lam, T., Hetherington, J.W., Greenman, J., et al., From total empiricism to a rational design ofmetronomic chemotherapy phase I dosing trials. Anticancer Drugs,2006.17(2): p.113-121.
79.陈庆华and张强,药物微囊化新技术及应用.2008:人民卫生出版社.
80. Williams, D.F., On the nature of biomaterials. Biomaterials,2009.30(30): p.5897-5909.
81. Shankaran, D.R. and Miura, N., Recent progress and challenges in nanotechnology for biomedicalapplications: an insight into the analysis of neurotransmitters. Recent Pat Nanotechnol,2007.1(3):p.210-223.
82. Barratt, G.M., Therapeutic applications of colloidal drug carriers. Pharm Sci Technolo Today,2000.3(5): p.163-171.
83. Singh, R. and Lillard, J.W., Jr., Nanoparticle-based targeted drug delivery. Exp Mol Pathol,2009.86(3): p.215-223.
84. Linhardt, R.J., Biodegradable polymers for controlled release of drugs. Controlled Release of Drugs,ed. M. Rosoff.1989, New York: VCH Publishers.43.
85. Desai, M.P., Labhasetwar, V., Walter, E., et al., The mechanism of uptake of biodegradablemicroparticles in Caco-2cells is size dependent. Pharm Res,1997.14(11): p.1568-1573.
86. Panyam, J. and Labhasetwar, V., Biodegradable nanoparticles for drug and gene delivery to cellsand tissue. Adv Drug Deliv Rev,2003.55(3): p.329-347.
87. Romero, E.L. and Morilla, M.J., Drug delivery systems against leishmaniasis? Still an openquestion. Expert Opin Drug Deliv,2008.5(7): p.805-823.
88. Hoffman, A.S., The origins and evolution of "controlled" drug delivery systems. J Control Release,
2008.132(3): p.153-163.
89. Orive, G., Anitua, E., Pedraz, J.L., et al., Biomaterials for promoting brain protection, repair andregeneration. Nat Rev Neurosci,2009.10(9): p.682-692.
90. Bangham, A.D., Standish, M.M. and Watkins, J.C., Diffusion of univalent ions across the lamellaeof swollen phospholipids. J Mol Biol,1965.13(1): p.238-252.
91. Rolf, D. Liposomes-Classification, Processing Technologies, Industry Applications and RiskAssessment.2005; Available from: http://www.azonano.com/Details.asp?ArticleID=1243.
92. Jakubowski. Lipid Structure.2010; Availablefrom: http://employees.csbsju.edu/hjakubowski/classes/ch331/lipidstruct/ollipidintro1.html.
93. Mouritsen, O.G. and Jorgensen, K., Dynamical order and disorder in lipid bilayers. Chem PhysLipids,1994.73(1-2): p.3-25.
94. Barenholz, Y., Sphingomyelin and cholesterol: from membrane biophysics and rafts to potentialmedical applications. Membrane Dynamics and Domain, Subcellular Biochemistry, ed. P.J. Quinn.Vol.37.2004, New York: Kluwer Academic/Plenum Publishers.49.
95. Rahman, Y.E., Cerny, E.A., Tollaksen, S.L., et al., Liposome-encapsulated actinomycin D: potentialin cancer chemotherapy. Proc Soc Exp Biol Med,1974.146(4): p.1173-1176.
96. Budai, M. and Szogyi, M.,[Liposomes as drug carrier systems. Preparation, classification andtherapeutic advantages of liposomes]. Acta Pharm Hung,2001.71(1): p.114-118.
97. Tan, M.L., Choong, P.F. and Dass, C.R., Recent developments in liposomes, microparticles andnanoparticles for protein and peptide drug delivery. Peptides,2010.31(1): p.184-193.
98. Moen, M.D., Lyseng-Williamson, K.A. and Scott, L.J., Liposomal amphotericin B: a review of itsuse as empirical therapy in febrile neutropenia and in the treatment of invasive fungal infections.Drugs,2009.69(3): p.361-392.
99. Ostro, M.J. and Cullis, P.R., Use of liposomes as injectable-drug delivery systems. Am J HospPharm,1989.46(8): p.1576-1587.
100. NeXstar Pharmaceuticals lauches DaunoXome. J Int Assoc Physicians AIDS Care,1996.2(6): p.
52.
101. Drummond, D.C., Meyer, O., Hong, K., et al., Optimizing liposomes for delivery ofchemotherapeutic agents to solid tumors. Pharmacol Rev,1999.51(4): p.691-743.
102. Gabizon, A. and Papahadjopoulos, D., Liposome formulations with prolonged circulation time inblood and enhanced uptake by tumors. Proc Natl Acad Sci U S A,1988.85(18): p.6949-6953.
103. Allen, T.M., Hansen, C. and Rutledge, J., Liposomes with prolonged circulation times: factorsaffecting uptake by reticuloendothelial and other tissues. Biochim Biophys Acta,1989.981(1): p.27-35.
104. Yamauchi, H., Yano, T., Kato, T., et al., Effects of sialic acid derivative on long circulation time andtumor concentration of liposomes International Journal of Pharmaceutics,1995.113(2): p.8.
105. Allen, T.M., Hansen, C., Martin, F., et al., Liposomes containing synthetic lipid derivatives ofpoly(ethylene glycol) show prolonged circulation half-lives in vivo. Biochim Biophys Acta,1991.1066(1): p.29-36.
106. Cattel, L., Ceruti, M. and Dosio, F., From conventional to stealth liposomes: a new Frontier incancer chemotherapy. J Chemother,2004.16Suppl4: p.94-97.
107. Allen, C., Dos Santos, N., Gallagher, R., et al., Controlling the physical behavior and biologicalperformance of liposome formulations through use of surface grafted poly(ethylene glycol). BiosciRep,2002.22(2): p.225-250.
108. Du, H., Chandaroy, P. and Hui, S.W., Grafted poly-(ethylene glycol) on lipid surfaces inhibitsprotein adsorption and cell adhesion. Biochim Biophys Acta,1997.1326(2): p.236-248.
109. Yan, X., Scherphof, G.L. and Kamps, J.A., Liposome opsonization. J Liposome Res,2005.15(1-2):p.109-139.
110. Vert, M. and Domurado, D., Poly(ethylene glycol): protein-repulsive or albumin-compatible? JBiomater Sci Polym Ed,2000.11(12): p.1307-1317.
111. Swenson, C.E., Bolcsak, L.E., Batist, G., et al., Pharmacokinetics of doxorubicin administered i.v.as Myocet (TLC D-99; liposome-encapsulated doxorubicin citrate) compared with conventionaldoxorubicin when given in combination with cyclophosphamide in patients with metastatic breastcancer. Anticancer Drugs,2003.14(3): p.239-246.
112. Ranson, M.R., Carmichael, J., O'Byrne, K., et al., Treatment of advanced breast cancer withsterically stabilized liposomal doxorubicin: results of a multicenter phase II trial. J Clin Oncol,
1997.15(10): p.3185-3191.
113. Harris, L., Winer, E. and Batist, G., Phase III study of TLC D-99(liposome-encapsulateddoxorubicin) vs free doxorubicin in patients with metastatic breast carcinoma (MBC) Proc AmSoc Clin Oncol1998.17(124a).
114. Bennett, C.L. and Calhoun, E.A., Pharmacoeconomics of liposomal anthracycline therapy. SeminOncol,2004.31(6Suppl13): p.191-195.
115. von Moos, R., Thuerlimann, B.J., Aapro, M., et al., Pegylated liposomal doxorubicin-associatedhand-foot syndrome: recommendations of an international panel of experts. Eur J Cancer,2008.44(6): p.781-790.
116. Ishida, T., Kashima, S. and Kiwada, H., The contribution of phagocytic activity of livermacrophages to the accelerated blood clearance (ABC) phenomenon of PEGylated liposomes inrats. J Control Release,2008.126(2): p.162-165.
117. Ishida, T. and Kiwada, H., Accelerated blood clearance (ABC) phenomenon upon repeated injectionof PEGylated liposomes. Int J Pharm,2008.354(1-2): p.56-62.
118. Shehata, T., Ogawara, K., Higaki, K., et al., Prolongation of residence time of liposome bysurface-modification with mixture of hydrophilic polymers. Int J Pharm,2008.359(1-2): p.272-279.
119. Chen, Q., Tong, S., Dewhirst, M.W., et al., Targeting tumor microvessels using doxorubicinencapsulated in a novel thermosensitive liposome. Mol Cancer Ther,2004.3(10): p.1311-1317.
120. Merlin, J.L., In vitro evaluation of the association of thermosensitive liposome-encapsulateddoxorubicin with hyperthermia. Eur J Cancer,1991.27(8): p.1031-1034.
121. Chelvi, T.P. and Ralhan, R., Hyperthermia potentiates antitumor effect ofthermosensitive-liposome-encapsulated melphalan and radiation in murine melanoma. Tumour Biol,
1997.18(4): p.250-260.
122. Needham, D., Anyarambhatla, G., Kong, G., et al., A new temperature-sensitive liposome for usewith mild hyperthermia: characterization and testing in a human tumor xenograft model. CancerRes,2000.60(5): p.1197-1201.
123. Banno, B., Ickenstein, L.M., Chiu, G.N., et al., The functional roles of poly(ethylene glycol)-lipidand lysolipid in the drug retention and release from lysolipid-containing thermosensitive liposomesin vitro and in vivo. J Pharm Sci,2010.99(5): p.2295-2308.
124. Woodburn, K.W., Engelman, C.J. and Blumenkranz, M.S., Photodynamic therapy for choroidalneovascularization: a review. Retina,2002.22(4): p.391-405; quiz527-398.
125. Richter, A.M., Waterfield, E., Jain, A.K., et al., Liposomal delivery of a photosensitizer,benzoporphyrin derivative monoacid ring A (BPD), to tumor tissue in a mouse tumor model.Photochem Photobiol,1993.57(6): p.1000-1006.
126. Hazemoto, N., Harada, M., Suzuki, S., et al., Effect of phosphatidylcholine and cholesterol onpH-sensitive liposomes. Chem Pharm Bull (Tokyo),1993.41(6): p.1003-1006.
127. Klegerman, M.E., Wassler, M., Huang, S.L., et al., Liposomal modular complexes for simultaneoustargeted delivery of bioactive gases and therapeutics. J Control Release,2010.142(3): p.326-331.
128. Kirpotin, D., Hong, K., Mullah, N., et al., Liposomes with detachable polymer coating:destabilization and fusion of dioleoylphosphatidylethanolamine vesicles triggered by cleavage ofsurface-grafted poly(ethylene glycol). FEBS Lett,1996.388(2-3): p.115-118.
129. Huang, Z., Li, W., MacKay, J.A., et al., Thiocholesterol-based lipids for ordered assembly ofbioresponsive gene carriers. Mol Ther,2005.11(3): p.409-417.
130. Wang, J., Sui, M. and Fan, W., Nanoparticles for tumor targeted therapies and theirpharmacokinetics. Curr Drug Metab,2010.11(2): p.129-141.
131. Garcia, M., Jemal, A., Ward, E.M., et al. Global Cancer Facts&Figures2007.2007.
132. Parkin, D.M., Bray, F., Ferlay, J., et al., Global Cancer Statistics,2002. CA Cancer J Clin,2005.55:p.35.
133.卫生部新闻办公室,第三次全国死因调查主要情况.中国肿瘤,2008.05: p.2.
134.董志伟,乔友林,李连弟, et al.,中国癌症控制策略研究报告.中国肿瘤,2002.05: p.11.
135. Smith, S.L., Ten years of Orthoclone OKT3(muromonab-CD3): a review. J Transpl Coord,1996.6(3): p.109-119; quiz120-101.
136. Shaw, T., Quan, J. and Totoritis, M.C., B cell therapy for rheumatoid arthritis: the rituximab(anti-CD20) experience. Ann Rheum Dis,2003.62Suppl2: p. ii55-59.
137. Maloney, D.G., Grillo-Lopez, A.J., White, C.A., et al., IDEC-C2B8(Rituximab) anti-CD20monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood,
1997.90(6): p.2188-2195.
138. Brufsky, A., Trastuzumab-based therapy for patients with HER2-positive breast cancer: from earlyscientific development to foundation of care. Am J Clin Oncol,2010.33(2): p.186-195.
139. Yang, S.X., Bevacizumab and breast cancer: current therapeutic progress and future perspectives.Expert Rev Anticancer Ther,2009.9(12): p.1715-1725.
140. Wagstaff, A.J., Keam, S.J. and McCormack, P.L., Bevacizumab plus platinum-based chemotherapy:in advanced non-small cell lung cancer. BioDrugs,2009.23(3): p.187-196.
141. Bogdahn, U., Schneider, T., Oliushine, V., et al., Randomized, active-controlled phase IIb studywith trabedersen (AP12009) in recurrent or refractory high-grade glioma patients: Basis for phaseIII endpoints, in2009ASCO Annual Meeting2009, J Clin Oncol. p.15s.
142. Bates, P.J., Laber, D.A., Miller, D.M., et al., Discovery and development of the G-richoligonucleotide AS1411as a novel treatment for cancer. Exp Mol Pathol,2009.86(3): p.151-164.
143. Soundararajan, S., Chen, W., Spicer, E.K., et al., The nucleolin targeting aptamer AS1411destabilizes Bcl-2messenger RNA in human breast cancer cells. Cancer Res,2008.68(7): p.2358-2365.
144. Yahagi, Y., Usui, N., Yamaguchi, Y., et al., Fractionated administration of gemtuzumab ozogamicinfor refractory acute myeloid leukemia. Rinsho Ketsueki,2009.50(11): p.1601-1606.
145. Goldsmith, S.J., Radioimmunotherapy of lymphoma: bexxar and zevalin. Semin Nucl Med,2010.40(2): p.122-135.
146. Thomas, F.C., Taskar, K., Rudraraju, V., et al., Uptake of ANG1005, a novel paclitaxel derivative,through the blood-brain barrier into brain and experimental brain metastases of breast cancer.Pharm Res,2009.26(11): p.2486-2494.
147. Holmberg, E., Maruyama, K., Litzinger, D.C., et al., Highly efficient immunoliposomes preparedwith a method which is compatible with various lipid compositions. Biochem Biophys ResCommun,1989.165(3): p.1272-1278.
148. Bogdanov, A.A., Jr., Klibanov, A.L. and Torchilin, V.P., Protein immobilization on the surface ofliposomes via carbodiimide activation in the presence of N-hydroxysulfosuccinimide. FEBS Lett,
1988.231(2): p.381-384.
149. Aragnol, D. and Leserman, L.D., Immune clearance of liposomes inhibited by an anti-Fc receptorantibody in vivo. Proc Natl Acad Sci U S A,1986.83(8): p.2699-2703.
150. Papahadjopoulos, D., Allen, T.M., Gabizon, A., et al., Sterically stabilized liposomes:improvements in pharmacokinetics and antitumor therapeutic efficacy. Proc Natl Acad Sci U S A,
1991.88(24): p.11460-11464.
151. Hosoda, J., Unezaki, S., Maruyama, K., et al., Antitumor activity of doxorubicin encapsulated inpoly(ethylene glycol)-coated liposomes. Biol Pharm Bull,1995.18(9): p.1234-1237.
152. Matsumura, Y., Gotoh, M., Muro, K., et al., Phase I and pharmacokinetic study of MCC-465, adoxorubicin (DXR) encapsulated in PEG immunoliposome, in patients with metastatic stomachcancer. Ann Oncol,2004.15(3): p.517-525.
153. Mori, A., Klibanov, A.L., Torchilin, V.P., et al., Influence of the steric barrier activity ofamphipathic poly(ethyleneglycol) and ganglioside GM1on the circulation time of liposomes and onthe target binding of immunoliposomes in vivo. FEBS Lett,1991.284(2): p.263-266.
154. Maruyama, K., PEG-immunoliposome. Biosci Rep,2002.22(2): p.251-266.
155. Weitman, S.D., Weinberg, A.G., Coney, L.R., et al., Cellular localization of the folate receptor:potential role in drug toxicity and folate homeostasis. Cancer Res,1992.52(23): p.6708-6711.
156. Wu, M., Gunning, W. and Ratnam, M., Expression of folate receptor type alpha in relation to celltype, malignancy, and differentiation in ovary, uterus, and cervix. Cancer Epidemiol BiomarkersPrev,1999.8(9): p.775-782.
157. Lee, R.J. and Low, P.S., Folate-mediated tumor cell targeting of liposome-entrapped doxorubicin invitro. Biochim Biophys Acta,1995.1233(2): p.134-144.
158. Shmeeda, H., Mak, L., Tzemach, D., et al., Intracellular uptake and intracavitary targeting offolate-conjugated liposomes in a mouse lymphoma model with up-regulated folate receptors. MolCancer Ther,2006.5(4): p.818-824.
159. Gabizon, A., Horowitz, A.T., Goren, D., et al., In vivo fate of folate-targeted polyethylene-glycolliposomes in tumor-bearing mice. Clin Cancer Res,2003.9(17): p.6551-6559.
160. Yamada, A., Taniguchi, Y., Kawano, K., et al., Design of folate-linked liposomal doxorubicin to itsantitumor effect in mice. Clin Cancer Res,2008.14(24): p.8161-8168.
161. Yamamoto, M., Ichinose, K., Ishii, N., et al., Utility of liposomes coated with polysaccharidebearing1-amino-lactose as targeting chemotherapy for AH66hepatoma cells. Oncol Rep,2000.7(1): p.107-111.
162. Diaz, C., Vargas, E. and Gatjens-Boniche, O., Cytotoxic effect induced by retinoic acid loaded intogalactosyl-sphingosine containing liposomes on human hepatoma cell lines. Int J Pharm,2006.325(1-2): p.108-115.
163. Allen, T.M., Brandeis, E., Hansen, C.B., et al., A new strategy for attachment of antibodies tosterically stabilized liposomes resulting in efficient targeting to cancer cells. Biochim Biophys Acta,
1995.1237(2): p.99-108.
164. Kirpotin, D., Park, J.W., Hong, K., et al., Sterically stabilized anti-HER2immunoliposomes: designand targeting to human breast cancer cells in vitro. Biochemistry,1997.36(1): p.66-75.
165. Park, J.W., Hong, K., Kirpotin, D.B., et al., Anti-HER2immunoliposomes for targeted therapy ofhuman tumors. Cancer Lett,1997.118(2): p.153-160.
166. Park, J.W., Kirpotin, D.B., Hong, K., et al., Tumor targeting using anti-her2immunoliposomes. JControl Release,2001.74(1-3): p.95-113.
167. Park, J.W., Hong, K., Kirpotin, D.B., et al., Anti-HER2immunoliposomes: enhanced efficacyattributable to targeted delivery. Clin Cancer Res,2002.8(4): p.1172-1181.
168. Mamot, C., Drummond, D.C., Greiser, U., et al., Epidermal growth factor receptor (EGFR)-targetedimmunoliposomes mediate specific and efficient drug delivery to EGFR-andEGFRvIII-overexpressing tumor cells. Cancer Res,2003.63(12): p.3154-3161.
169. Mamot, C., Ritschard, R., Kung, W., et al., EGFR-targeted immunoliposomes derived from themonoclonal antibody EMD72000mediate specific and efficient drug delivery to a variety ofcolorectal cancer cells. J Drug Target,2006.14(4): p.215-223.
170. Roth, P., Hammer, C., Piguet, A.C., et al., Effects on hepatocellular carcinoma ofdoxorubicin-loaded immunoliposomes designed to target the VEGFR-2. J Drug Target,2007.15(9):p.623-631.
171. Xu, L., Tang, W.H., Huang, C.C., et al., Systemic p53gene therapy of cancer withimmunolipoplexes targeted by anti-transferrin receptor scFv. Mol Med,2001.7(10): p.723-734.
172. Sapra, P. and Allen, T.M., Improved outcome when B-cell lymphoma is treated with combinationsof immunoliposomal anticancer drugs targeted to both the CD19and CD20epitopes. Clin CancerRes,2004.10(7): p.2530-2537.
173. Matsudaira, H., Asakura, T., Aoki, K., et al., Target chemotherapy of anti-CD147antibody-labeledliposome encapsulated GSH-DXR conjugate on CD147highly expressed carcinoma cells. Int JOncol,2010.36(1): p.77-83.
174. Uyama, I., Kumai, K., Yasuda, T., et al., Improvement of therapeutic effect by using Fab' fragmentin the treatment of carcinoembryonic antigen-positive human solid tumors withadriamycin-entrapped immunoliposomes. Jpn J Cancer Res,1994.85(4): p.434-440.
175. Brignole, C., Marimpietri, D., Gambini, C., et al., Development of Fab' fragments of anti-GD(2)immunoliposomes entrapping doxorubicin for experimental therapy of human neuroblastoma.Cancer Lett,2003.197(1-2): p.199-204.
176. Kannagi, R., Use of liposomes containing carbohydrates for production of monoclonal antibodies.Methods Mol Biol,2002.199: p.203-218.
177. Graf, J., Ogle, R.C., Robey, F.A., et al., A pentapeptide from the laminin B1chain mediates celladhesion and binds the67,000laminin receptor. Biochemistry,1987.26(22): p.6896-6900.
178. Lopez-Barcons, L.A., Polo, D., Reig, F., et al., Pentapeptide YIGSR-mediated HT-1080fibrosarcoma cells targeting of adriamycin encapsulated in sterically stabilized liposomes. J BiomedMater Res A,2004.69(1): p.155-163.
179. D'Souza, S.E., Ginsberg, M.H. and Plow, E.F., Arginyl-glycyl-aspartic acid (RGD): a cell adhesionmotif. Trends Biochem Sci,1991.16(7): p.246-250.
180. Koning, G.A., Fretz, M.M., Woroniecka, U., et al., Targeting liposomes to tumor endothelial cellsfor neutron capture therapy. Appl Radiat Isot,2004.61(5): p.963-967.
181. Schiffelers, R.M., Koning, G.A., ten Hagen, T.L., et al., Anti-tumor efficacy of tumorvasculature-targeted liposomal doxorubicin. J Control Release,2003.91(1-2): p.115-122.
182. Janssen, A.P., Schiffelers, R.M., ten Hagen, T.L., et al., Peptide-targeted PEG-liposomes inanti-angiogenic therapy. Int J Pharm,2003.254(1): p.55-58.
183. Garg, A., Tisdale, A.W., Haidari, E., et al., Targeting colon cancer cells using PEGylated liposomesmodified with a fibronectin-mimetic peptide. Int J Pharm,2009.366(1-2): p.201-210.
184. Demirgoz, D., Garg, A. and Kokkoli, E., PR_b-targeted PEGylated liposomes for prostate cancertherapy. Langmuir,2008.24(23): p.13518-13524.
185. Kondo, M., Asai, T., Katanasaka, Y., et al., Anti-neovascular therapy by liposomal drug targeted tomembrane type-1matrix metalloproteinase. Int J Cancer,2004.108(2): p.301-306.
186. Song, S., Liu, D., Peng, J., et al., Peptide ligand-mediated liposome distribution and targeting toEGFR expressing tumor in vivo. Int J Pharm,2008.363(1-2): p.155-161.
187. Maeda, N., Takeuchi, Y., Takada, M., et al., Synthesis of angiogenesis-targeted peptide andhydrophobized polyethylene glycol conjugate. Bioorg Med Chem Lett,2004.14(4): p.1015-1017.
188. Pastorino, F., Brignole, C., Marimpietri, D., et al., Vascular damage and anti-angiogenic effects oftumor vessel-targeted liposomal chemotherapy. Cancer Res,2003.63(21): p.7400-7409.
189. Akita, N., Maruta, F., Seymour, L.W., et al., Identification of oligopeptides binding to peritonealtumors of gastric cancer. Cancer Sci,2006.97(10): p.1075-1081.
190. Song, S., Liu, D., Peng, J., et al., Novel peptide ligand directs liposomes toward EGF-Rhigh-expressing cancer cells in vitro and in vivo. FASEB J,2009.23(5): p.1396-1404.
191. Goncalves, V., Gautier, B., Coric, P., et al., Rational design, structure, and biological evaluation ofcyclic peptides mimicking the vascular endothelial growth factor. J Med Chem,2007.50(21): p.5135-5146.
192. Li, X., Ding, L., Xu, Y., et al., Targeted delivery of doxorubicin using stealth liposomes modifiedwith transferrin. Int J Pharm,2009.373(1-2): p.116-123.
193. Rosenberg, M.B., Breakefield, X.O. and Hawrot, E., Targeting of liposomes to cells bearing nervegrowth factor receptors mediated by biotinylated nerve growth factor. J Neurochem,1987.48(3): p.865-875.
194. Kang, H., O'Donoghue, M.B., Liu, H., et al., A liposome-based nanostructure for aptamer directeddelivery. Chem Commun (Camb),2010.46(2): p.249-251.
195. Brown, K.C., Peptidic tumor targeting agents: the road from phage display peptide selections toclinical applications. Curr Pharm Des,2010.16(9): p.1040-1054.
196. Ekins, S., Mestres, J. and Testa, B., In silico pharmacology for drug discovery: methods for virtualligand screening and profiling. Br J Pharmacol,2007.152(1): p.9-20.
197. Klebe, G., Virtual ligand screening: strategies, perspectives and limitations. Drug Discov Today,
2006.11(13-14): p.580-594.
198. Pick, D., Novel scoring methods in virtual ligand screening. Methods Mol Biol,2004.275: p.439-448.
199.吴楚and诸慧,噬菌体展示技术.安徽农业科学,2009.37(3): p.3.
200. Peters, E.A., Schatz, P.J., Johnson, S.S., et al., Membrane insertion defects caused by positivecharges in the early mature region of protein pIII of filamentous phage fd can be corrected by prlAsuppressors. J Bacteriol,1994.176(14): p.4296-4305.
201. Willcox, M.D., Hume, E.B., Aliwarga, Y., et al., A novel cationic-peptide coating for the preventionof microbial colonization on contact lenses. J Appl Microbiol,2008.105(6): p.1817-1825.
202. Fidai, S., Farmer, S.W. and Hancock, R.E., Interaction of cationic peptides with bacterialmembranes. Methods Mol Biol,1997.78: p.187-204.
203. Mogi, T. and Kita, K., Gramicidin S and polymyxins: the revival of cationic cyclic peptideantibiotics. Cell Mol Life Sci,2009.66(23): p.3821-3826.
204. Adey, N.B., Mataragnon, A.H., Rider, J.E., et al., Characterization of phage that bind plastic fromphage-displayed random peptide libraries. Gene,1995.156(1): p.27-31.
205. Ph.D.-12phage display peptide library kit instruction manual, version2.7.2006.
206. van de Wijngaart, D.J., Dubbink, H.J., Molier, M., et al., Functional screening of FxxLF-likepeptide motifs identifies SMARCD1/BAF60a as an androgen receptor cofactor that modulatesTMPRSS2expression. Mol Endocrinol,2009.23(11): p.1776-1786.
207. Regina, A., Demeule, M., Che, C., et al., Antitumour activity of ANG1005, a conjugate betweenpaclitaxel and the new brain delivery vector Angiopep-2. Br J Pharmacol,2008.155(2): p.185-197.
208. Demeule, M., Regina, A., Che, C., et al., Identification and design of peptides as a new drugdelivery system for the brain. J Pharmacol Exp Ther,2008.324(3): p.1064-1072.
209. Barton, W.A., Tzvetkova-Robev, D., Miranda, E.P., et al., Crystal structures of the Tie2receptorectodomain and the angiopoietin-2-Tie2complex. Nat Struct Mol Biol,2006.13(6): p.524-532.
210. Giordano, R.J., Cardo-Vila, M., Lahdenranta, J., et al., Biopanning and rapid analysis of selectiveinteractive ligands. Nat Med,2001.7(11): p.1249-1253.
211. White, S.J., Nicklin, S.A., Sawamura, T., et al., Identification of peptides that target the endothelialcell-specific LOX-1receptor. Hypertension,2001.37(2Part2): p.449-455.
212. Ding, N., Xiao, H., Wang, F., et al., A FQHPSFI peptide selectively binds to LPS-activated alveolarmacrophages and inhibits LPS-induced MIP-2production. Inflamm Res,2010.
213. Liu, S., Sivakumar, S., Sparks, W.O., et al., A peptide that binds the pea aphid gut impedes entry ofPea enation mosaic virus into the aphid hemocoel. Virology,2010.401(1): p.107-116.
214. Vrielink, J., Heins, M.S., Setroikromo, R., et al., Synthetic constrained peptide selectively binds andantagonizes death receptor5. FEBS J,2010.277(7): p.1653-1665.
215. Li, Z.J. and Cho, C.H., Development of Peptides as Potential Drugs for Cancer Therapy. CurrPharm Des,2010.
216. Ohkubo, S., Miyadera, K., Sugimoto, Y., et al., Identification of substrate sequences for membranetype-1matrix metalloproteinase using bacteriophage peptide display library. Biochem Biophys ResCommun,1999.266(2): p.308-313.
217. Oku, N., Asai, T., Watanabe, K., et al., Anti-neovascular therapy using novel peptides homing toangiogenic vessels. Oncogene,2002.21(17): p.2662-2669.
218. Kolonin, M.G., Sun, J., Do, K.A., et al., Synchronous selection of homing peptides for multipletissues by in vivo phage display. FASEB J,2006.20(7): p.979-981.
219. Pasqualini, R. and Ruoslahti, E., Organ targeting in vivo using phage display peptide libraries.Nature,1996.380(6572): p.364-366.
220. Lam, P.Y., Jadhav, P.K., Eyermann, C.J., et al., Rational design of potent, bioavailable, nonpeptidecyclic ureas as HIV protease inhibitors. Science,1994.263(5145): p.380-384.
221. Pornillos, O., Alam, S.L., Rich, R.L., et al., Structure and functional interactions of the Tsg101UEV domain. EMBO J,2002.21(10): p.2397-2406.
222.王正鸾,化疗药物的不良反应及护理.中华中西医杂志,2007.8(16).
223. Peters, K.G., Coogan, A., Berry, D., et al., Expression of Tie2/Tek in breast tumour vasculatureprovides a new marker for evaluation of tumour angiogenesis. Br J Cancer,1998.77(1): p.51-56.
224. Willam, C., Koehne, P., Jurgensen, J.S., et al., Tie2receptor expression is stimulated by hypoxiaand proinflammatory cytokines in human endothelial cells. Circ Res,2000.87(5): p.370-377.
225. Martin, V., Liu, D., Fueyo, J., et al., Tie2: a journey from normal angiogenesis to cancer and beyond.Histol Histopathol,2008.23(6): p.773-780.
226. Wade, M.H., de Feijter, A.W. and Frame, M.K., Quantitative fluorescence imaging techniques forthe study of organization and signaling mechanisms in cells. Methods Biochem Anal,1994.37: p.117-141.
227. Pinto, A.L. and Lippard, S.J., Binding of the antitumor drug cis-diamminedichloroplatinum(II)(cisplatin) to DNA. Biochim Biophys Acta,1985.780(3): p.167-180.
228. Pinzani, V., Bressolle, F., Haug, I.J., et al., Cisplatin-induced renal toxicity and toxicity-modulatingstrategies: a review. Cancer Chemother Pharmacol,1994.35(1): p.1-9.
229. Rosenthal, D.I., Yom, S.S., Liu, L., et al., A phase I study of SPI-077(Stealth liposomal cisplatin)concurrent with radiation therapy for locally advanced head and neck cancer. Invest New Drugs,
2002.20(3): p.343-349.
230. Harrington, K.J., Lewanski, C.R., Northcote, A.D., et al., Phase I-II study of pegylated liposomalcisplatin (SPI-077) in patients with inoperable head and neck cancer. Ann Oncol,2001.12(4): p.493-496.
231. White, S.C., Lorigan, P., Margison, G.P., et al., Phase II study of SPI-77(sterically stabilisedliposomal cisplatin) in advanced non-small-cell lung cancer. Br J Cancer,2006.95(7): p.822-828.
232. Bandak, S., Goren, D., Horowitz, A., et al., Pharmacological studies of cisplatin encapsulated inlong-circulating liposomes in mouse tumor models. Anticancer Drugs,1999.10(10): p.911-920.
233. Schroeder, A., Honen, R., Turjeman, K., et al., Ultrasound triggered release of cisplatin fromliposomes in murine tumors. J Control Release,2009.137(1): p.63-68.
234. Schroeder, A., Avnir, Y., Weisman, S., et al., Controlling liposomal drug release with low frequencyultrasound: mechanism and feasibility. Langmuir,2007.23(7): p.4019-4025.
235. Woo, J., Chiu, G.N., Karlsson, G., et al., Use of a passive equilibration methodology to encapsulatecisplatin into preformed thermosensitive liposomes. Int J Pharm,2008.349(1-2): p.38-46.
236. Szoka, F., Jr. and Papahadjopoulos, D., Procedure for preparation of liposomes with large internalaqueous space and high capture by reverse-phase evaporation. Proc Natl Acad Sci U S A,1978.75(9): p.4194-4198.
237. Peleg-Shulman, T., Gibson, D., Cohen, R., et al., Characterization of sterically stabilized cisplatinliposomes by nuclear magnetic resonance. Biochim Biophys Acta,2001.1510(1-2): p.278-291.
238. Andrews, P.A., Wung, W.E. and Howell, S.B., A high-performance liquid chromatographic assaywith improved selectivity for cisplatin and active platinum (II) complexes in plasma ultrafiltrate.Anal Biochem,1984.143(1): p.46-56.
239. Bohl Kullberg, E., Bergstrand, N., Carlsson, J., et al., Development of EGF-conjugated liposomesfor targeted delivery of boronated DNA-binding agents. Bioconjug Chem,2002.13(4): p.737-743.
240. Amin, D.N., Hida, K., Bielenberg, D.R., et al., Tumor endothelial cells express epidermal growthfactor receptor (EGFR) but not ErbB3and are responsive to EGF and to EGFR kinase inhibitors.Cancer Res,2006.66(4): p.2173-2180.
241. Shojaei, F. and Ferrara, N., Antiangiogenesis to treat cancer and intraocular neovascular disorders.Lab Invest,2007.87(3): p.227-230.
242. Sathornsumetee, S. and Rich, J.N., Antiangiogenic therapy in malignant glioma: promise andchallenge. Curr Pharm Des,2007.13(35): p.3545-3558.
243. Griffioen, A.W., Therapeutic approaches of angiogenesis inhibition: are we tackling the problem atthe right level? Trends Cardiovasc Med,2007.17(5): p.171-176.
244. El-Mousawi, M., Tchistiakova, L., Yurchenko, L., et al., A vascular endothelial growth factor highaffinity receptor1-specific peptide with antiangiogenic activity identified using a phage displaypeptide library. J Biol Chem,2003.278(47): p.46681-46691.
245. Benzinger, P., Martiny-Baron, G., Reusch, P., et al., Targeting of endothelial KDR receptors with3G2immunoliposomes in vitro. Biochim Biophys Acta,2000.1466(1-2): p.71-78.
246. Wu, X., Li, Z., Yao, M., et al., Identification and characterization of a novel peptide ligand of Tie2for targeting gene therapy. Acta Biochim Biophys Sin (Shanghai),2008.40(3): p.217-225.
247. Thapa, N., Hong, H.Y., Sangeetha, P., et al., Identification of a peptide ligand recognizingdysfunctional endothelial cells for targeting atherosclerosis. J Control Release,2008.131(1): p.27-33.
248. Hui, X., Han, Y., Liang, S., et al., Specific targeting of the vasculature of gastric cancer by a newtumor-homing peptide CGNSNPKSC. J Control Release,2008.131(2): p.86-93.
249. Qasim, W., Gaspar, H.B. and Thrasher, A.J., Progress and prospects: gene therapy for inheritedimmunodeficiencies. Gene Ther,2009.16(11): p.1285-1291.
250. Cideciyan, A.V., Hauswirth, W.W., Aleman, T.S., et al., Vision1year after gene therapy for Leber'scongenital amaurosis. N Engl J Med,2009.361(7): p.725-727.
251. Jiao, L.R., Havlik, R., Nicholls, J., et al., Suicide gene therapy in liver tumors. Methods Mol Med,
2004.90: p.433-450.
252. Brade, A.M., Szmitko, P., Ngo, D., et al., Heat-directed suicide gene therapy for breast cancer.Cancer Gene Ther,2003.10(4): p.294-301.
253. Foloppe, J., Kintz, J., Futin, N., et al., Targeted delivery of a suicide gene to human colorectaltumors by a conditionally replicating vaccinia virus. Gene Ther,2008.15(20): p.1361-1371.
254. Peng, J., Zhao, Y., Mai, J., et al., Inhibition of hepatitis B virus replication by various RNAiconstructs and their pharmacodynamic properties. J Gen Virol,2005.86(Pt12): p.3227-3234.
255. Luo, D. and Saltzman, W.M., Synthetic DNA delivery systems. Nat Biotechnol,2000.18(1): p.33-37.
256. Rolland, A.P., From genes to gene medicines: recent advances in nonviral gene delivery. Crit RevTher Drug Carrier Syst,1998.15(2): p.143-198.
257. Felgner, P.L., Gadek, T.R., Holm, M., et al., Lipofection: a highly efficient, lipid-mediatedDNA-transfection procedure. Proc Natl Acad Sci U S A,1987.84(21): p.7413-7417.
258. Sieverling, N. Cationic copolymers for non-viral gene delivery Availablefrom: http://www.nano-lifescience.com/research/gene-delivery.html.
259. Xia, C.F., Zhang, Y., Boado, R.J., et al., Intravenous siRNA of brain cancer with receptor targetingand avidin-biotin technology. Pharm Res,2007.24(12): p.2309-2316.
260. Watanabe, T., Umehara, T., Yasui, F., et al., Liver target delivery of small interfering RNA to theHCV gene by lactosylated cationic liposome. J Hepatol,2007.47(6): p.744-750.
261. Ishikawa, A., Zhou, Y.M., Kambe, N., et al., Enhancement of star vector-based gene delivery toendothelial cells by addition of RGD-peptide. Bioconjug Chem,2008.19(2): p.558-561.
262. Casey, G., Cashman, J.P., Morrissey, D., et al., Sonoporation mediated immunogene therapy ofsolid tumors. Ultrasound Med Biol,2010.36(3): p.430-440.
263. Suzuki, R., Namai, E., Oda, Y., et al., Cancer gene therapy by IL-12gene delivery using liposomalbubbles and tumoral ultrasound exposure. J Control Release,2010.142(2): p.245-250.
264. Sheyn, D., Kimelman-Bleich, N., Pelled, G., et al., Ultrasound-based nonviral gene deliveryinduces bone formation in vivo. Gene Ther,2008.15(4): p.257-266.
265. Sakai, T., Kawaguchi, M. and Kosuge, Y., siRNA-mediated gene silencing in the salivary glandusing in vivo microbubble-enhanced sonoporation. Oral Dis,2009.15(7): p.505-511.
266. Clement, N.R. and Gould, J.M., Pyranine (8-hydroxy-1,3,6-pyrenetrisulfonate) as a probe ofinternal aqueous hydrogen ion concentration in phospholipid vesicles. Biochemistry,1981.20(6): p.1534-1538.
267. Clerc, S. and Barenholz, Y., Loading of amphipathic weak acids into liposomes in response totransmembrane calcium acetate gradients. Biochim Biophys Acta,1995.1240(2): p.257-265.
268. Barreto, J. and Lichtenberger, L.M., Vesicle acidification driven by a millionfold proton gradient: amodel for acid influx through gastric cell membranes. Am J Physiol,1992.262(1Pt1): p. G30-34.
269. Biegel, C.M. and Gould, J.M., Kinetics of hydrogen ion diffusion across phospholipid vesiclemembranes. Biochemistry,1981.20(12): p.3474-3479.
270. Zhang, X.H., Khan, A. and Ducker, W.A., A nanoscale gas state. Phys Rev Lett,2007.98(13): p.136101.
271. Jin, F., Ye, X. and Wu, C., Observation of kinetic and structural scalings during slow coalescence ofnanobubbles in an aqueous solution. J Phys Chem B,2007.111(46): p.13143-13146.
272. Carambassis, A., Jonker, L.C., Attard, P., et al., Forces Measured between Hydrophobic Surfacesdue to a Submicroscopic Bridging Bubble. Physical Review Letters,1998.80(24): p.4.
273. Lou, S., Ouyang, Z.Q., Zhang, Y., et al., Nanobubbles on solid surface imaged by atomic forcemicroscopy. J. Vac. Sci. Technol B,2000.18(5): p.3.
274. Edelstein, M. Gene Therapy Clinical Trials Worldwide.2009Dec; Availablefrom: www.wiley.co.uk/genmed/clinical.
275. Audouy, S.A., de Leij, L.F., Hoekstra, D., et al., In vivo characteristics of cationic liposomes asdelivery vectors for gene therapy. Pharm Res,2002.19(11): p.1599-1605.
276. Bedikian, A.Y., Richards, J., Kharkevitch, D., et al., A phase2study of high-dose Allovectin-7inpatients with advanced metastatic melanoma. Melanoma Res,2010.20(3): p.218-226.
277. Bedikian, A.Y. and Del Vecchio, M., Allovectin-7therapy in metastatic melanoma. Expert OpinBiol Ther,2008.8(6): p.839-844.
278. Gonzalez, R., Hutchins, L., Nemunaitis, J., et al., Phase2trial of Allovectin-7in advancedmetastatic melanoma. Melanoma Res,2006.16(6): p.521-526.
279. Galanis, E., Technology evaluation: Allovectin-7, Vical. Curr Opin Mol Ther,2002.4(1): p.80-87.
280. Yoon, C.S. and Park, J.H., Ultrasound-mediated gene delivery. Expert Opin Drug Deliv,2010.7(3):p.321-330.
281. Liang, H.D., Lu, Q.L., Xue, S.A., et al., Optimisation of ultrasound-mediated gene transfer(sonoporation) in skeletal muscle cells. Ultrasound Med Biol,2004.30(11): p.1523-1529.
282. Lentacker, I., Smedt, S.C.D., Demeester, J., et al., Lipoplex-Loaded Microbubbles for GeneDelivery: A Trojan Horse Controlled by Ultrasound. Adv Funct Mater,2007.17(12): p.7.
283. Adkins, S.S., Chen, X., Chan, I., et al., Morphology and stability of CO2-in-water foams withnonionic hydrocarbon surfactants. Langmuir,2010.26(8): p.5335-5348.
284. Wang, X., Liang, H.D., Dong, B., et al., Gene transfer with microbubble ultrasound and plasmidDNA into skeletal muscle of mice: comparison between commercially available microbubblecontrast agents. Radiology,2005.237(1): p.224-229.
285.王燕芳,刘力,魏龙, et al.,小动物正电子断层扫描仪(Micro-PET)技术概述中国体视学与图像分析,2005.3: p.2.
286. Machin, K. and Webb, S., Cone-beam x-ray microtomography of small specimens. Phys Med Biol,
1994.39(10): p.1639-1657.
287.胡广书,李.A.郭.A.唐.A.张.A.,基于X射线的小动物成像micro-CT系统.清华大学学报(自然科学版),2009(06): p.900-903.
288. Sun, X., Annala, A.J., Yaghoubi, S.S., et al., Quantitative imaging of gene induction in livinganimals. Gene Ther,2001.8(20): p.1572-1579.
289. Funovics, M., Weissleder, R. and Tung, C.H., Protease sensors for bioimaging. Anal Bioanal Chem,
2003.377(6): p.956-963.
290. Wang, Y., Yu, Y.A., Shabahang, S., et al., Renilla luciferase-Aequorea GFP (Ruc-GFP) fusionprotein, a novel dual reporter for real-time imaging of gene expression in cell cultures and in liveanimals. Mol Genet Genomics,2002.268(2): p.160-168.
291. Caceres, G., Zhu, X.Y., Jiao, J.A., et al., Imaging of luciferase and GFP-transfected human tumoursin nude mice. Luminescence,2003.18(4): p.218-223.
292. Haran, G., Cohen, R., Bar, L.K., et al., Transmembrane ammonium sulfate gradients in liposomesproduce efficient and stable entrapment of amphipathic weak bases. Biochim Biophys Acta,1993.1151(2): p.201-215.
293. Zucker, D., Marcus, D., Barenholz, Y., et al., Liposome drugs' loading efficiency: a working modelbased on loading conditions and drug's physicochemical properties. J Control Release,2009.139(1):p.73-80.
294. O'Brien, P.C., Procedures for comparing samples with multiple endpoints. Biometrics,1984.40(4):p.1079-1087.
295. Sapra, P., Moase, E.H., Ma, J., et al., Improved therapeutic responses in a xenograft model ofhuman B lymphoma (Namalwa) for liposomal vincristine versus liposomal doxorubicin targeted viaanti-CD19IgG2a or Fab' fragments. Clin Cancer Res,2004.10(3): p.1100-1111.
296. Hobbs, S.K., Monsky, W.L., Yuan, F., et al., Regulation of transport pathways in tumor vessels: roleof tumor type and microenvironment. Proc Natl Acad Sci U S A,1998.95(8): p.4607-4612.
297. Wu, N.Z., Da, D., Rudoll, T.L., et al., Increased microvascular permeability contributes topreferential accumulation of Stealth liposomes in tumor tissue. Cancer Res,1993.53(16): p.3765-3770.
298. Tardi, P., Bally, M.B. and Harasym, T.O., Clearance properties of liposomes involving conjugatedproteins for targeting. Adv Drug Deliv Rev,1998.32(1-2): p.99-118.
299. Gabizon, A.A., Shmeeda, H. and Zalipsky, S., Pros and cons of the liposome platform in cancerdrug targeting. J Liposome Res,2006.16(3): p.175-183.
300. Mastrobattista, E., Koning, G.A. and Storm, G., Immunoliposomes for the targeted delivery ofantitumor drugs. Adv Drug Deliv Rev,1999.40(1-2): p.103-127.
301. Ishida, T., Atobe, K., Wang, X., et al., Accelerated blood clearance of PEGylated liposomes uponrepeated injections: effect of doxorubicin-encapsulation and high-dose first injection. J ControlRelease,2006.115(3): p.251-258.
302. Wang, X., Ishida, T. and Kiwada, H., Anti-PEG IgM elicited by injection of liposomes is involvedin the enhanced blood clearance of a subsequent dose of PEGylated liposomes. J Control Release,
2007.119(2): p.236-244.
303. Koide, H., Asai, T., Hatanaka, K., et al., T cell-independent B cell response is responsible for ABCphenomenon induced by repeated injection of PEGylated liposomes. Int J Pharm,2010.
304. Koning, G.A., Morselt, H.W., Gorter, A., et al., Interaction of differently designedimmunoliposomes with colon cancer cells and Kupffer cells. An in vitro comparison. Pharm Res,
2003.20(8): p.1249-1257.
305. Koning, G.A., Morselt, H.W., Gorter, A., et al., Pharmacokinetics of differently designedimmunoliposome formulations in rats with or without hepatic colon cancer metastases. Pharm Res,
2001.18(9): p.1291-1298.
306. Derksen, J.T., Morselt, H.W. and Scherphof, G.L., Uptake and processing ofimmunoglobulin-coated liposomes by subpopulations of rat liver macrophages. Biochim BiophysActa,1988.971(2): p.127-136.
307. Maruyama, K., Takahashi, N., Tagawa, T., et al., Immunoliposomes bearingpolyethyleneglycol-coupled Fab' fragment show prolonged circulation time and high extravasationinto targeted solid tumors in vivo. FEBS Lett,1997.413(1): p.177-180.
308. Huwyler, J., Yang, J. and Pardridge, W.M., Receptor mediated delivery of daunomycin usingimmunoliposomes: pharmacokinetics and tissue distribution in the rat. J Pharmacol Exp Ther,1997.282(3): p.1541-1546.
2008.359(23): p.2505-a-2506.
2. Folkman, J., Tumor angiogenesis: therapeutic implications. N Engl J Med,1971.285(21): p.1182-1186.
3. Schindl, M., Schoppmann, S.F., Samonigg, H., et al., Overexpression of hypoxia-inducible factor1alpha is associated with an unfavorable prognosis in lymph node-positive breast cancer. ClinCancer Res,2002.8(6): p.1831-1837.
4.刘泽隆,范红霞and王淑芳,对vasculogenesis和angiogenesis中文翻译的探讨.中国科技术语,2007(04): p.53-54+52.
5. Risau, W., Mechanisms of angiogenesis. Nature,1997.386(6626): p.671-674.
6. Hendrix, M.J., Seftor, E.A., Hess, A.R., et al., Vasculogenic mimicry and tumour-cell plasticity:lessons from melanoma. Nat Rev Cancer,2003.3(6): p.411-421.
7. Seftor, E.A., Meltzer, P.S., Schatteman, G.C., et al., Expression of multiple molecular phenotypesby aggressive melanoma tumor cells: role in vasculogenic mimicry. Crit Rev Oncol Hematol,2002.44(1): p.17-27.
8. Furuya, M., Yonemitsu, Y. and Aoki, I., III. Angiogenesis: complexity of tumor vasculature andmicroenvironment. Curr Pharm Des,2009.15(16): p.1854-1867.
9. Witmer, A.N., Vrensen, G.F., Van Noorden, C.J., et al., Vascular endothelial growth factors andangiogenesis in eye disease. Prog Retin Eye Res,2003.22(1): p.1-29.
10. Gariano, R.F. and Gardner, T.W., Retinal angiogenesis in development and disease. Nature,2005.438(7070): p.960-966.
11. Haddrill, M. and Slonim, C. Age-Related Macular Degeneration. Availablefrom: http://www.allaboutvision.com/conditions/amd.htm.
12. Michaelson, I.C., The mode of development of the vascular system of the retina, with someobservations on its significance for certain retinal diseases. Trans Ophthalmol Soc UK,1948.65: p.
4.
13. Wise, G.N., Factors influencing retinal new vessel formation. Am J Ophthalmol,1961.52: p.637-650.
14. Aiello, L.P., Avery, R.L., Arrigg, P.G., et al., Vascular endothelial growth factor in ocular fluid ofpatients with diabetic retinopathy and other retinal disorders. N Engl J Med,1994.331(22): p.1480-1487.
15. Kliffen, M., Sharma, H.S., Mooy, C.M., et al., Increased expression of angiogenic growth factors inage-related maculopathy. Br J Ophthalmol,1997.81(2): p.154-162.
16. Funatsu, H., Yamashita, H., Shimizu, E., et al., Relationship between vascular endothelial growthfactor and interleukin-6in diabetic retinopathy. Retina,2001.21(5): p.469-477.
17. Watanabe, D., Suzuma, K., Suzuma, I., et al., Vitreous levels of angiopoietin2and vascularendothelial growth factor in patients with proliferative diabetic retinopathy. Am J Ophthalmol,2005.139(3): p.476-481.
18. Watanabe, D., Suzuma, K., Matsui, S., et al., Erythropoietin as a retinal angiogenic factor inproliferative diabetic retinopathy. N Engl J Med,2005.353(8): p.782-792.
19. Tolentino, M.J., Current molecular understanding and future treatment strategies for pathologicocular neovascularization. Curr Mol Med,2009.9(8): p.973-981.
20. Yoshida, T.,[Molecular mechanism of choroidal neovascularization in age-related maculardegeneration]. Nippon Ganka Gakkai Zasshi,2007.111(11): p.881-891.
21. Hanahan, D. and Folkman, J., Patterns and emerging mechanisms of the angiogenic switch duringtumorigenesis. Cell,1996.86(3): p.353-364.
22. Kerbel, R.S., Tumor angiogenesis: past, present and the near future. Carcinogenesis,2000.21(3): p.505-515.
23. Foekens, J.A., Peters, H.A., Grebenchtchikov, N., et al., High tumor levels of vascular endothelialgrowth factor predict poor response to systemic therapy in advanced breast cancer. Cancer Res,
2001.61(14): p.5407-5414.
24. Nakopoulou, L., Stefanaki, K., Panayotopoulou, E., et al., Expression of the vascular endothelialgrowth factor receptor-2/Flk-1in breast carcinomas: correlation with proliferation. Hum Pathol,
2002.33(9): p.863-870.
25. Banerjee, S., Dowsett, M., Ashworth, A., et al., Mechanisms of disease: angiogenesis and themanagement of breast cancer. Nat Clin Pract Oncol,2007.4(9): p.536-550.
26. Nowak, D.G., Woolard, J., Amin, E.M., et al., Expression of pro-and anti-angiogenic isoforms ofVEGF is differentially regulated by splicing and growth factors. J Cell Sci,2008.121(Pt20): p.3487-3495.
27. Woolard, J., Wang, W.Y., Bevan, H.S., et al., VEGF165b, an inhibitory vascular endothelial growthfactor splice variant: mechanism of action, in vivo effect on angiogenesis and endogenous proteinexpression. Cancer Res,2004.64(21): p.7822-7835.
28. Bates, D.O., Cui, T.G., Doughty, J.M., et al., VEGF165b, an inhibitory splice variant of vascularendothelial growth factor, is down-regulated in renal cell carcinoma. Cancer Res,2002.62(14): p.4123-4131.
29. Varey, A.H., Rennel, E.S., Qiu, Y., et al., VEGF165b, an antiangiogenic VEGF-A isoform, bindsand inhibits bevacizumab treatment in experimental colorectal carcinoma: balance of pro-andantiangiogenic VEGF-A isoforms has implications for therapy. Br J Cancer,2008.98(8): p.1366-1379.
30. Soker, S., Takashima, S., Miao, H.Q., et al., Neuropilin-1is expressed by endothelial and tumorcells as an isoform-specific receptor for vascular endothelial growth factor. Cell,1998.92(6): p.735-745.
31. Pan, Q., Chathery, Y., Wu, Y., et al., Neuropilin-1binds to VEGF121and regulates endothelial cellmigration and sprouting. J Biol Chem,2007.282(33): p.24049-24056.
32. Partanen, J., Armstrong, E., Makela, T.P., et al., A novel endothelial cell surface receptor tyrosinekinase with extracellular epidermal growth factor homology domains. Mol Cell Biol,1992.12(4): p.1698-1707.
33. Ziegler, S.F., Bird, T.A., Schneringer, J.A., et al., Molecular cloning and characterization of a novelreceptor protein tyrosine kinase from human placenta. Oncogene,1993.8(3): p.663-670.
34. Marron, M.B., Hughes, D.P., Edge, M.D., et al., Evidence for heterotypic interaction between thereceptor tyrosine kinases TIE-1and TIE-2. J Biol Chem,2000.275(50): p.39741-39746.
35. Thomas, M. and Augustin, H.G., The role of the Angiopoietins in vascular morphogenesis.Angiogenesis,2009.12(2): p.125-137.
36. Eklund, L. and Olsen, B.R., Tie receptors and their angiopoietin ligands are context-dependentregulators of vascular remodeling. Exp Cell Res,2006.312(5): p.630-641.
37. Fiedler, U., Scharpfenecker, M., Koidl, S., et al., The Tie-2ligand angiopoietin-2is stored in andrapidly released upon stimulation from endothelial cell Weibel-Palade bodies. Blood,2004.103(11):p.4150-4156.
38. Kim, I., Kim, J.H., Moon, S.O., et al., Angiopoietin-2at high concentration can enhance endothelialcell survival through the phosphatidylinositol3'-kinase/Akt signal transduction pathway. Oncogene,
2000.19(39): p.4549-4552.
39. Lin, P., Buxton, J.A., Acheson, A., et al., Antiangiogenic gene therapy targeting theendothelium-specific receptor tyrosine kinase Tie2. Proc Natl Acad Sci U S A,1998.95(15): p.8829-8834.
40. Raikwar, S.P., Temm, C.J., Raikwar, N.S., et al., Adenoviral vectors expressing humanendostatin-angiostatin and soluble Tie2: enhanced suppression of tumor growth and antiangiogeniceffects in a prostate tumor model. Mol Ther,2005.12(6): p.1091-1100.
41. Hayes, A.J., Huang, W.Q., Mallah, J., et al., Angiopoietin-1and its receptor Tie-2participate in theregulation of capillary-like tubule formation and survival of endothelial cells. Microvasc Res,1999.58(3): p.224-237.
42. Santel, A., Aleku, M., Keil, O., et al., A novel siRNA-lipoplex technology for RNA interference inthe mouse vascular endothelium. Gene Ther,2006.13(16): p.1222-1234.
43. Niu, Q., Perruzzi, C., Voskas, D., et al., Inhibition of Tie-2signaling induces endothelial cellapoptosis, decreases Akt signaling, and induces endothelial cell expression of the endogenousanti-angiogenic molecule, thrombospondin-1. Cancer Biol Ther,2004.3(4): p.402-405.
44. Tournaire, R., Simon, M.P., le Noble, F., et al., A short synthetic peptide inhibits signal transduction,migration and angiogenesis mediated by Tie2receptor. EMBO Rep,2004.5(3): p.262-267.
45. Popkov, M., Jendreyko, N., McGavern, D.B., et al., Targeting tumor angiogenesis withadenovirus-delivered anti-Tie-2intrabody. Cancer Res,2005.65(3): p.972-981.
46. Suzuki, Y., Komi, Y., Ashino, H., et al., Retinoic acid controls blood vessel formation bymodulating endothelial and mural cell interaction via suppression of Tie2signaling in vascularprogenitor cells. Blood,2004.104(1): p.166-169.
47. Johnson, N.W., Semones, M., Adams, J.L., et al., Optimization of triarylimidazoles for Tie2:influence of conformation on potency. Bioorg Med Chem Lett,2007.17(20): p.5514-5517.
48. Fiedler, U. and Augustin, H.G., Angiopoietins: a link between angiogenesis and inflammation.Trends Immunol,2006.27(12): p.552-558.
49. Matsumura, Y. and Maeda, H., A new concept for macromolecular therapeutics in cancerchemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agentsmancs. Cancer Res,1986.46(12Pt1): p.6387-6392.
50. Maeda, H., Tumor-Selective Delivery of Macromolecular Drugs via the EPR Effect: Backgroundand Future Prospects. Bioconjug Chem,2010.
51. Greish, K., Enhanced permeability and retention of macromolecular drugs in solid tumors: a royalgate for targeted anticancer nanomedicines. J Drug Target,2007.15(7-8): p.457-464.
52. Duncan R. and T-N., S., Tumour targeting by enhanced permeability and retention (EPR) effect.Ann. Oncol.,1998.9(Suppl.2).
53. Yuan, F., Dellian, M., Fukumura, D., et al., Vascular permeability in a human tumor xenograft:molecular size dependence and cutoff size. Cancer Res,1995.55(17): p.3752-3756.
54. Ishida, O., Maruyama, K., Sasaki, K., et al., Size-dependent extravasation and interstitiallocalization of polyethyleneglycol liposomes in solid tumor-bearing mice. Int J Pharm,1999.190(1): p.49-56.
55. Iyer, A.K., Khaled, G., Fang, J., et al., Exploiting the enhanced permeability and retention effect fortumor targeting. Drug Discov Today,2006.11(17-18): p.812-818.
56. Fahr, A., van Hoogevest, P., May, S., et al., Transfer of lipophilic drugs between liposomalmembranes and biological interfaces: consequences for drug delivery. Eur J Pharm Sci,2005.26(3-4): p.251-265.
57. Scott, L.J. and Goa, K.L., Verteporfin. Drugs Aging,2000.16(2): p.139-146; discussion147-138.
58. Browder, T., Butterfield, C.E., Kraling, B.M., et al., Antiangiogenic scheduling of chemotherapyimproves efficacy against experimental drug-resistant cancer. Cancer Res,2000.60(7): p.1878-1886.
59. Kerbel, R.S. and Kamen, B.A., The anti-angiogenic basis of metronomic chemotherapy. Nat RevCancer,2004.4(6): p.423-436.
60. Andre, N., Padovani, L. and Verschuur, A., Metronomic chemotherapy: Back to the future! DrugNews Perspect,2010.23(2): p.143-151.
61. Wong, N.S., Buckman, R.A., Clemons, M., et al., Phase I/II trial of metronomic chemotherapy withdaily dalteparin and cyclophosphamide, twice-weekly methotrexate, and daily prednisone astherapy for metastatic breast cancer using vascular endothelial growth factor and soluble vascularendothelial growth factor receptor levels as markers of response. J Clin Oncol,2010.28(5): p.723-730.
62. Tonini, G., Schiavon, G., Silletta, M., et al., Antiangiogenic properties of metronomicchemotherapy in breast cancer. Future Oncol,2007.3(2): p.183-190.
63. Hanahan, D., Bergers, G. and Bergsland, E., Less is more, regularly: metronomic dosing ofcytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest,2000.105(8): p.1045-1047.
64.侯继院,沈方臻and安永恒,低剂量节律化疗——抗肿瘤血管生成的新思路.国际肿瘤学杂志,2007.34(9): p.4.
65. Bocci, G., Francia, G., Man, S., et al., Thrombospondin1, a mediator of the antiangiogenic effectsof low-dose metronomic chemotherapy. Proc Natl Acad Sci U S A,2003.100(22): p.12917-12922.
66. Hamano, Y., Sugimoto, H., Soubasakos, M.A., et al., Thrombospondin-1associated with tumormicroenvironment contributes to low-dose cyclophosphamide-mediated endothelial cell apoptosisand tumor growth suppression. Cancer Res,2004.64(5): p.1570-1574.
67.王云,杜伟and李醒亚,以抗血管生成为基础的节律化疗研究进展.现代肿瘤医学,2007.15(10): p.3.
68. Mutsaers, A.J., Metronomic chemotherapy. Top Companion Anim Med,2009.24(3): p.137-143.
69. Bocci, G., Nicolaou, K.C. and Kerbel, R.S., Protracted low-dose effects on human endothelial cellproliferation and survival in vitro reveal a selective antiangiogenic window for variouschemotherapeutic drugs. Cancer Res,2002.62(23): p.6938-6943.
70. Emmenegger, U., Man, S., Shaked, Y., et al., A comparative analysis of low-dose metronomiccyclophosphamide reveals absent or low-grade toxicity on tissues highly sensitive to the toxiceffects of maximum tolerated dose regimens. Cancer Res,2004.64(11): p.3994-4000.
71. Wang, J., Lou, P., Lesniewski, R., et al., Paclitaxel at ultra low concentrations inhibits angiogenesiswithout affecting cellular microtubule assembly. Anticancer Drugs,2003.14(1): p.13-19.
72. Hashimoto, K., Man, S., Xu, P., et al., Potent preclinical impact of metronomic low-dose oraltopotecan combined with the antiangiogenic drug pazopanib for the treatment of ovarian cancer.Mol Cancer Ther,2010.9(4): p.996-1006.
73. Tang, T.C., Man, S., Lee, C.R., et al., Impact of metronomic UFT/cyclophosphamide chemotherapyand antiangiogenic drug assessed in a new preclinical model of locally advanced orthotopichepatocellular carcinoma. Neoplasia,2010.12(3): p.264-274.
74. Daenen, L.G., Shaked, Y., Man, S., et al., Low-dose metronomic cyclophosphamide combined withvascular disrupting therapy induces potent antitumor activity in preclinical human tumor xenograftmodels. Mol Cancer Ther,2009.8(10): p.2872-2881.
75. Clarke, J.L., Iwamoto, F.M., Sul, J., et al., Randomized phase II trial of chemoradiotherapyfollowed by either dose-dense or metronomic temozolomide for newly diagnosed glioblastoma. JClin Oncol,2009.27(23): p.3861-3867.
76. Glode, L.M., Barqawi, A., Crighton, F., et al., Metronomic therapy with cyclophosphamide anddexamethasone for prostate carcinoma. Cancer,2003.98(8): p.1643-1648.
77. El Bary, N.A., Hashem, T., Metwally, H., et al., A phase II study of high-dose celecoxib andmetronomic 'low-dose' cyclophosphamide and methotrexate in patients with relapsed and refractorylymphoma. Hematol Oncol Stem Cell Ther,2010.3(1): p.13-18.
78. Lam, T., Hetherington, J.W., Greenman, J., et al., From total empiricism to a rational design ofmetronomic chemotherapy phase I dosing trials. Anticancer Drugs,2006.17(2): p.113-121.
79.陈庆华and张强,药物微囊化新技术及应用.2008:人民卫生出版社.
80. Williams, D.F., On the nature of biomaterials. Biomaterials,2009.30(30): p.5897-5909.
81. Shankaran, D.R. and Miura, N., Recent progress and challenges in nanotechnology for biomedicalapplications: an insight into the analysis of neurotransmitters. Recent Pat Nanotechnol,2007.1(3):p.210-223.
82. Barratt, G.M., Therapeutic applications of colloidal drug carriers. Pharm Sci Technolo Today,2000.3(5): p.163-171.
83. Singh, R. and Lillard, J.W., Jr., Nanoparticle-based targeted drug delivery. Exp Mol Pathol,2009.86(3): p.215-223.
84. Linhardt, R.J., Biodegradable polymers for controlled release of drugs. Controlled Release of Drugs,ed. M. Rosoff.1989, New York: VCH Publishers.43.
85. Desai, M.P., Labhasetwar, V., Walter, E., et al., The mechanism of uptake of biodegradablemicroparticles in Caco-2cells is size dependent. Pharm Res,1997.14(11): p.1568-1573.
86. Panyam, J. and Labhasetwar, V., Biodegradable nanoparticles for drug and gene delivery to cellsand tissue. Adv Drug Deliv Rev,2003.55(3): p.329-347.
87. Romero, E.L. and Morilla, M.J., Drug delivery systems against leishmaniasis? Still an openquestion. Expert Opin Drug Deliv,2008.5(7): p.805-823.
88. Hoffman, A.S., The origins and evolution of "controlled" drug delivery systems. J Control Release,
2008.132(3): p.153-163.
89. Orive, G., Anitua, E., Pedraz, J.L., et al., Biomaterials for promoting brain protection, repair andregeneration. Nat Rev Neurosci,2009.10(9): p.682-692.
90. Bangham, A.D., Standish, M.M. and Watkins, J.C., Diffusion of univalent ions across the lamellaeof swollen phospholipids. J Mol Biol,1965.13(1): p.238-252.
91. Rolf, D. Liposomes-Classification, Processing Technologies, Industry Applications and RiskAssessment.2005; Available from: http://www.azonano.com/Details.asp?ArticleID=1243.
92. Jakubowski. Lipid Structure.2010; Availablefrom: http://employees.csbsju.edu/hjakubowski/classes/ch331/lipidstruct/ollipidintro1.html.
93. Mouritsen, O.G. and Jorgensen, K., Dynamical order and disorder in lipid bilayers. Chem PhysLipids,1994.73(1-2): p.3-25.
94. Barenholz, Y., Sphingomyelin and cholesterol: from membrane biophysics and rafts to potentialmedical applications. Membrane Dynamics and Domain, Subcellular Biochemistry, ed. P.J. Quinn.Vol.37.2004, New York: Kluwer Academic/Plenum Publishers.49.
95. Rahman, Y.E., Cerny, E.A., Tollaksen, S.L., et al., Liposome-encapsulated actinomycin D: potentialin cancer chemotherapy. Proc Soc Exp Biol Med,1974.146(4): p.1173-1176.
96. Budai, M. and Szogyi, M.,[Liposomes as drug carrier systems. Preparation, classification andtherapeutic advantages of liposomes]. Acta Pharm Hung,2001.71(1): p.114-118.
97. Tan, M.L., Choong, P.F. and Dass, C.R., Recent developments in liposomes, microparticles andnanoparticles for protein and peptide drug delivery. Peptides,2010.31(1): p.184-193.
98. Moen, M.D., Lyseng-Williamson, K.A. and Scott, L.J., Liposomal amphotericin B: a review of itsuse as empirical therapy in febrile neutropenia and in the treatment of invasive fungal infections.Drugs,2009.69(3): p.361-392.
99. Ostro, M.J. and Cullis, P.R., Use of liposomes as injectable-drug delivery systems. Am J HospPharm,1989.46(8): p.1576-1587.
100. NeXstar Pharmaceuticals lauches DaunoXome. J Int Assoc Physicians AIDS Care,1996.2(6): p.
52.
101. Drummond, D.C., Meyer, O., Hong, K., et al., Optimizing liposomes for delivery ofchemotherapeutic agents to solid tumors. Pharmacol Rev,1999.51(4): p.691-743.
102. Gabizon, A. and Papahadjopoulos, D., Liposome formulations with prolonged circulation time inblood and enhanced uptake by tumors. Proc Natl Acad Sci U S A,1988.85(18): p.6949-6953.
103. Allen, T.M., Hansen, C. and Rutledge, J., Liposomes with prolonged circulation times: factorsaffecting uptake by reticuloendothelial and other tissues. Biochim Biophys Acta,1989.981(1): p.27-35.
104. Yamauchi, H., Yano, T., Kato, T., et al., Effects of sialic acid derivative on long circulation time andtumor concentration of liposomes International Journal of Pharmaceutics,1995.113(2): p.8.
105. Allen, T.M., Hansen, C., Martin, F., et al., Liposomes containing synthetic lipid derivatives ofpoly(ethylene glycol) show prolonged circulation half-lives in vivo. Biochim Biophys Acta,1991.1066(1): p.29-36.
106. Cattel, L., Ceruti, M. and Dosio, F., From conventional to stealth liposomes: a new Frontier incancer chemotherapy. J Chemother,2004.16Suppl4: p.94-97.
107. Allen, C., Dos Santos, N., Gallagher, R., et al., Controlling the physical behavior and biologicalperformance of liposome formulations through use of surface grafted poly(ethylene glycol). BiosciRep,2002.22(2): p.225-250.
108. Du, H., Chandaroy, P. and Hui, S.W., Grafted poly-(ethylene glycol) on lipid surfaces inhibitsprotein adsorption and cell adhesion. Biochim Biophys Acta,1997.1326(2): p.236-248.
109. Yan, X., Scherphof, G.L. and Kamps, J.A., Liposome opsonization. J Liposome Res,2005.15(1-2):p.109-139.
110. Vert, M. and Domurado, D., Poly(ethylene glycol): protein-repulsive or albumin-compatible? JBiomater Sci Polym Ed,2000.11(12): p.1307-1317.
111. Swenson, C.E., Bolcsak, L.E., Batist, G., et al., Pharmacokinetics of doxorubicin administered i.v.as Myocet (TLC D-99; liposome-encapsulated doxorubicin citrate) compared with conventionaldoxorubicin when given in combination with cyclophosphamide in patients with metastatic breastcancer. Anticancer Drugs,2003.14(3): p.239-246.
112. Ranson, M.R., Carmichael, J., O'Byrne, K., et al., Treatment of advanced breast cancer withsterically stabilized liposomal doxorubicin: results of a multicenter phase II trial. J Clin Oncol,
1997.15(10): p.3185-3191.
113. Harris, L., Winer, E. and Batist, G., Phase III study of TLC D-99(liposome-encapsulateddoxorubicin) vs free doxorubicin in patients with metastatic breast carcinoma (MBC) Proc AmSoc Clin Oncol1998.17(124a).
114. Bennett, C.L. and Calhoun, E.A., Pharmacoeconomics of liposomal anthracycline therapy. SeminOncol,2004.31(6Suppl13): p.191-195.
115. von Moos, R., Thuerlimann, B.J., Aapro, M., et al., Pegylated liposomal doxorubicin-associatedhand-foot syndrome: recommendations of an international panel of experts. Eur J Cancer,2008.44(6): p.781-790.
116. Ishida, T., Kashima, S. and Kiwada, H., The contribution of phagocytic activity of livermacrophages to the accelerated blood clearance (ABC) phenomenon of PEGylated liposomes inrats. J Control Release,2008.126(2): p.162-165.
117. Ishida, T. and Kiwada, H., Accelerated blood clearance (ABC) phenomenon upon repeated injectionof PEGylated liposomes. Int J Pharm,2008.354(1-2): p.56-62.
118. Shehata, T., Ogawara, K., Higaki, K., et al., Prolongation of residence time of liposome bysurface-modification with mixture of hydrophilic polymers. Int J Pharm,2008.359(1-2): p.272-279.
119. Chen, Q., Tong, S., Dewhirst, M.W., et al., Targeting tumor microvessels using doxorubicinencapsulated in a novel thermosensitive liposome. Mol Cancer Ther,2004.3(10): p.1311-1317.
120. Merlin, J.L., In vitro evaluation of the association of thermosensitive liposome-encapsulateddoxorubicin with hyperthermia. Eur J Cancer,1991.27(8): p.1031-1034.
121. Chelvi, T.P. and Ralhan, R., Hyperthermia potentiates antitumor effect ofthermosensitive-liposome-encapsulated melphalan and radiation in murine melanoma. Tumour Biol,
1997.18(4): p.250-260.
122. Needham, D., Anyarambhatla, G., Kong, G., et al., A new temperature-sensitive liposome for usewith mild hyperthermia: characterization and testing in a human tumor xenograft model. CancerRes,2000.60(5): p.1197-1201.
123. Banno, B., Ickenstein, L.M., Chiu, G.N., et al., The functional roles of poly(ethylene glycol)-lipidand lysolipid in the drug retention and release from lysolipid-containing thermosensitive liposomesin vitro and in vivo. J Pharm Sci,2010.99(5): p.2295-2308.
124. Woodburn, K.W., Engelman, C.J. and Blumenkranz, M.S., Photodynamic therapy for choroidalneovascularization: a review. Retina,2002.22(4): p.391-405; quiz527-398.
125. Richter, A.M., Waterfield, E., Jain, A.K., et al., Liposomal delivery of a photosensitizer,benzoporphyrin derivative monoacid ring A (BPD), to tumor tissue in a mouse tumor model.Photochem Photobiol,1993.57(6): p.1000-1006.
126. Hazemoto, N., Harada, M., Suzuki, S., et al., Effect of phosphatidylcholine and cholesterol onpH-sensitive liposomes. Chem Pharm Bull (Tokyo),1993.41(6): p.1003-1006.
127. Klegerman, M.E., Wassler, M., Huang, S.L., et al., Liposomal modular complexes for simultaneoustargeted delivery of bioactive gases and therapeutics. J Control Release,2010.142(3): p.326-331.
128. Kirpotin, D., Hong, K., Mullah, N., et al., Liposomes with detachable polymer coating:destabilization and fusion of dioleoylphosphatidylethanolamine vesicles triggered by cleavage ofsurface-grafted poly(ethylene glycol). FEBS Lett,1996.388(2-3): p.115-118.
129. Huang, Z., Li, W., MacKay, J.A., et al., Thiocholesterol-based lipids for ordered assembly ofbioresponsive gene carriers. Mol Ther,2005.11(3): p.409-417.
130. Wang, J., Sui, M. and Fan, W., Nanoparticles for tumor targeted therapies and theirpharmacokinetics. Curr Drug Metab,2010.11(2): p.129-141.
131. Garcia, M., Jemal, A., Ward, E.M., et al. Global Cancer Facts&Figures2007.2007.
132. Parkin, D.M., Bray, F., Ferlay, J., et al., Global Cancer Statistics,2002. CA Cancer J Clin,2005.55:p.35.
133.卫生部新闻办公室,第三次全国死因调查主要情况.中国肿瘤,2008.05: p.2.
134.董志伟,乔友林,李连弟, et al.,中国癌症控制策略研究报告.中国肿瘤,2002.05: p.11.
135. Smith, S.L., Ten years of Orthoclone OKT3(muromonab-CD3): a review. J Transpl Coord,1996.6(3): p.109-119; quiz120-101.
136. Shaw, T., Quan, J. and Totoritis, M.C., B cell therapy for rheumatoid arthritis: the rituximab(anti-CD20) experience. Ann Rheum Dis,2003.62Suppl2: p. ii55-59.
137. Maloney, D.G., Grillo-Lopez, A.J., White, C.A., et al., IDEC-C2B8(Rituximab) anti-CD20monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood,
1997.90(6): p.2188-2195.
138. Brufsky, A., Trastuzumab-based therapy for patients with HER2-positive breast cancer: from earlyscientific development to foundation of care. Am J Clin Oncol,2010.33(2): p.186-195.
139. Yang, S.X., Bevacizumab and breast cancer: current therapeutic progress and future perspectives.Expert Rev Anticancer Ther,2009.9(12): p.1715-1725.
140. Wagstaff, A.J., Keam, S.J. and McCormack, P.L., Bevacizumab plus platinum-based chemotherapy:in advanced non-small cell lung cancer. BioDrugs,2009.23(3): p.187-196.
141. Bogdahn, U., Schneider, T., Oliushine, V., et al., Randomized, active-controlled phase IIb studywith trabedersen (AP12009) in recurrent or refractory high-grade glioma patients: Basis for phaseIII endpoints, in2009ASCO Annual Meeting2009, J Clin Oncol. p.15s.
142. Bates, P.J., Laber, D.A., Miller, D.M., et al., Discovery and development of the G-richoligonucleotide AS1411as a novel treatment for cancer. Exp Mol Pathol,2009.86(3): p.151-164.
143. Soundararajan, S., Chen, W., Spicer, E.K., et al., The nucleolin targeting aptamer AS1411destabilizes Bcl-2messenger RNA in human breast cancer cells. Cancer Res,2008.68(7): p.2358-2365.
144. Yahagi, Y., Usui, N., Yamaguchi, Y., et al., Fractionated administration of gemtuzumab ozogamicinfor refractory acute myeloid leukemia. Rinsho Ketsueki,2009.50(11): p.1601-1606.
145. Goldsmith, S.J., Radioimmunotherapy of lymphoma: bexxar and zevalin. Semin Nucl Med,2010.40(2): p.122-135.
146. Thomas, F.C., Taskar, K., Rudraraju, V., et al., Uptake of ANG1005, a novel paclitaxel derivative,through the blood-brain barrier into brain and experimental brain metastases of breast cancer.Pharm Res,2009.26(11): p.2486-2494.
147. Holmberg, E., Maruyama, K., Litzinger, D.C., et al., Highly efficient immunoliposomes preparedwith a method which is compatible with various lipid compositions. Biochem Biophys ResCommun,1989.165(3): p.1272-1278.
148. Bogdanov, A.A., Jr., Klibanov, A.L. and Torchilin, V.P., Protein immobilization on the surface ofliposomes via carbodiimide activation in the presence of N-hydroxysulfosuccinimide. FEBS Lett,
1988.231(2): p.381-384.
149. Aragnol, D. and Leserman, L.D., Immune clearance of liposomes inhibited by an anti-Fc receptorantibody in vivo. Proc Natl Acad Sci U S A,1986.83(8): p.2699-2703.
150. Papahadjopoulos, D., Allen, T.M., Gabizon, A., et al., Sterically stabilized liposomes:improvements in pharmacokinetics and antitumor therapeutic efficacy. Proc Natl Acad Sci U S A,
1991.88(24): p.11460-11464.
151. Hosoda, J., Unezaki, S., Maruyama, K., et al., Antitumor activity of doxorubicin encapsulated inpoly(ethylene glycol)-coated liposomes. Biol Pharm Bull,1995.18(9): p.1234-1237.
152. Matsumura, Y., Gotoh, M., Muro, K., et al., Phase I and pharmacokinetic study of MCC-465, adoxorubicin (DXR) encapsulated in PEG immunoliposome, in patients with metastatic stomachcancer. Ann Oncol,2004.15(3): p.517-525.
153. Mori, A., Klibanov, A.L., Torchilin, V.P., et al., Influence of the steric barrier activity ofamphipathic poly(ethyleneglycol) and ganglioside GM1on the circulation time of liposomes and onthe target binding of immunoliposomes in vivo. FEBS Lett,1991.284(2): p.263-266.
154. Maruyama, K., PEG-immunoliposome. Biosci Rep,2002.22(2): p.251-266.
155. Weitman, S.D., Weinberg, A.G., Coney, L.R., et al., Cellular localization of the folate receptor:potential role in drug toxicity and folate homeostasis. Cancer Res,1992.52(23): p.6708-6711.
156. Wu, M., Gunning, W. and Ratnam, M., Expression of folate receptor type alpha in relation to celltype, malignancy, and differentiation in ovary, uterus, and cervix. Cancer Epidemiol BiomarkersPrev,1999.8(9): p.775-782.
157. Lee, R.J. and Low, P.S., Folate-mediated tumor cell targeting of liposome-entrapped doxorubicin invitro. Biochim Biophys Acta,1995.1233(2): p.134-144.
158. Shmeeda, H., Mak, L., Tzemach, D., et al., Intracellular uptake and intracavitary targeting offolate-conjugated liposomes in a mouse lymphoma model with up-regulated folate receptors. MolCancer Ther,2006.5(4): p.818-824.
159. Gabizon, A., Horowitz, A.T., Goren, D., et al., In vivo fate of folate-targeted polyethylene-glycolliposomes in tumor-bearing mice. Clin Cancer Res,2003.9(17): p.6551-6559.
160. Yamada, A., Taniguchi, Y., Kawano, K., et al., Design of folate-linked liposomal doxorubicin to itsantitumor effect in mice. Clin Cancer Res,2008.14(24): p.8161-8168.
161. Yamamoto, M., Ichinose, K., Ishii, N., et al., Utility of liposomes coated with polysaccharidebearing1-amino-lactose as targeting chemotherapy for AH66hepatoma cells. Oncol Rep,2000.7(1): p.107-111.
162. Diaz, C., Vargas, E. and Gatjens-Boniche, O., Cytotoxic effect induced by retinoic acid loaded intogalactosyl-sphingosine containing liposomes on human hepatoma cell lines. Int J Pharm,2006.325(1-2): p.108-115.
163. Allen, T.M., Brandeis, E., Hansen, C.B., et al., A new strategy for attachment of antibodies tosterically stabilized liposomes resulting in efficient targeting to cancer cells. Biochim Biophys Acta,
1995.1237(2): p.99-108.
164. Kirpotin, D., Park, J.W., Hong, K., et al., Sterically stabilized anti-HER2immunoliposomes: designand targeting to human breast cancer cells in vitro. Biochemistry,1997.36(1): p.66-75.
165. Park, J.W., Hong, K., Kirpotin, D.B., et al., Anti-HER2immunoliposomes for targeted therapy ofhuman tumors. Cancer Lett,1997.118(2): p.153-160.
166. Park, J.W., Kirpotin, D.B., Hong, K., et al., Tumor targeting using anti-her2immunoliposomes. JControl Release,2001.74(1-3): p.95-113.
167. Park, J.W., Hong, K., Kirpotin, D.B., et al., Anti-HER2immunoliposomes: enhanced efficacyattributable to targeted delivery. Clin Cancer Res,2002.8(4): p.1172-1181.
168. Mamot, C., Drummond, D.C., Greiser, U., et al., Epidermal growth factor receptor (EGFR)-targetedimmunoliposomes mediate specific and efficient drug delivery to EGFR-andEGFRvIII-overexpressing tumor cells. Cancer Res,2003.63(12): p.3154-3161.
169. Mamot, C., Ritschard, R., Kung, W., et al., EGFR-targeted immunoliposomes derived from themonoclonal antibody EMD72000mediate specific and efficient drug delivery to a variety ofcolorectal cancer cells. J Drug Target,2006.14(4): p.215-223.
170. Roth, P., Hammer, C., Piguet, A.C., et al., Effects on hepatocellular carcinoma ofdoxorubicin-loaded immunoliposomes designed to target the VEGFR-2. J Drug Target,2007.15(9):p.623-631.
171. Xu, L., Tang, W.H., Huang, C.C., et al., Systemic p53gene therapy of cancer withimmunolipoplexes targeted by anti-transferrin receptor scFv. Mol Med,2001.7(10): p.723-734.
172. Sapra, P. and Allen, T.M., Improved outcome when B-cell lymphoma is treated with combinationsof immunoliposomal anticancer drugs targeted to both the CD19and CD20epitopes. Clin CancerRes,2004.10(7): p.2530-2537.
173. Matsudaira, H., Asakura, T., Aoki, K., et al., Target chemotherapy of anti-CD147antibody-labeledliposome encapsulated GSH-DXR conjugate on CD147highly expressed carcinoma cells. Int JOncol,2010.36(1): p.77-83.
174. Uyama, I., Kumai, K., Yasuda, T., et al., Improvement of therapeutic effect by using Fab' fragmentin the treatment of carcinoembryonic antigen-positive human solid tumors withadriamycin-entrapped immunoliposomes. Jpn J Cancer Res,1994.85(4): p.434-440.
175. Brignole, C., Marimpietri, D., Gambini, C., et al., Development of Fab' fragments of anti-GD(2)immunoliposomes entrapping doxorubicin for experimental therapy of human neuroblastoma.Cancer Lett,2003.197(1-2): p.199-204.
176. Kannagi, R., Use of liposomes containing carbohydrates for production of monoclonal antibodies.Methods Mol Biol,2002.199: p.203-218.
177. Graf, J., Ogle, R.C., Robey, F.A., et al., A pentapeptide from the laminin B1chain mediates celladhesion and binds the67,000laminin receptor. Biochemistry,1987.26(22): p.6896-6900.
178. Lopez-Barcons, L.A., Polo, D., Reig, F., et al., Pentapeptide YIGSR-mediated HT-1080fibrosarcoma cells targeting of adriamycin encapsulated in sterically stabilized liposomes. J BiomedMater Res A,2004.69(1): p.155-163.
179. D'Souza, S.E., Ginsberg, M.H. and Plow, E.F., Arginyl-glycyl-aspartic acid (RGD): a cell adhesionmotif. Trends Biochem Sci,1991.16(7): p.246-250.
180. Koning, G.A., Fretz, M.M., Woroniecka, U., et al., Targeting liposomes to tumor endothelial cellsfor neutron capture therapy. Appl Radiat Isot,2004.61(5): p.963-967.
181. Schiffelers, R.M., Koning, G.A., ten Hagen, T.L., et al., Anti-tumor efficacy of tumorvasculature-targeted liposomal doxorubicin. J Control Release,2003.91(1-2): p.115-122.
182. Janssen, A.P., Schiffelers, R.M., ten Hagen, T.L., et al., Peptide-targeted PEG-liposomes inanti-angiogenic therapy. Int J Pharm,2003.254(1): p.55-58.
183. Garg, A., Tisdale, A.W., Haidari, E., et al., Targeting colon cancer cells using PEGylated liposomesmodified with a fibronectin-mimetic peptide. Int J Pharm,2009.366(1-2): p.201-210.
184. Demirgoz, D., Garg, A. and Kokkoli, E., PR_b-targeted PEGylated liposomes for prostate cancertherapy. Langmuir,2008.24(23): p.13518-13524.
185. Kondo, M., Asai, T., Katanasaka, Y., et al., Anti-neovascular therapy by liposomal drug targeted tomembrane type-1matrix metalloproteinase. Int J Cancer,2004.108(2): p.301-306.
186. Song, S., Liu, D., Peng, J., et al., Peptide ligand-mediated liposome distribution and targeting toEGFR expressing tumor in vivo. Int J Pharm,2008.363(1-2): p.155-161.
187. Maeda, N., Takeuchi, Y., Takada, M., et al., Synthesis of angiogenesis-targeted peptide andhydrophobized polyethylene glycol conjugate. Bioorg Med Chem Lett,2004.14(4): p.1015-1017.
188. Pastorino, F., Brignole, C., Marimpietri, D., et al., Vascular damage and anti-angiogenic effects oftumor vessel-targeted liposomal chemotherapy. Cancer Res,2003.63(21): p.7400-7409.
189. Akita, N., Maruta, F., Seymour, L.W., et al., Identification of oligopeptides binding to peritonealtumors of gastric cancer. Cancer Sci,2006.97(10): p.1075-1081.
190. Song, S., Liu, D., Peng, J., et al., Novel peptide ligand directs liposomes toward EGF-Rhigh-expressing cancer cells in vitro and in vivo. FASEB J,2009.23(5): p.1396-1404.
191. Goncalves, V., Gautier, B., Coric, P., et al., Rational design, structure, and biological evaluation ofcyclic peptides mimicking the vascular endothelial growth factor. J Med Chem,2007.50(21): p.5135-5146.
192. Li, X., Ding, L., Xu, Y., et al., Targeted delivery of doxorubicin using stealth liposomes modifiedwith transferrin. Int J Pharm,2009.373(1-2): p.116-123.
193. Rosenberg, M.B., Breakefield, X.O. and Hawrot, E., Targeting of liposomes to cells bearing nervegrowth factor receptors mediated by biotinylated nerve growth factor. J Neurochem,1987.48(3): p.865-875.
194. Kang, H., O'Donoghue, M.B., Liu, H., et al., A liposome-based nanostructure for aptamer directeddelivery. Chem Commun (Camb),2010.46(2): p.249-251.
195. Brown, K.C., Peptidic tumor targeting agents: the road from phage display peptide selections toclinical applications. Curr Pharm Des,2010.16(9): p.1040-1054.
196. Ekins, S., Mestres, J. and Testa, B., In silico pharmacology for drug discovery: methods for virtualligand screening and profiling. Br J Pharmacol,2007.152(1): p.9-20.
197. Klebe, G., Virtual ligand screening: strategies, perspectives and limitations. Drug Discov Today,
2006.11(13-14): p.580-594.
198. Pick, D., Novel scoring methods in virtual ligand screening. Methods Mol Biol,2004.275: p.439-448.
199.吴楚and诸慧,噬菌体展示技术.安徽农业科学,2009.37(3): p.3.
200. Peters, E.A., Schatz, P.J., Johnson, S.S., et al., Membrane insertion defects caused by positivecharges in the early mature region of protein pIII of filamentous phage fd can be corrected by prlAsuppressors. J Bacteriol,1994.176(14): p.4296-4305.
201. Willcox, M.D., Hume, E.B., Aliwarga, Y., et al., A novel cationic-peptide coating for the preventionof microbial colonization on contact lenses. J Appl Microbiol,2008.105(6): p.1817-1825.
202. Fidai, S., Farmer, S.W. and Hancock, R.E., Interaction of cationic peptides with bacterialmembranes. Methods Mol Biol,1997.78: p.187-204.
203. Mogi, T. and Kita, K., Gramicidin S and polymyxins: the revival of cationic cyclic peptideantibiotics. Cell Mol Life Sci,2009.66(23): p.3821-3826.
204. Adey, N.B., Mataragnon, A.H., Rider, J.E., et al., Characterization of phage that bind plastic fromphage-displayed random peptide libraries. Gene,1995.156(1): p.27-31.
205. Ph.D.-12phage display peptide library kit instruction manual, version2.7.2006.
206. van de Wijngaart, D.J., Dubbink, H.J., Molier, M., et al., Functional screening of FxxLF-likepeptide motifs identifies SMARCD1/BAF60a as an androgen receptor cofactor that modulatesTMPRSS2expression. Mol Endocrinol,2009.23(11): p.1776-1786.
207. Regina, A., Demeule, M., Che, C., et al., Antitumour activity of ANG1005, a conjugate betweenpaclitaxel and the new brain delivery vector Angiopep-2. Br J Pharmacol,2008.155(2): p.185-197.
208. Demeule, M., Regina, A., Che, C., et al., Identification and design of peptides as a new drugdelivery system for the brain. J Pharmacol Exp Ther,2008.324(3): p.1064-1072.
209. Barton, W.A., Tzvetkova-Robev, D., Miranda, E.P., et al., Crystal structures of the Tie2receptorectodomain and the angiopoietin-2-Tie2complex. Nat Struct Mol Biol,2006.13(6): p.524-532.
210. Giordano, R.J., Cardo-Vila, M., Lahdenranta, J., et al., Biopanning and rapid analysis of selectiveinteractive ligands. Nat Med,2001.7(11): p.1249-1253.
211. White, S.J., Nicklin, S.A., Sawamura, T., et al., Identification of peptides that target the endothelialcell-specific LOX-1receptor. Hypertension,2001.37(2Part2): p.449-455.
212. Ding, N., Xiao, H., Wang, F., et al., A FQHPSFI peptide selectively binds to LPS-activated alveolarmacrophages and inhibits LPS-induced MIP-2production. Inflamm Res,2010.
213. Liu, S., Sivakumar, S., Sparks, W.O., et al., A peptide that binds the pea aphid gut impedes entry ofPea enation mosaic virus into the aphid hemocoel. Virology,2010.401(1): p.107-116.
214. Vrielink, J., Heins, M.S., Setroikromo, R., et al., Synthetic constrained peptide selectively binds andantagonizes death receptor5. FEBS J,2010.277(7): p.1653-1665.
215. Li, Z.J. and Cho, C.H., Development of Peptides as Potential Drugs for Cancer Therapy. CurrPharm Des,2010.
216. Ohkubo, S., Miyadera, K., Sugimoto, Y., et al., Identification of substrate sequences for membranetype-1matrix metalloproteinase using bacteriophage peptide display library. Biochem Biophys ResCommun,1999.266(2): p.308-313.
217. Oku, N., Asai, T., Watanabe, K., et al., Anti-neovascular therapy using novel peptides homing toangiogenic vessels. Oncogene,2002.21(17): p.2662-2669.
218. Kolonin, M.G., Sun, J., Do, K.A., et al., Synchronous selection of homing peptides for multipletissues by in vivo phage display. FASEB J,2006.20(7): p.979-981.
219. Pasqualini, R. and Ruoslahti, E., Organ targeting in vivo using phage display peptide libraries.Nature,1996.380(6572): p.364-366.
220. Lam, P.Y., Jadhav, P.K., Eyermann, C.J., et al., Rational design of potent, bioavailable, nonpeptidecyclic ureas as HIV protease inhibitors. Science,1994.263(5145): p.380-384.
221. Pornillos, O., Alam, S.L., Rich, R.L., et al., Structure and functional interactions of the Tsg101UEV domain. EMBO J,2002.21(10): p.2397-2406.
222.王正鸾,化疗药物的不良反应及护理.中华中西医杂志,2007.8(16).
223. Peters, K.G., Coogan, A., Berry, D., et al., Expression of Tie2/Tek in breast tumour vasculatureprovides a new marker for evaluation of tumour angiogenesis. Br J Cancer,1998.77(1): p.51-56.
224. Willam, C., Koehne, P., Jurgensen, J.S., et al., Tie2receptor expression is stimulated by hypoxiaand proinflammatory cytokines in human endothelial cells. Circ Res,2000.87(5): p.370-377.
225. Martin, V., Liu, D., Fueyo, J., et al., Tie2: a journey from normal angiogenesis to cancer and beyond.Histol Histopathol,2008.23(6): p.773-780.
226. Wade, M.H., de Feijter, A.W. and Frame, M.K., Quantitative fluorescence imaging techniques forthe study of organization and signaling mechanisms in cells. Methods Biochem Anal,1994.37: p.117-141.
227. Pinto, A.L. and Lippard, S.J., Binding of the antitumor drug cis-diamminedichloroplatinum(II)(cisplatin) to DNA. Biochim Biophys Acta,1985.780(3): p.167-180.
228. Pinzani, V., Bressolle, F., Haug, I.J., et al., Cisplatin-induced renal toxicity and toxicity-modulatingstrategies: a review. Cancer Chemother Pharmacol,1994.35(1): p.1-9.
229. Rosenthal, D.I., Yom, S.S., Liu, L., et al., A phase I study of SPI-077(Stealth liposomal cisplatin)concurrent with radiation therapy for locally advanced head and neck cancer. Invest New Drugs,
2002.20(3): p.343-349.
230. Harrington, K.J., Lewanski, C.R., Northcote, A.D., et al., Phase I-II study of pegylated liposomalcisplatin (SPI-077) in patients with inoperable head and neck cancer. Ann Oncol,2001.12(4): p.493-496.
231. White, S.C., Lorigan, P., Margison, G.P., et al., Phase II study of SPI-77(sterically stabilisedliposomal cisplatin) in advanced non-small-cell lung cancer. Br J Cancer,2006.95(7): p.822-828.
232. Bandak, S., Goren, D., Horowitz, A., et al., Pharmacological studies of cisplatin encapsulated inlong-circulating liposomes in mouse tumor models. Anticancer Drugs,1999.10(10): p.911-920.
233. Schroeder, A., Honen, R., Turjeman, K., et al., Ultrasound triggered release of cisplatin fromliposomes in murine tumors. J Control Release,2009.137(1): p.63-68.
234. Schroeder, A., Avnir, Y., Weisman, S., et al., Controlling liposomal drug release with low frequencyultrasound: mechanism and feasibility. Langmuir,2007.23(7): p.4019-4025.
235. Woo, J., Chiu, G.N., Karlsson, G., et al., Use of a passive equilibration methodology to encapsulatecisplatin into preformed thermosensitive liposomes. Int J Pharm,2008.349(1-2): p.38-46.
236. Szoka, F., Jr. and Papahadjopoulos, D., Procedure for preparation of liposomes with large internalaqueous space and high capture by reverse-phase evaporation. Proc Natl Acad Sci U S A,1978.75(9): p.4194-4198.
237. Peleg-Shulman, T., Gibson, D., Cohen, R., et al., Characterization of sterically stabilized cisplatinliposomes by nuclear magnetic resonance. Biochim Biophys Acta,2001.1510(1-2): p.278-291.
238. Andrews, P.A., Wung, W.E. and Howell, S.B., A high-performance liquid chromatographic assaywith improved selectivity for cisplatin and active platinum (II) complexes in plasma ultrafiltrate.Anal Biochem,1984.143(1): p.46-56.
239. Bohl Kullberg, E., Bergstrand, N., Carlsson, J., et al., Development of EGF-conjugated liposomesfor targeted delivery of boronated DNA-binding agents. Bioconjug Chem,2002.13(4): p.737-743.
240. Amin, D.N., Hida, K., Bielenberg, D.R., et al., Tumor endothelial cells express epidermal growthfactor receptor (EGFR) but not ErbB3and are responsive to EGF and to EGFR kinase inhibitors.Cancer Res,2006.66(4): p.2173-2180.
241. Shojaei, F. and Ferrara, N., Antiangiogenesis to treat cancer and intraocular neovascular disorders.Lab Invest,2007.87(3): p.227-230.
242. Sathornsumetee, S. and Rich, J.N., Antiangiogenic therapy in malignant glioma: promise andchallenge. Curr Pharm Des,2007.13(35): p.3545-3558.
243. Griffioen, A.W., Therapeutic approaches of angiogenesis inhibition: are we tackling the problem atthe right level? Trends Cardiovasc Med,2007.17(5): p.171-176.
244. El-Mousawi, M., Tchistiakova, L., Yurchenko, L., et al., A vascular endothelial growth factor highaffinity receptor1-specific peptide with antiangiogenic activity identified using a phage displaypeptide library. J Biol Chem,2003.278(47): p.46681-46691.
245. Benzinger, P., Martiny-Baron, G., Reusch, P., et al., Targeting of endothelial KDR receptors with3G2immunoliposomes in vitro. Biochim Biophys Acta,2000.1466(1-2): p.71-78.
246. Wu, X., Li, Z., Yao, M., et al., Identification and characterization of a novel peptide ligand of Tie2for targeting gene therapy. Acta Biochim Biophys Sin (Shanghai),2008.40(3): p.217-225.
247. Thapa, N., Hong, H.Y., Sangeetha, P., et al., Identification of a peptide ligand recognizingdysfunctional endothelial cells for targeting atherosclerosis. J Control Release,2008.131(1): p.27-33.
248. Hui, X., Han, Y., Liang, S., et al., Specific targeting of the vasculature of gastric cancer by a newtumor-homing peptide CGNSNPKSC. J Control Release,2008.131(2): p.86-93.
249. Qasim, W., Gaspar, H.B. and Thrasher, A.J., Progress and prospects: gene therapy for inheritedimmunodeficiencies. Gene Ther,2009.16(11): p.1285-1291.
250. Cideciyan, A.V., Hauswirth, W.W., Aleman, T.S., et al., Vision1year after gene therapy for Leber'scongenital amaurosis. N Engl J Med,2009.361(7): p.725-727.
251. Jiao, L.R., Havlik, R., Nicholls, J., et al., Suicide gene therapy in liver tumors. Methods Mol Med,
2004.90: p.433-450.
252. Brade, A.M., Szmitko, P., Ngo, D., et al., Heat-directed suicide gene therapy for breast cancer.Cancer Gene Ther,2003.10(4): p.294-301.
253. Foloppe, J., Kintz, J., Futin, N., et al., Targeted delivery of a suicide gene to human colorectaltumors by a conditionally replicating vaccinia virus. Gene Ther,2008.15(20): p.1361-1371.
254. Peng, J., Zhao, Y., Mai, J., et al., Inhibition of hepatitis B virus replication by various RNAiconstructs and their pharmacodynamic properties. J Gen Virol,2005.86(Pt12): p.3227-3234.
255. Luo, D. and Saltzman, W.M., Synthetic DNA delivery systems. Nat Biotechnol,2000.18(1): p.33-37.
256. Rolland, A.P., From genes to gene medicines: recent advances in nonviral gene delivery. Crit RevTher Drug Carrier Syst,1998.15(2): p.143-198.
257. Felgner, P.L., Gadek, T.R., Holm, M., et al., Lipofection: a highly efficient, lipid-mediatedDNA-transfection procedure. Proc Natl Acad Sci U S A,1987.84(21): p.7413-7417.
258. Sieverling, N. Cationic copolymers for non-viral gene delivery Availablefrom: http://www.nano-lifescience.com/research/gene-delivery.html.
259. Xia, C.F., Zhang, Y., Boado, R.J., et al., Intravenous siRNA of brain cancer with receptor targetingand avidin-biotin technology. Pharm Res,2007.24(12): p.2309-2316.
260. Watanabe, T., Umehara, T., Yasui, F., et al., Liver target delivery of small interfering RNA to theHCV gene by lactosylated cationic liposome. J Hepatol,2007.47(6): p.744-750.
261. Ishikawa, A., Zhou, Y.M., Kambe, N., et al., Enhancement of star vector-based gene delivery toendothelial cells by addition of RGD-peptide. Bioconjug Chem,2008.19(2): p.558-561.
262. Casey, G., Cashman, J.P., Morrissey, D., et al., Sonoporation mediated immunogene therapy ofsolid tumors. Ultrasound Med Biol,2010.36(3): p.430-440.
263. Suzuki, R., Namai, E., Oda, Y., et al., Cancer gene therapy by IL-12gene delivery using liposomalbubbles and tumoral ultrasound exposure. J Control Release,2010.142(2): p.245-250.
264. Sheyn, D., Kimelman-Bleich, N., Pelled, G., et al., Ultrasound-based nonviral gene deliveryinduces bone formation in vivo. Gene Ther,2008.15(4): p.257-266.
265. Sakai, T., Kawaguchi, M. and Kosuge, Y., siRNA-mediated gene silencing in the salivary glandusing in vivo microbubble-enhanced sonoporation. Oral Dis,2009.15(7): p.505-511.
266. Clement, N.R. and Gould, J.M., Pyranine (8-hydroxy-1,3,6-pyrenetrisulfonate) as a probe ofinternal aqueous hydrogen ion concentration in phospholipid vesicles. Biochemistry,1981.20(6): p.1534-1538.
267. Clerc, S. and Barenholz, Y., Loading of amphipathic weak acids into liposomes in response totransmembrane calcium acetate gradients. Biochim Biophys Acta,1995.1240(2): p.257-265.
268. Barreto, J. and Lichtenberger, L.M., Vesicle acidification driven by a millionfold proton gradient: amodel for acid influx through gastric cell membranes. Am J Physiol,1992.262(1Pt1): p. G30-34.
269. Biegel, C.M. and Gould, J.M., Kinetics of hydrogen ion diffusion across phospholipid vesiclemembranes. Biochemistry,1981.20(12): p.3474-3479.
270. Zhang, X.H., Khan, A. and Ducker, W.A., A nanoscale gas state. Phys Rev Lett,2007.98(13): p.136101.
271. Jin, F., Ye, X. and Wu, C., Observation of kinetic and structural scalings during slow coalescence ofnanobubbles in an aqueous solution. J Phys Chem B,2007.111(46): p.13143-13146.
272. Carambassis, A., Jonker, L.C., Attard, P., et al., Forces Measured between Hydrophobic Surfacesdue to a Submicroscopic Bridging Bubble. Physical Review Letters,1998.80(24): p.4.
273. Lou, S., Ouyang, Z.Q., Zhang, Y., et al., Nanobubbles on solid surface imaged by atomic forcemicroscopy. J. Vac. Sci. Technol B,2000.18(5): p.3.
274. Edelstein, M. Gene Therapy Clinical Trials Worldwide.2009Dec; Availablefrom: www.wiley.co.uk/genmed/clinical.
275. Audouy, S.A., de Leij, L.F., Hoekstra, D., et al., In vivo characteristics of cationic liposomes asdelivery vectors for gene therapy. Pharm Res,2002.19(11): p.1599-1605.
276. Bedikian, A.Y., Richards, J., Kharkevitch, D., et al., A phase2study of high-dose Allovectin-7inpatients with advanced metastatic melanoma. Melanoma Res,2010.20(3): p.218-226.
277. Bedikian, A.Y. and Del Vecchio, M., Allovectin-7therapy in metastatic melanoma. Expert OpinBiol Ther,2008.8(6): p.839-844.
278. Gonzalez, R., Hutchins, L., Nemunaitis, J., et al., Phase2trial of Allovectin-7in advancedmetastatic melanoma. Melanoma Res,2006.16(6): p.521-526.
279. Galanis, E., Technology evaluation: Allovectin-7, Vical. Curr Opin Mol Ther,2002.4(1): p.80-87.
280. Yoon, C.S. and Park, J.H., Ultrasound-mediated gene delivery. Expert Opin Drug Deliv,2010.7(3):p.321-330.
281. Liang, H.D., Lu, Q.L., Xue, S.A., et al., Optimisation of ultrasound-mediated gene transfer(sonoporation) in skeletal muscle cells. Ultrasound Med Biol,2004.30(11): p.1523-1529.
282. Lentacker, I., Smedt, S.C.D., Demeester, J., et al., Lipoplex-Loaded Microbubbles for GeneDelivery: A Trojan Horse Controlled by Ultrasound. Adv Funct Mater,2007.17(12): p.7.
283. Adkins, S.S., Chen, X., Chan, I., et al., Morphology and stability of CO2-in-water foams withnonionic hydrocarbon surfactants. Langmuir,2010.26(8): p.5335-5348.
284. Wang, X., Liang, H.D., Dong, B., et al., Gene transfer with microbubble ultrasound and plasmidDNA into skeletal muscle of mice: comparison between commercially available microbubblecontrast agents. Radiology,2005.237(1): p.224-229.
285.王燕芳,刘力,魏龙, et al.,小动物正电子断层扫描仪(Micro-PET)技术概述中国体视学与图像分析,2005.3: p.2.
286. Machin, K. and Webb, S., Cone-beam x-ray microtomography of small specimens. Phys Med Biol,
1994.39(10): p.1639-1657.
287.胡广书,李.A.郭.A.唐.A.张.A.,基于X射线的小动物成像micro-CT系统.清华大学学报(自然科学版),2009(06): p.900-903.
288. Sun, X., Annala, A.J., Yaghoubi, S.S., et al., Quantitative imaging of gene induction in livinganimals. Gene Ther,2001.8(20): p.1572-1579.
289. Funovics, M., Weissleder, R. and Tung, C.H., Protease sensors for bioimaging. Anal Bioanal Chem,
2003.377(6): p.956-963.
290. Wang, Y., Yu, Y.A., Shabahang, S., et al., Renilla luciferase-Aequorea GFP (Ruc-GFP) fusionprotein, a novel dual reporter for real-time imaging of gene expression in cell cultures and in liveanimals. Mol Genet Genomics,2002.268(2): p.160-168.
291. Caceres, G., Zhu, X.Y., Jiao, J.A., et al., Imaging of luciferase and GFP-transfected human tumoursin nude mice. Luminescence,2003.18(4): p.218-223.
292. Haran, G., Cohen, R., Bar, L.K., et al., Transmembrane ammonium sulfate gradients in liposomesproduce efficient and stable entrapment of amphipathic weak bases. Biochim Biophys Acta,1993.1151(2): p.201-215.
293. Zucker, D., Marcus, D., Barenholz, Y., et al., Liposome drugs' loading efficiency: a working modelbased on loading conditions and drug's physicochemical properties. J Control Release,2009.139(1):p.73-80.
294. O'Brien, P.C., Procedures for comparing samples with multiple endpoints. Biometrics,1984.40(4):p.1079-1087.
295. Sapra, P., Moase, E.H., Ma, J., et al., Improved therapeutic responses in a xenograft model ofhuman B lymphoma (Namalwa) for liposomal vincristine versus liposomal doxorubicin targeted viaanti-CD19IgG2a or Fab' fragments. Clin Cancer Res,2004.10(3): p.1100-1111.
296. Hobbs, S.K., Monsky, W.L., Yuan, F., et al., Regulation of transport pathways in tumor vessels: roleof tumor type and microenvironment. Proc Natl Acad Sci U S A,1998.95(8): p.4607-4612.
297. Wu, N.Z., Da, D., Rudoll, T.L., et al., Increased microvascular permeability contributes topreferential accumulation of Stealth liposomes in tumor tissue. Cancer Res,1993.53(16): p.3765-3770.
298. Tardi, P., Bally, M.B. and Harasym, T.O., Clearance properties of liposomes involving conjugatedproteins for targeting. Adv Drug Deliv Rev,1998.32(1-2): p.99-118.
299. Gabizon, A.A., Shmeeda, H. and Zalipsky, S., Pros and cons of the liposome platform in cancerdrug targeting. J Liposome Res,2006.16(3): p.175-183.
300. Mastrobattista, E., Koning, G.A. and Storm, G., Immunoliposomes for the targeted delivery ofantitumor drugs. Adv Drug Deliv Rev,1999.40(1-2): p.103-127.
301. Ishida, T., Atobe, K., Wang, X., et al., Accelerated blood clearance of PEGylated liposomes uponrepeated injections: effect of doxorubicin-encapsulation and high-dose first injection. J ControlRelease,2006.115(3): p.251-258.
302. Wang, X., Ishida, T. and Kiwada, H., Anti-PEG IgM elicited by injection of liposomes is involvedin the enhanced blood clearance of a subsequent dose of PEGylated liposomes. J Control Release,
2007.119(2): p.236-244.
303. Koide, H., Asai, T., Hatanaka, K., et al., T cell-independent B cell response is responsible for ABCphenomenon induced by repeated injection of PEGylated liposomes. Int J Pharm,2010.
304. Koning, G.A., Morselt, H.W., Gorter, A., et al., Interaction of differently designedimmunoliposomes with colon cancer cells and Kupffer cells. An in vitro comparison. Pharm Res,
2003.20(8): p.1249-1257.
305. Koning, G.A., Morselt, H.W., Gorter, A., et al., Pharmacokinetics of differently designedimmunoliposome formulations in rats with or without hepatic colon cancer metastases. Pharm Res,
2001.18(9): p.1291-1298.
306. Derksen, J.T., Morselt, H.W. and Scherphof, G.L., Uptake and processing ofimmunoglobulin-coated liposomes by subpopulations of rat liver macrophages. Biochim BiophysActa,1988.971(2): p.127-136.
307. Maruyama, K., Takahashi, N., Tagawa, T., et al., Immunoliposomes bearingpolyethyleneglycol-coupled Fab' fragment show prolonged circulation time and high extravasationinto targeted solid tumors in vivo. FEBS Lett,1997.413(1): p.177-180.
308. Huwyler, J., Yang, J. and Pardridge, W.M., Receptor mediated delivery of daunomycin usingimmunoliposomes: pharmacokinetics and tissue distribution in the rat. J Pharmacol Exp Ther,1997.282(3): p.1541-1546.