摘要
经皮腔内冠状动脉成形术(Percutaneous Transluminal CoronaryAngioplasty，P7CA)是冠状动脉硬化性心脏病的主要治疗手段，但PTCA术后血管再狭窄的发生率高达15—60％，迄今仍是临床亟待解决的难题。如今，局部给药治疗血管再狭窄的方法主要有药物洗脱支架(Drug-eluting stent，DES)和基于球囊导管的药物传递系统。虽然已经有DES进入了临床应用，但是DES仍然存在一些有效性和安全性的问题。DES重要的缺陷就是在支架撑杆上药物浓度最高，抗增殖药物可抑制内皮的愈合，而此部位的内皮愈合是最重要的。另一方面，支架边缘和撑杆之间的部位却不能完全抑制新生内膜的形成，从而影响了DES的疗效。此外，DES不能应用在小血管和分支血管的病变部位。一些重要的安全问题也没有完全明确，如血栓、晚期支架贴壁不良、形成动脉瘤、边缘效应、用于结合药物所选用的聚合物引起的晚期炎症反应、释放毒素。因此，有必要开发其它局部药物传递系统作为DES的补充。这些系统可以将药物输送到没有被支架直接覆盖的血管部位，特别是小血管和多支血管。然而局部灌注药物溶液的传递效率和在血管腔内驻留的时间都相当低，影响了药物疗效充分发挥。因此，局部灌注纳米粒悬液也存在动脉壁内驻留效率低的问题。使用阳离子表面活性剂溴化双十二烷基二甲基铵(didodecyldimethylammonium bromide，DMAB)修饰纳米粒可增加其在动脉壁的驻留，从而增加其防治血管再狭窄的效果。紫杉醇能抑制兔颈动脉剥脱损伤模型的新生内膜的增生，达到此效果所需的血药浓度比治疗肿瘤所需的浓度低100到1000倍，由于很小的剂量即能抑制新生内膜的增生，因此被选用为本实验的治疗药物。
本文第一章综述了PTCA术后再狭窄的发病机理及局部药物传递治疗血管再狭窄的现状。
本文具体研究内容如下：
1．制备了载尿激酶和紫杉醇PLGA纳米微球，用物理吸附法对载紫杉醇纳米微球进行DMAB表面修饰。首先对纳米微球进行表征，使用高效液相色谱仪对包封率和体外蓟物释放进行分析，测定了纳米微球的粒径和表面Zeta电位。建立兔颈动脉损伤模型，在血管局部灌注不同浓度的修饰纳米粒。28天后，取出局部给药的颈动脉血管，进行HE染色和弹力纤维染色。结果显示，尿激酶纳米微球呈两相的体外释放特征，48小时后，其在释放液中释放的尿激酶的活性急剧下降。尿激酶不适合作为纳米粒子缓释制剂应用。同时制备成粒径300纳米左右、包封率80％以上且表面带正电荷的载紫杉醇纳米微球。体外药物释放呈两相释放。28天后，血管内局部灌注紫杉醇纳米悬液可有效抑制血管内皮增生，抑制效果随纳米粒悬液浓度的增加而提高。浓度达到30mg／ml时，可完全抑制血管内膜增生。相比于未修饰纳米粒，DMAB修饰纳米粒能显著抑制新生内膜的增生(P＜0.05)。(第二章)
2．合成PCL／F68材料，并利用溶剂替代法制备了载紫杉醇PCL／F68纳米微球，用物理吸附法对载紫杉醇纳米微球进行DMAB表面修饰。首先对纳米微球进行表征，载药量、包封率和体外药物释放使用高效液相色谱仪进行分析，测定了纳米粒子的粒径和表面Zeta电位。建立兔颈动脉损伤模型，在血管局部灌注不同浓度的修饰纳米粒。90天后，取出局部给药的颈动脉血管，进行HE染色和弹力纤维染色。结果合成了粘均分子量为44，000的材料，制备成包封效率75％以上，载药量3.5％左右，平均粒径在300nm左右，粒径范围窄，体外释放药物呈两相特征的表面带正电荷的载紫杉醇PCL／F68纳米粒。90天后，血管内局部灌注载紫杉醇PCL／F68纳米悬液可有效抑制血管内皮增生，其抑制效果比载紫杉醇PLGA纳米悬液要好(P＜0.05)。(第三章)
综上所述，DMAB修饰纳米粒能显著抑制新生内膜的增生，其效果比未修饰纳米粒更好。纳米制剂与介入治疗相结合将提供一种极具前途的血管再狭窄的治疗方法。
PTCA (Percutaneous Transluminal Coronary Angioplasty) has become one of the most important strategies to treat coronary artery diseases. However, restenosis has been observed in pathological and clinical studies, and poses a formidable problem (15-60%). Currently, there are mainly two local drug delivery syetems are employed to prevent restensis after balloon angioplasty including drug-eluting stent/radioactive stent and catheter-based drug delivery system. The proliferation of VSMC, the cause of restenosis development, could be inhibited by the application of radioactive and drug eluting stents. However, their efficacy and safety have not been confirmed in all clinical settings. It should be also noted that 30-40% of critical lesions cannot be stented, largely because they occur at branch sites or in small arteries. Important safety issues such as thrombosis, late stent malapposition, aneurysm formation, edge effect, late inflammation due to choice of polymer used to bind the drug, the release of toxins, and potential interaction with brachytherapy have not been completely addressed. Thus, non-stent-based local delivery of antiproliferative drugs may offer additional flexibility and efficacy in the entire range of applications. It may also deliver drugs to vessel areas not directly covered by the stent, which could be of special interest for small and tortuous vessels. However, the delivery efficiency and intramural retention time of infused drug solution remains rather low. Nanoparticles modified with a cationic surfactant, didodecyldimethylammonium bromide (DMAB) can greatly enhance arterial retention in animal angioplasty models. Paclitaxel can inhibit neointimal formation in vivo with plasma paclitaxel levels about 100 to 1000 times lower than the concentrations to treat neoplasms. Thus, paclitaxel was selected as a better pharmacologic component to be formulated into nanoparticles.
In chapter 1, the recent progress of the research topic was reviewed.
The major contents of this paper are shown as follows:
Chapter 2. This study tested the possibility of localized intravascular infusion of positive charged paclitaxel-loaded nanoparticles (NPs) to better prevent neointimal formation in a rabbit carotid artery injury model. Paclitaxel-loaded NPs were prepared by oil/water emulsion/solvent evaporation technique using biodegradable poly (lactide-co-glycolide) (PLGA). Urokinase-loaded PLGA NPs were prepared by w/o/w emulsion/solvent evaporation technique. A cationic surfactant, didodecyldimethylammonium bromide (DMAB), was absorbed on the NP surface by electrostatic attraction between positive and negative charges. NPs were characterized in such aspects as size, surface morphology, surface charges as well as in vitro drug release profile. Balloon-injured rabbit carotid arteries were treated with single infusion of paclitaxel-loaded NP suspension and observed for 28 days. The inhibitory effects of NPs on neointima formation were evaluated as end-point. NPs showed spherical shape with a diameter ranging from 200 to 500 nm. Negatively charged PLGA NPs shifted to positive after the DMAB modification. The in vitro drug release profile showed a biphasic release pattern. After 48 hours, the specific activity of released urokinase droped dramatically, indicating that urokinase cann't be used to prepare nanoparticles for a prolonged release. Morphometric analyses on the retrieved artery samples revealed that the inhibitory effect of intima proliferation was dose-dependent. At a concentration of 30 mg ml~(-1), NP infusion completely inhibited intima proliferation in a rabbit vascular injury model. Paclitaxel-loaded NPs with DMAB modification were proven an effective means of inhibiting proliferative response to vascular injury in a rabbit model.
Chapter 3. PCL/F68 was synthesized by bulk polymerization as described previously. Paclitaxel-loaded nanoparticles(NPs) were prepared by solvent displacement method using biodegradable PCL/F68. A cationic surfactant, didodecyldimethylammonium bromide (DMAB), was absorbed on the NP surface by electrostatic attraction between positive and negative charges. NPs were characterized in such aspects as size, surface morphology, surface charges as well as in vitro drug release profile. Balloon-injured rabbit carotid arteries were treated with single infusion of paclitaxel-loaded NP suspension and observed for 90 days. The inhibitory effects of NPs on neointima formation were evaluated as end-point. The obtained PCL/F68 compound has a viscosity average molecular weight of 44,000. PCL/F68 NPs showed porous surface and spherical shape with a mean diameter around 300nm. Negatively charged PLGA NPs shifted to positive after the DMAB modification. The in vitro drug release profile showed a biphasic release pattern. Morphometric analyses on the retrieved artery samples revealed that PCL/F68 NP infusion completely inhibited intima proliferation in a rabbit vascular injury model. Compared with PLGA NPs, the paclitaxel-loaded PCL/F68 has a better effect of inhibiting intima proliferation in animal model (P＜0.05). Paclitaxel-loaded PCL/F68 NPs with DMAB modification represents a longer delay and an effective means of inhibiting proliferative response to vascular injury in a rabbit model.
In conclusion, the modified paclitaxel-loaded nanoparticles as local delivery system provide an effective means of inhibting proliferative response to vascular injury in the rabbits.
引文
1. Williams, D.O., R. Holubkov, W. Yeh, et al., Pereutaneous coronary intervention in the current era compared with 1985-1986: the National Heart, Lung, and Blood Institute Registries. [J].Circulation, 2000. 102(24). 2945-51.
2. Mehran, R., G. Dangas, A.S. Abizaid, et al., Angiographic patterns of in-stent restenosis: classification and implications for long-term outcome. [J].Circulation, 1999. 100(18). 1872-8.
3. Fischman, D.L., M.B. Leon, D.S. Baim, et al., A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. [J]. N Engl J Med, 1994. 331(8). 496-501.
4. Serruys, P.W., D.P. Foley, M.J. Suttorp, et al., A randomized comparison of the value of additional stenting after optimal balloon angioplasty for long coronary lesions: final results of the additional value of NIR stents for treatment of long coronary lesions (ADVANCE) study. [J].J Am Coil Cardiol, 2002.39(3). 393-9.
5. Kuntz, R.E. and D.S. Baim, Defining coronary restenosis. Newer clinical and angiographic paradigms. [J].Circulation, 1993.88(3). 1310-23.
6. Farb, A., G. Sangiorgi, A.J. Carter, et al., Pathology of acute and chronic coronary stenting in humans. [J].Circulation, 1999.99(1). 44-52.
7. Nobuyoshi, M., T. Kimura, H. Nosaka, et al., Restenosis after successful percutaneous transluminal coronary angioplasty: serial angiographic follow-up of 229 patients. [J].J Am Coil Cardiol, 1988.12(3). 616-23.
8. Heitzer, T., H. Just, and T. Munzel, Antioxidant vitamin C improves endothelial dysfunction in chronic smokers. [J].Circulation, 1996.94(1). 6-9.
9. Isner, J.M., M. Kearney, S. Bortman, et al., Apoptosis in human atherosclerosis and restenosis. [J].Circulation, 1995.91(11). 2703-11.
10. Bittl J.A., Advances in coronary angioplasty. [J]. N Engl J Med, 1996. 335(17). 1290-1302.
11. Garasic J., C. Rogers, E.R. Edelman, Stent design and the biologic response, in: R. Beyar, et al., (Eds.), Frontiers in Interventional Cardiology, Marin Dunitz Ltd., London, 1997, pp. 95-100.
12. Violaris, A.G., R. Melkert, J.P. Herrman, et al., Role of angiographically identifiable thrombus on long-term luminal renarrowing after coronary angioplasty: a quantitative angiographic analysis. [J].Circulation, 1996.93(5). 889-97.
13. Komatsu, R., M. Ueda, T. Naruko, et al., Neointimal tissue response at sites of coronary stenting in humans: macroscopic, histological, and immunohistochemical analyses. [J]. Circulation, 1998.98(3). 224-33.
14. Speidel, C.M., P.R. Eisenberg, W. Ruf, et al., Tissue factor mediates prolonged procoagulant activity on the luminal surface of balloon-injured aortas in rabbits. [J].Circulation, 1995. 92(11). 3323-30.
15. Rekhter, M.D., E. O'Brien, N. Shah, et al., The importance of thrombus organization and stellate cell phenotype in collagen Ⅰ gene expression in human, coronary atherosclerotic and restenotic lesions. [J].Cardiovasc Res, 1996.32(3). 496-502.
16. Bar-Shavit, R., M. Benezra, A. Eldor, et al., Thrombin immobilized to extracellular matrix is a potent mitogen for vascular smooth muscle cells: nonenzymatic mode of action. [J].Cell Regul, 1990. 1(6). 453-63.
17. Gasic, G.P., C.P. Arenas, T.B. Gasic, et al., Coagulation factors X, Xa, and protein S as potent mitogens of cultured aortic smooth muscle cells. [J].Proc Natl Acad Sci U S A, 1992.89(6). 2317-20.
18. Moreno, P.R., V.H. Bernardi, J. Lopez-Cuellar, et al., Macrophage infiltration predicts restenosis after coronary intervention in patients with unstable angina. [J].Circulation, 1996. 94(12). 3098-102.
19. Mickelson, J.K., N.M. Lakkis, G. Villarreal-Levy, et al., Leukocyte activation with platelet adhesion after coronary angioplasty: a mechanism for recurrent disease? [J].J Am Coll Cardiol, 1996.28(2). 345-53.
20. Castronuovo, J.J., Jr., S.B. Guss, D. Mysh, et al., Cytokine therapy for arterial restenosis: inhibition of neointimal hyperplasia by gamma-interferon. [J].Cardiovasc Surg, 1995. 3(5). 463-8.
21. Lincoff, A.M., J.G. Furst, S.G. Ellis, et al., Sustained local delivery of dexamethasone by a novel intravascular eluting stent to prevent restenosis in the porcine coronary injury model [J].J Am Coll Cardiol, 1997.29(4). 808-16.
22. Bauters, C., P. de Groote, M. Adamantidis, et al., Proto-oncogene expression in rabbit aorta after wall injury. First marker of the cellular process leading to restenosis after angioplasty? [J].Eur Heart J, 1992. 13(4). 556-9.
23. Ciezki, J.P., U.O. Hafeli, P. Song, et al., Parenchymal cell proliferation in coronary arteries after percutaneous transluminal coronary angioplasty: a human tissue bank study. [J].Int J Radiat Oncol Biol Phys, 1999.45(4). 963-8.
24. Moreno, P.R., I.F. Palacios, M.N. Leon, et al., Histopathologic comparison of human coronary in-stent and post-balloon angioplasty restenotic tissue. [J].Am J Cardiol, 1999.84(4). 462-6, A9.
25. Gordon, P.C., C.M. Gibson, D.J. Cohen, et al., Mechanisms of restenosis and redilation within coronary stents--quantitative angiographic assessment. [J].J Am Coll Cardiol, 1993. 21(5). 1166-74.
26. Kornowski, R., G.S. Mintz, K.M. Kent, et al., Increased restenosis in diabetes mellitus after coronary interventions is due to exaggerated intimal hyperplasia. A serial intravascular ultrasound study. [J].Circulation, 1997.95(6). 1366-9.
27. Arakawa, K., K. Isoda, Y. Sugiyabu, et al., Intimal proliferation after stenting reflected by increased stent-to-vessel cross-sectional area ratio: serial intravascular ultrasound study. [J].J Cardiol, 1998.32(6). 379-89.
28. de Smet, B.J., J. van der Zande, Y.J. van der Helm, et al., The atherosclerotic Yucatan animal model to study the arterial response after balloon angioplasty: the natural history of remodeling. [J].Cardiovasc Res, 1998.39(1). 224-32.
29. Mintz, G.S., J.J. Popma, A.D. Pichard, et al., Intravascular Ultrasound Assessment of the Mechanisms and Predictors of Restenosis Following Coronary Angioplasty. [J].J Invasive Cardiol, 1997.9(4). 303-314.
30. Cho, A., L. Mitchell, D. Koopmans, et al., Effects of changes in blood flow rate on cell death and cell proliferation in carotid arteries of immature rabbits. [J].Circ Res, 1997. 81(3). 328-37.
31. Guarda, E., L.C. Katwa, S.E. Campbell, et al., Extracellular matrix collagen synthesis and degradation following coronary balloon angioplasty. [J].J Mol Cell Cardiol, 1996. 28(4). 699-706.
32. Lafont, A., E. Durand, J.L. Samuel, et al., Endothelial dysfunction and collagen accumulation: two independent factors for restenosis and constrictive remodeling after experimental angioplasty. [J]. Circulation, 1999. 100(10). 1109-15.
33. Waksman, R., J.C. Rodriguez, K.A. Robinson, et al., Effect of intravascular irradiation on cell proliferation, apoptosis, and vascular remodeling after balloon overstretch injury of porcine coronary arteries. [J].Circulation, 1997.96(6). 1944-52.
34. Yee, K.O. and S.M. Schwartz, Why atherosclerotic vessels narrow: the fibrin hypothesis. [J].Thromb Haemost, 1999.82(2). 762-71.
35. Kastrati A., H. Schuhlen, J. Hausleiter, et al., Restenosis after coronary stent placement and randomization to a 4-week combined antiplatelet or anticoagulant therapy: six-month angiographic follow-up of the Intracoronary Stenting and Antithrombotic Regimen (ISAR) Trial. [J].Circulation, 1997.96(2).462-467.
36. Lee C.W., J.K. Chae, H.Y. Lira, et al., Prospective randomized trial of corticosteroids for the prevention of restenosis after intracoronary stent implantation. [J].Am Heart J, 1999.138(1 Pt 1) 60-63.
37. Meurice T., C. Bauters, X. Hermant, et al., Effect of ACE inhibitors on angiographic restenosis after coronary stenting (PARIS): a randomised, double-blind, placebo-controlled trial. [J] .Lancet, 2001.357(9265). 1321-1324.
38. Serruys P.W., D.P. Foley, G. Jackson, et al., A randomized placebocontrolled trial of fluvastatin for prevention of restenosis after successful coronary balloon angioplasty; final results of the fluvastatin angiographic restenosis (FLARE) trial. [J]. Eur Heart J, 1999.20(1). 58-69.
39. Serruys P.W., D.P. Foley, M. Pieper, et al., The TRAPIST Study. A multicentre randomized placebo controlled clinical trial of trapidil for prevention of restenosis after coronary stenting, measured by 3-D intravascular ultrasound. [J]. Eur Heart J, 2001.22(20). 1938-1947.
40. Ellis S.G., Acute platelet inhibition with abciximab does not reduce instent restenosis (ERASER study). [J]. Circulation, 1999.1D0(8).799-806.
41. Serrus P.W., J.P. Herman, R. Simon, et al., A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty. [J]. N Eng J Med, 1995. 333. 757-763.
42. McEwan J., A. Henney, and S. Humphries, Vascular disease: the next target for local molecular therapeutics (editorial). [J]. Br Med J, 1994. 308.995-996.
43. Lincoff A.M., E.J. Topol, and S.G. Ellis, Local drug delivery for theprevention ofrestenosis. Fact, fancy, and future. [J]. Circulation, 1994.90.2070-2084.
44. Riessen R., and J.M. Isnar, Prospects for site-specific delivery of pharmacologic and molecular therapies. [J]. J Am Coll Cardiol, 1994.23.1234-1244.
45. Brieger D., and E. Topol, Local drug delivery systems and prevention of restenosis. [J]. Cardiovasc Res, 1997.35(3).405-413.
46. Kamath K.R., J.J. Barry, and K.M. Miller, The TaxusTM drug-eluting stent: a new paradigm in controlled drug delivery. [J]. Adv Drug Deliv Rev, 2006.58(3). 412-436.
47. Labhasetwar V., C. Song, and R.J. Levy, Nanoparticle drug delivery system for restenosis. [J]. Adv Drug Deliv Rev, 1997.24:63-85.
48. Topol E.J., and P.W. Serruys, Frontiers in interventional cardiology. [J]. Circulation, 1998. 98(17).1802-1820.
49. Scheller B., U. Speck, C. Abramjuk, U. et al., Paclitaxel balloon coating, a novel method for prevention and therapy of restenosis. [J]. Circulation, 2004.110(7): 810-814.
50. Banai S., M. Chorny, S.D. Gertz, et al., Locally delivered nanoencapsulated tyrphostin (AGL-2043) reduces neointima formation in balloon-injured rat carotid and stented porcine coronary arteries. [J]. Biomaterials, 2005.26:4898-4901.
51. Schwartz R.S., K.C. Huber, J.G. Murphy et al., Restenosis and the proportional neointimal response to coronary artery injury: results in a porcine model. [J]. J Am Coll Cardiol, 1992. 19(2). 267-274.
52. Kuntz R.E., C.M. Gibson, M. Nobuyoshi et al., Generalized model of restenosis after conventional balloon angioplasty, stenting and directional atherectomy. [J]. J Am Coll Cardiol, 1993.21(1). 15-25.
53. Raja S.G., Drug-eluting stents: Is it the beginning of the end for coronary artery bypass surgery? [J]. Chin Med J (Engl), 2004. 117. 1377-1387.
54. Raja S.G., and G.D. Dreyfus, Efficacy and safety of drug-eluting stents: current best available evidence. [J]. J Card Surg, 2006.21(6). 605-612.
55. Camenzind E., Treatment of in-stent restenosis--back to the future? [J]. N Engl J Med, 2006. 355(20). 2149-2151.
56. Luscher T.F., J. Steffel, F. R. Eberli, et al., Drug-eluting stent and coronary thrombosis: biological mechanisms and clinical implications. [J]. Circulation, 2007. 115(8). 1051-1058.
57. Daemen J., P. Wenaweser, K. Tsuchida, et al., Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study. [J]. Lancet, 2007. 369(9562). 667-678.
58. Shuchman M., Debating the risks of drug-eluting stents. [J]. N Engl J Med, 2007. 356(4). 325-328.
59. Shuchman M., Trading restenosis for thrombosis? New questions about drug-eluting stents. [J]. N Engl J Med, 2006. 355(19). 1949-52.
60. Fischell T.A., and D.R. Jr. Homes, Late DES thrombosis: A lot of smoke, very little fire? [J]. Catheter Cardiovasc Interv, 2007.69(4). 609-15.
61. Bertrand M.E., H.J. Rupprecht, P. Urban, et al., Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS). [J]. Circulation, 2000. 102:624-629.
62. Farb A., A.P. Burke, F.D. Kolodgie, et al., Pathological mechanisms of fatal late coronary stent thrombosis in humans. [J]. Circulation, 2003. 108. 1701-1706.
63. Joner M., A.V. Finn, A. Farb, et al., Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. [J]. J Am Coll Cardiol, 2006.48.193-202.
64. McFadden E.P., E. Stabile, E. Regar, et al., Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy.[J]. Lancet, 2004. 364. 1519-1521.
65. Moreno R., C. Fernandez, R. Hernandez, et al., Drug-eluting stent thrombosis: results from a pooled analysis including 10 randomized studies. [J]. J Am Coll Cardiol, 2005.45.954-959
66. Bavry A.A., D.J. Kumbhani, T.J. Helton, et al., What is the risk of stent thrombosis associated with the use of paclitaxel-eluting stents for percutaneous coronary intervention? A meta-analysis. [J]. J Am Coll Cardiol, 2005.45. 941-946.
67. FDA advises physicians of adverse events associated with Cordis Cypher coronary stents. US Food and Drug Administration Public Health Web Notification. October 29, 2003;T03-T71. Available at: http://www.fda.gov/bbs/topics/ANSWERS/2003/ANS01257.html. Accessed February 10, 2007.
68. Iakovou I., T. Schmidt, E. Bonizzoni, et al., Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. [J]. JAMA, 2005. 293.2126-2130.
69. Ong A.T., E.P. McFadden, E. Regar, et al., Late angiographic stent thrombosis (LAST) events with drug-eluting stents. [J]. J Am Coll Cardiol, 2005.45. 2088-2092.
70. US Food and Drug Administration. Update to FDA statement on coronary drug-eluting stents. Available at: http://www.fda.gov/cdrh/news/010407.html. Accessed February 10, 2007.
71. Windecker S., R. Simon, M. Lins, et al., Randomized comparison of a titanium-nitride-oxide-coated stent with a stainless steel stent for coronary revascularization: the TiNOX trial. [J]. Circulation, 2005. 111. 2617-2622.
72. Aoki J., P.W. Serruys, H. van Beusekom, et al., Endothelial progenitor cell capture by stents coated with antibody against CD34: the HEALING-FIM (Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth-First In Man) Registry. [J]. J Am Coll Cardiol, 2005.45. 1574-1579.
73. Blindt R., F. Vogt, I. Astafieva , et al., A novel drug-eluting stent coated with an integrin-binding cyclic Arg-Gly-Asp peptide inhibits neointimal hyperplasia by recruiting endothelial progenitor cells. [J]. J Am Coll Cardiol, 2006.47. 1786-1795.
74. Smith E.J., A.K. Jain, M.T. Rothman, New developments in coronary stent technology. [J]. J Interv Cardiol, 2006. 19(6). 493-9.
75. The Clinical Performance and Angiographic Results of the Coronary Stenting and Absorbable Metal Stents Study. PROGRESS AMS. I2 summit. American College of Cardiology Annual Scientific Sessions, 2006.
76. Bhargava B, N.K. Reddy, G. Karthikeyan, et al., A novel paclitaxel-eluting porous carbon-carbon nanoparticle coated, nonpolymeric cobalt-chromium stent: evaluation in a porcine model. [J]. Catheter Cardiovasc Interv, 2006.67(5). 698-702.
77．高润霖，也谈药物冼脱支架的安全性．[J]．中华心血管病杂志，2006．34(11)．964-965
78. Goldman B., H. Blanke, and H. Wolinsky, Influence of pressure on permeability of normal and diseased muscular arteries to horseradish peroxidase: a new catheter approach. [J]. Atherosclerosis, 1987.65. 215-25.
79. Camenzind E, De Scheerder I. Local drug delivery for coronary artery disease: established and emerging applications. Oxford, England: Taylor & Francis, 2005.
80. Wilensky R.L., K.L. March, I. Gradus-Pizlo, et al, Regional and arterial localization of radioactive microparticles after local delivery by unsupported or supported porous balloon catheters. [J]. Am Heart J, 1995.129. 852-9.
81. Camenzind E., W.H. Bakker, A. Reijs, et al, Site-specific intracoronary heparin delivery in humans after balloon angioplasty: a radioisotopic assessment of regional pharmacokinetics. [J]. Circulation, 1997.96. 154-65.
82. Lambert T.L., V. Dev, E. Rechavia et al., Localized arterial wall drug delivery from a polymer-coated removable metallic stent. Kinetics, distribution, and bioactivity of forskolin. [J]. Circulation, 1994.90(2).1003-1011.
83. Eccleston D.S., and A.M. Lincoff, Catheter-based drug delivery for restenosis. [J]. Adv Drug Del Rev, 1997.24.31-43.
84. Mitchel J.F., D.B. Fram, D.F. Palme, et al., Enhanced intracoronary thrombolysis with urokinase using a novel, local drug delivery system. In vitro, in vivo, and clinical studies. [J]. Circulation, 1995.91(3). 785-793.
85. Muller D.W., E.J. Topol, G.D. Abrams, et al., Intramural methotrexate therapy for the prevention of neointimal thickening after balloon angioplasty. [J]. J Am Coll Cardiol, 1992. 20(2). 460-466.
86. Wilensky R.L., K.L. March and D.R. Hathaway, Direct intraarterial wall injection of microparticles via a catheter: a potential drug delivery strategy following angioplasty. [J]. Am Heart J, 1991. 122(4 Pt 1). 1136-1140.
87. Gradus-Pizlo I., R.L. Wilensky, K.L. March et al., Local delivery of biodegradable microparticles containing colchicine or a colchicines analogue: effects on restenosis and implications for catheter-based drug delivery. [J]. J Am Cotl Cardiol, 1995. 26(6).1549-1557.
88. Nasser T.K., R.L. Wilensky, K. Mehdi, et al., Microparticle deposition in periarterial microvasculature and intramural dissections after porous balloon delivery into atherosclerotic vessels: quantitation and localization by confocal scanning laser microscopy. [J]. Am Heart J, 1996. 131(5). 892-898.
89. Valero F., M. Hamon, C. Fournier et al., Intramural injection of biodegradable microspheres as a local drug- delivery system to inhibit neointimal thickening in a rabbit model of balloon angioplasty. [J]. J Cardiovasc Pharmacol, 1997.31 (4). 513-519.
90. Rome J., V. Shayani, M. Flugelman et al., Anatomic barriers influence the distribution of in vivo gene transfer into the arterial wall: modeling with microscopic tracer particles and verification with a recombinant adenoviral vector. [J]. Arteriosclerosis and Thrombosis, 1994. 14(1). 148-161.
91. Anderson J.M., Biodegradation and biocompatibility of PLA and PLGA microparticles. [J]. Adv Drug Del Rev, 1997.28.5-24.
92. Labhasetwar V., C. Song, W. Humphrey, et al., Arterial Uptake of Biodegradable Nanoparticles: Effect of Surface Modifications. [J]. J Pharm Sci, 1998.87(10). 1229-1234.
93. Dev V., N. Eigler, M.C. Fishbein et al., Sustained local drug delivery to the arterial wall via biodegradable microspheres. [J]. Cathet Cardiovasc Diagn, 1997.41(3). 324-332.
94. Guzman L.A., V. Labhasetwar, C. Song et al., Local intraluminal infusion of biodegradable polymeric nanoparticles: a novel approach for prolonged drug delivery after balloon angioplasty. [J]. Circulation, 1996.94.1441-1448.
95. Westedt U., L. Barbu-Tudoran, A.K. Schaper, et al., Effects of different application parameters on penetration characteristics and arterial vessel wall integrity after local nanoparticle delivery using a porous balloon catheter. [J]. Eur J Pharm Biopharm, 2004.58(1). 161-168.
96. Lanza G., E Winter, T. Cyrus, et al., Nanomedicine opportunities in cardiology. [J]. Ann N Y Acad Sci, 2006. 1080.451-465.
97. Lanza G.M.,X. Yu, EM. Winter, et al., Targeted antiproliferative drug delivery to vascular smooth muscle cells with a magnetic resonance imaging nanoparticle contrast agent: implications for rational therapy of restenosis. [J]. Circulation, 2002. 106(22). 2842-2847.
98. Scheller B., U. Speck, C. Abramjuk, et al., Paclitaxel balloon coating, a novel method for prevention and therapy of restenosis. [J]. Circulation, 2004.110(7). 810-814.
99. Scheller B., C. Hehrlein, W. Bocksch, et al., Treatment of coronary in-stent restenosis with a paclitaxel-coated balloon catheter. [J]. N Engl J Med, 2006.355(20). 2113-2124.
100. Wang H.Y., Y.M Li., and M.Q. Liu, Advances in study on mechanism of antitumor action by Taxol [J]. Prog Pharm Sci (药学进展), 1999.23.209-214.
101. Wu X.J., and L. Huang. Microtubule inhibiton agents applied in neointimal proliferation and arterial remodeling after balloon angioplasty. [J].Chin Cir J (中国循环杂志),2001.16(5). 397-398.
102. Schiff P.B., J. Fant, and S.B. Horwitz, Promotion of microtubule assembly in vitro by taxol. [J]. Nature, 1979. 277. 665-667.
103. Rowinsky E.K., and R.S. Donehower, Drug therapy, paclitaxel (Taxol). [J]. N Engl J Med, 1995. 332.1004-1014.
104. Belotti D., M. Rieppi, M.I. Nicoletti, et al, Paclitaxel (TaxolR) inhibits motility of paclitaxel-resistant human ovarian carcinoma cells. [J]. Clin Cancer Res, 1996. 2. 1725-1730.
105. Belotti D., V. Vergani, T. Drudis, et al., The microtubule-affecting drug paclitaxel has antiangiogenic activity. [J]. Clin. Cancer Res, 1996.2.1843-1849.
106. Wang J., P. Lou, R. Lesniewski, et al., Paclitaxel at ultra low concentrations inhibits angiogenesis without affecting cellular microtubule assembly. [J]. Anti-Cancer Drugs, 2003.14. 13-19.
107. Giannakakou P., R. Robey, T. Fojo, et al., Low concentrations of paclitaxel induce cell type-dependent p53, p21 and G1/G2 arrest instead of mitotic arrest: molecular determinants of paclitaxel-induced cytotoxicity. [J]. Oncogene, 2001.20. 3806-3813.
108. Tange S., M.N. Scherer, C. Graeb, et al., The antineoplastic drug paclitaxel has immunosuppressive properties that can effectively promote allografi survival in a rat transplant model. [J]. Transplantation, 2002.73.216-223.
109. Mullins D.W., M.D. Koci, C.J. Burger, et al., Interleukin-12 overcomes paclitaxel-mediated suppression of T-cell proliferation, Immunopharmacol. [J]. Immunotoxicol, 1998. 20. 473-492.
110. Hui A., W.X. Min, J. Tang, T.F. Cruz, Inhibition of activator protein 1 activity by paclitaxel suppresses interleukin-1-induced collagenase and stromelysin expression by bovine chondrocytes. [J]. Arthritis Rheum. 41 (1998) 869-876.
111. Axel D.I., W. Kunert, C. Go "ggelmann, et al., Paclitaxel inhibits arterial smooth muscle cell proliferation and migration in vitro and in vivo using local drug delivery. [J]. Circulation, 1997.96. 636-645.
112. Suh H., B. Jeong, R. Rathi, et al., Regulation of smooth muscle cell proliferation using paclitaxel-loaded poly(ethylene oxide)-poly(lactide/glycolide) nanospheres. [J]. J Biomed Mater Res, 1998.42. 331-338.
113. Wiskierchen J., W. Schober, N. Schart, et al., The effects of paclitaxel on the three phases of restenosis, smooth muscle cell proliferation, migration, and matrix formation: an in vitro study. [J]. Invest Radiol, 2004.39. 565-571.
114. Sollot S.J., L. Cheng, R.R. Pauly, et al., Taxol inhibits neointimal smooth muscle cell accumulation after angioplasty in the rat. [J]. J Clin Invest, 1995.95. 1869-1876.
115. Drachman D.E., E.R. Edelman, P. Seifert, et al., Neointimal thickening after stent delivery of paclitaxel: change in composition and arrest of growth over six months. [J]. J Am Coll Cardiol, 2000.36. 2325-2332.
116. Heldman A.W., L. Cheng, M. Jenkins, et al., Paclitaxel stent coating inhibits neointimal hyperplasia at 4 weeks in a porcine model of coronary restenosis. [J]. Circulation, 2001.103. 2289-2295.
117. Farb A., P.F. Heller, A.J. Carter, et al., Paclitaxel polymercoated stents reduce neointima, American Heart Association, Abstracts from the 70th Scientific Sessions, Supplement to Circulation, 1997, pp. Ⅰ-608.
118. Drachman D.E., E.R. Edelman, K.R. Kamath, et al., Sustained stent-based delivery of paclitaxel arrests neointimal thickening and cell proliferation, American Heart Association, Abstracts from the 71 st Scientific Sessions, Supplement to Circulation, 1998, pp. Ⅰ-740.
119. Signore P.E., L.S. Machan, J.K. Jackson, et al., Complete inhibition of intimal hyperplasia by perivascular delivery of paclitaxel in balloon injured rat carotid arteries. [J]. J Vasc Interv Radiol, 2001.12 (2001) 79-88.
120. Oberhoff M., W. Kunert, C. Herdeg, et al., Inhibition of smooth muscle cell proliferation after local drug delivery of the antimitotic drug paclitaxel using a porous balloon catheter. [J]. Basic Res Cardiol, 2001.96. 275-282.
121. Canizares C., N. Vivar, and M. Herdoiza, The effects of taxol, a potent platelet antiaggregant, may be due to its microtubular stabilization activity. [J]. Platelets, 1997.8.61-63.
122. Celleti F.L., J.M. Waugh, P.G. Amabile, et al., Inhibition of vascular endothelial growth factor-mediated neointima progression with angisostatin or paclitaxel. [J]. J Vasc Interv Radiol, 2002.13.703- 707.
123. Kim D.W., J.S. Kwon, Y.G. Kim, et al., Novel oral formulation of paclitaxel inhibits neointimal hyperplasia in a rat carotid artery injury model. [J]. Circulation, 2004. 109. 1558-1563.
1. Couveur P., C. Duberner, and F. Puisieux, Controlled drug delivery with nanoparticles: current possibilities and future trends. [J]. Eur J Pharm Biopharm, 1995.41 (1). 2-11.
2. Allemann E., R. Gurny, and E. Doelker, Drug-loaded nanoparticles preparation methods and drug targeting issues. [J]. Eur J Pharm Biopharm, 1993.39(5). 173-191.
3. Kreuter J., Nanoparticles and microparticles for drug and vaccine delivery. [J]. J Anat, 1996. 189.503-505.
4. Mehran, R., G. Dangas, A.S. Abizaid, et al., Angiographic patterns of in-stent restenosis: classification and implications for long-term outcome. [J].Circutation, 1999. 100(18). 1872-8.
5. Song C.X., V. Labhasetwar, and R.J. Levy., Formulation and characterization of biodegradable nanoparticles for intravascular local drug delivery. [J]. J Controlled Release, 1997.37(1). 67-74.
6. Bittl J.A., Advances in coronary angioplasty. [J]. N Engl J Med, 1996. 335.1290-1302.
7. Uwatoku T., H. Shimokawa, K. Abe, et al., Application of nanoparticle technology for the prevention of restenosis after balloon injury in rats [J]. Cite Res,2003.92(7). e62-9.
8. Westedt U., L. Barbu-Tudoran, A.K. Schaper, et al., Deposition of Nanoparticles in the Arterial Vessel by Porous Balloon Catheters: Localization by Confocal Laser Scanning Microscopy and Transmission Electron Microscopy. [J]. AAPS PharmSci, 2004.4(4). 1-6.
9. Mintz G.S., J.J. Popma, A.D. Pichard, et al., Arterial remodeling after coronary angioplasty: a serial intravascular ultrasound study. [J]. Circulation, 1996.94(1). 35-43
10. Kimura T., S. Kaburagi, T. Tamura, et al., Remodeling of human coronary arteries undergoing coronary angioplasty or atherectomy. [J]. Circulation. 96(2). 475-483.
11. Hanke H., T. Strohschneider, M. Oberhoff, et al., Time course of smooth muscle cell proliferation in the intima and media of arteries following experimental angioplasty. [J]. Circ Res, 1990. 67(3). 651-659.
12. Shi Y., J.E. O'Brien, L. Ala-Kokko, et al., Origin of extracellular matrix synthesis during coronary repair. [J]. Circulation, 1997.95(4). 997-1006.
13. Hehrlein C., C. Gollan, K. Donges, et al., Low -dose radioactive endovascular stents prevent smooth muscle cell proliferation and neointimal hyperplasia in rabbits. [J]. Circulation, 1995. 92(6). 1570-1575.
14. Regar E., G. Sianos, and P.W. Serruys, Stent development and local drug delivery. [J]. Br Med Bull, 2001.59(1). 227-248.
15. Grube E., S. Silber, K.E. Hauptmann, et al., TAXUS I: six- and 12-month results from a randomized, double-blind trial on a slow-release paclitaxeleluting stent for de novo coronary lesions. [J]. Circulation, 2003. 107:38-42.
16. Park S.J., W.H. Shim, D.S. Ho, et al., A paclitaxel-eluting stent for the prevention of coronary restenosis. [J]. N Engl J Med, 2003. 348:1537-1545.
17. Moses J.W., M.B. Leon, J.J. Popma, et al., Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. [J]. N Engl J Med, 2003. 349. 1315-1323.
18. Bahai S., M. Chorny, S.D. Gertz, et al., Locally delivered nanoencapsulated tyrphostin (AGL-2043) reduces neointima formation in balloon-injured rat carotid and stented porcine coronary arteries. [J]. Biomaterials, 2005.26. 4898-4901.
19. Camenzind E., Treatment of in-stent restenosis--back to the future? [J]. N Engl J Med, 2006. 355(20). 2149-2151.
20. Luscher T.F., J. Steffel, F.R. Eberli, et al., Drug-eluting stent and coronary thrombosis: biological mechanisms and clinical implications. [J]. Circulation, 2007.115(8). 1051-1058.
21. Daemen J., P. Wenaweser, K. Tsuchida, et al., Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study. [J]. Lancet, 2007. 369(9562). 667-678.
22. Shuchman M., Debating the risks of drug-eluting stents. [J]. N Engl J Med, 2007. 356(4). 325-328.
23. Shuchman M., Trading restenosis for thrombosis? New questions about drug-eluting stents. [J]. N Engl J Med, 2006. 355(19). 1949-52.
24. Fischell T.A., and D.R. Jr. Homes, Late DES thrombosis: A lot of smoke, very little fire? [J]. Catheter Cardiovasc Interv, 2007.69(4). 609-15.
25. Wolinsky H., and S.N. Thung., Use of a perforated balloon catheter to deliver concentrated heparin into the wall of the normal canine artery. [J]. J Am Coll Cardiol, 1990.15(2). 475-481.
26. Scheller B., U. Speck, C. Abramjuk, et al., Paclitaxel balloon coating, a novel method for prevention and therapy of restenosis. [J]. Circulation, 2004.110(7). 810-814.
27. Muller D.W., E.J. Topol, G.D. Abrams, et al., Intramural methotrexate therapy for the prevention of neointimal thickening after balloon angioplasty. [J]. J Am Coll Cardiol, 1992.20(2). 460-466.
28. Lambert T.L., V. Dev, E. Rechavia, et al., Eigler. Localized arterial wall drug delivery from a polymer-coated removable metallic stent: kinetics, distribution, and bioactivity of forskolin. [J]. Circulation, 1994.90(2). 1003-1011.
29. Valero F., M. Hamon, C. Fournier, et al., Intramural injection of biodegradable microspheres as a local drug-delivery system to inhibit neointimal thickening in a rabbit model of balloon angioplasty. [J]. J Cardiovasc Pharmacol, 1998.31 (4). 513-519.
30. Wilensky R.L., K.L. March, I. Gradus-Pizlo, et al., Regional and arterial localization of radioactive microparticles after local delivery by unsupported or supported porous balloon catheters. [J]. Am Heart J, 1995. 129(5). 852-859.
31. Guzman L.A., V. Labhasetwar, C. Song, et al., Local intraluminal infusion of biodegradable polymeric nanoparticles: a novel approach for prolonged drug delivery after balloon angioplasty. [J]. Circulation, 1996.94.1441-1448.
32. Labhasetwar V., C. Song, and R.J. Levy., Nanoparticle drug delivery system for restenosis. [J]. Adv Drug Deliv Rev, 1997.24:63-85.
33. Humphrey W.R., L.A. Erickson, C.A. Simmons, et al., The effect of intramural delivery of polymeric nanoparticles loaded with the anti-proliferative 2-aminochromone U-86983 on neointimal hyperplasia development in balloon-injured porcine coronary. [J]. Adv Drug Deliv Rev, 1997.24: 87-108.
34. Song C., V. Labhasetwar, X. Cui, T. et al., Arterial uptake of biodegradable nanoparticles for intravascular local drug delivery: results with an acute dog model. [J]. J Control Rel, 1998.54(2). 201-211.
35. Labhasetwar V., C. Song, W. Humphrey, et al., Arterial uptake of biodegradable nanoparticles: effect of surface modifications. [J]. J Pharm Sci, 1998.87(10). 1229-1234.
36. Kamath K.R., J.J. Barry, and K.M. Miller. The Taxus~(TM) drug-eluting stent: a new paradigm in controlled drug delivery. [J]. Adv Drug Deliv Rev, 2006.58(3). 412-436.
37. Kim D.W., J.S. Kwon, Y.G. Kim, et al., Novel oral formulation of paclitaxel inhibits neointimal hyperplasia in a rat carotid artery injury model. [J]. Circulation, 2004.109. 1558-1563.
38. Huh K.M., S.C. Lee, Y.W. Cho, et al., Hydrotropic polymer micelle system for delivery of paclitaxel. [J]. J Control Release, 2005.101(1-3).59-68.
39. Nasser T.K., R.L. Wilensky, K. Mehdi, et al., Microparticle deposition in periarterial microvasculature and intramural dissections after porous balloon delivery into atherosclerotic vessels: quantitation and localization by confocal scanning laser microscopy. [J]. Am Heart J, 1996. 131(5). 892-898.
40. Rome J.J., V. Shayani, M.Y. Flugelman, et al., Dichek. Anatomic barriers influence the distribution of in vivo gene transfer into the arterial wall: modeling with microscopic tracer particles and verification with a recombinant adenoviral vector. [J]. Arterioscler Thromb, 1994. 14: 148-161.
41. Anderson J.M., and M.S. Shive., Biodegradation and biocompatibility of PLA and PLGA microspheres. [J]. Adv Drug Deliv Rev, 1997.28. 5-24.
42. Gradus-Pizlo I., R.L. Wilensky, K.L. March, et al., Local delivery of biodegradable microparticles containing colchicine or a colchicine analogue: effects on restenosis and implications for catheter-based drug delivery. [J]. J Am Coll Cardiol, 1995.26(6). 1549-1557.
43. Dev V., N. Eigler, M.C. Fishbein, et al., Sustained local drug delivery to the arterial wall via biodegradable microspheres. [J]. Cathet Cardiovasc Diagn, 1997.41(3). 324-332.
44. Rupert L.A.M., D. Hoekstra, and B.F.N. Engberts, Fusogenic behavior of didodecyldimethylammonium bromide bilayer vesicles. [J]. J Am Chem Soc, 1985. 107. 2628-2631.
45. Kelly R., Clinical and laboratory evaluation of a new synthetic absorbable suture. [J]. Rev. Surg., 1970.2. 142-143.
46. Schindler A., R. Jeffcoat, G. Kimmel, et al., Biodegradable polymers for sustained drug delivery. [J]. Contemp. Top. Polymer. Sci., 1977.2.251-287.
47. Aguado M., and P. Lambert, Controlled-release vaccine-biodegradable polylactide/polyglycolide(PL/PG) microspheres as antigen vechiles. [J]. Immunobiol., 1992. 184. 113-125.
48. Gref R., Y. Minamitake, M.T. Peracchia, et al., Biodegradable long-circulating polymeric nanospheres. [J]. Science, 1994. 263. 1600-1603.
49. Suh H., B. Jeong, R. Rathi, et al., Regulation of smooth muscle cell proliferation using paclitaxel-loaded poly(ethyleneoxide)-poly(lactide/glycolide) nanospheres. [J]. J Biomed Mater Res, 1998.42. 331-338.
50. Jackson J.K., K.C. Skinner, L. Burgess, et al., Paclitaxel-loaded crosslinked hyaluronic acid films for the prevention of postsurgical adhesions. [J]. Pharrn Res, 2002.19. 411-417.
51. Kunou N., Y. Ogura, M. Hashizoe, et al., Controlled intraocular delivery of ganciclovir with use of biodegradable scleral implant in rabbits. [J]. J Control Rel, 1995.37.143-150.
52. Pitt C.G., M.M. Gratzl, A.R. Jeffcoat, et al., Sustained drug delivery systems. Ⅱ. Factors affecting release rates from poly(ε-caprolactone) and related biodegradable polymers. [J]. J Pharm Sci,1979.68. 1534-1538.
53. Hora M.S., R.K. Rana, J.H. Nunberg, et al., Release of human serum albumin from retinitis with intravitreal injection of liposome encapsulated poly(lactide-co-glycolide) microspheres. [J]. Pharm Res, 1990.7.1190-1194.
54. Yasukawa T., H. Kimura, Y. Tabata, et al., Biodegradable scleral plugs for vitreoretinal drug delivery. [J]. Adv Drug Deliv Rev, 2001.52.25-36.
55. Panyam J., M.M. Dali, S.K. Sahoo, et al., Polymer degradation and in vitro release of a model protein from poly(D,L-lactide-co-glycolide) nano- and microparticles. [J]. J Control Rel, 2003.92. 173-187.
56. Manil L., J. Davin, C. Duchenne, et al., Uptake of nanoparticles by rat glomerular mesangial cells in vivo and in vitro. [J]. Pharm Res, 1994. 11. 1160-1167.
57. Wright J.J., and L. Illum, Active targeting of microcapsules and microspheres to specific regions, in: M. Donbrow (Ed.), Microcapsules and Nanoparticles in Medicine and Pharmacy. CRC Press, Boca Raton, FL, 1992, pp. 282-293.
58. You J., M Kamihira, and S. Iijima, Surfactant-mediated gene transfer for animal cells. [J]. Cytotechnology, 1997. 25. 45-52.
1. Mei L., H.F. Sun, X. Jin, et al., Modified paclitaxel-loaded nanoparticles for the prevention of restenosis in a rabbit arterial balloon injury model. [J]. Pharm. Res., 2007. (Published on line)
2. Sun H.F., L. Mei, C.X. Song, et al., The in vivo degradation, absorption and excretion of PCL-based implant. [J]. Biomaterials, 2006.27. 1735-1740.
3．侯惠民，王浩，张光杰，药用辅料应用技术．北京：中国医药科技出版社，2002：220-221．
4. Ma G.., C. Song, H. Sun, et al., A biodegradable levonorgestrel-releasing implant made of PCL/F68 compound as tested in rats and dogs. [J]. Contraception, 2006.74(2). 141-147.
5. Ma G.., and C. Song, PCL/poloxamer 188 blend microsphere for paclitaxel delivery: Influence of poloxamer 188 on morphology and drug release. [J]. J. Appl. Polym. Sci., 2007. 104(3). 1895-1899.
6. Pitt C.G., Poly(e-caprolactone) and its copolymers. In: Chasin M, Langer R, editors. Biodegradable polymers as drug deliver systems. New York: Marcel Dekker, Inc.; 1991. p. 71-82.
7. Halabalova V., L. Simek, J. Dostal, et al. Note on the relationship between the parameters of the Mark-Houwink-Kuhn-Sakurada equation. [J]. Int J Polym Anal Charact, 2004.9.65-75.
8. Pitt C.G., M.M. Gratzl G.L. Kimmel et al., Aliphatic polyesters. Ⅱ. The degradation of poly (dllactide), poly (epsilon-caprolactone), and their copolymers in vivo. [J]. Biomaterials, 1981.2. 215-220.
9. Woodward S.C., P.S. Brewer, F. Moatamed, et al., The intracellular degradation of poly(epsiloncaprolactone). [J]. J. Biomed. Mater. Res., 1985.19. 437-444.
10. Pitt C.G., 1990. Poly(o-caprolactone) and its copolymers. In: Langer, R., Chasin, M. (Eds.), Bioderadable Polymers as Drug Delivery Systems. Marcel Decker Inc, New York, NY, pp. 71-120.
11. Ponsart S., J. Coudane, and M. Vert, A novel route to poly(o-caprolactone) based copolymers via anionic derivatization. [J]. Biomacromolecules, 2000.1,275-281.
12. Labhasetwar V., C. Song, W. Humphrey, et al., Arterial uptake of biodegradable nanoparticles: effect of surface modifications. [J]. J Pharm Sci, 1998.87(10). 1229-1234.
13. Rupert L.A.M., D. Hoekstra, and B.F.N. Engberts, Fusogenic behavior of didodecyldimethylammonium bromide bilayer vesicles. [J]. J Am Chem Soc, 1985. 107. 2628-2631.
14. Song C., V. Labhasetwar, X. Cui, T. et al., Arterial uptake of biodegradable nanoparticles for intravascular local drug delivery: results with an acute dog model. [J]. J Control Rel, 1998.54(2). 201-211.
15. Chawla J.S., and M.M. Amiji, Biodegradable poly(epsilon -caprolactone) nanoparticles for tumor-targeted delivery of tamoxifen.[J].Int. J. Pharm.,2002.249(1-2). 127-138.
16. Fessi, H., F. Puisieux, J. P. Devissaguet, C. Thies, 1987. US Patent No. 5,118,528.
17. Nasser T.K., R.L. Wilensky, K. Mehdi, et al., Microparticle deposition in periarterial microvasculature and intramural dissections after porous balloon delivery into atherosclerotic vessels: quantitation and localization by confocal scanning laser microscopy. [J]. Am Heart J, 1996. 131(5). 892-898.
18. Rome J.J., V. Shayani, M.Y. Flugelman, et al., Dichek. Anatomic barriers influence the distribution of in vivo gene transfer into the arterial wall: modeling with microscopic tracer particles and verification with a recombinant adenoviral vector, [J]. Arterioscler Thromb, 1994. 14: 148-161.
19. Waksman, R., J.C. Rodriguez, K.A. Robinson, et al., Effect of intravascular irradiation on cell proliferation, apoptosis, and vascular remodeling after balloon overstretch injury of porcine coronary arteries. [J].Circulation, 1997.96(6). 1944-52.
20. Anderson J.M., and M.S. Shive., Biodegradation and biocompatibility of PLA and PLGA microspheres. [J]. Adv Drug Deliv Rev, 1997.28. 5-24.
21. Gradus-Pizlo I., R.L. Wilensky, K.L. March, et al., Local delivery of biodegradable microparticles containing colchicine or a colchicine analogue: effects on restenosis and implications for catheter-based drug delivery. [J]. J Am Coll Cardiol, 1995.26(6). 1549-1557.
22. Dev V., N. Eigler, M.C. Fishbein, et al., Sustained local drug delivery to the arterial wall via biodegradable microspheres. [J]. Cathet Cardiovasc Diagn, 1997.41(3). 324-332.
23. Guzman L.A., V. Labhasetwar, C. Song, et al., Local intraluminal infusion of biodegradable polymeric nanoparticles: a novel approach for prolonged drug delivery after balloon angioplasty. [J]. Circulation, 1996.94.1441-1448.
24. Song C., V. Labhasetwar, X. Cui, T. et al., Arterial uptake of biodegradable nanoparticles for intravascular local drug delivery: results with an acute dog model. [J]. J Control Rel, 1998.54(2). 201-211.
25. Labhasetwar V., C. Song, W. Humphrey, et al., Arterial uptake of biodegradable nanoparticles: effect of surface modifications. [J]. J Pharm Sci, 1998.87(10). 1229-1234.
26. Rupert L.A.M., D. Hoekstra, and B.F.N. Engberts, Fusogenic behavior of didodecyldimethylammonium bromide bilayer vesicles. [J]. J Am Chem Soc, 1985. 107. 2628-2631.
27. Kim D.W., J.S. Kwon, Y.G. Kim, et al., Novel oral formulation of paclitaxel inhibits neointimal hyperplasia in a rat carotid artery injury model. [J]. Circulation, 2004. 109. 1558-1563.
28. Kunou N., Y. Ogura, M. Hashizoe, et al., Controlled intraocular delivery of ganciclovir with use of biodegradable scleral implant in rabbits. [J]. J Control Rel, 1995.37.143-150.
29. Pitt C.G., M.M. Gratzl, A.R. Jeffcoat, et al., Sustained drug delivery systems. Ⅱ. Factors affecting release rates from poly(ε-caprolactone) and related biodegradable polymers. [J]. J Pharm Sci,1979.68. 1534-1538.
30. Hora M.S., R.K. Rana, J.H. Nunberg, et al., Release of human serum albumin from retinitis with intravitreal injection of liposome encapsulated poly(lactide-co-glycolide) microspheres. [J]. Pharm Res, 1990.7.1190-1194.
31. Yasukawa T., H. Kimura, Y. Tabata, et al., Biodegradable scleral plugs for vitreoretinal drug delivery. [J]. Adv Drug Deliv Rev, 2001.52.25-36.
32. O'Keefe J.H.J., McCallister B.D., Bateman T.M., et al., Ineffectiveness of colchicines for the prevention of restenosis after coronary angioplasty. [J]. J. Am. Coll. Cardiol., 1992.19. 1597-1600.
33. Serruys P.W., W. Rutsch, G.R. Heyndricks, et al., Prevention of restenosis after percutaneous transluminal coronary angioplasty with thromboxane A2-receptor blockade. A randomized, double- blind, placebo-controlled trial Coronary Artery Restenosis Prevention on Repeated Thromboxane-Antagonism Study (CARPORT). [J]. Circulation, 1991.84. 1568-1580.
34. Does the new angiotensin converting enzyme inhibitor cilazapril prevent restenosis after percutaneous transluminal coronary angioplasty? Results of the MERCATOR study: a multicenter, randomized, double-blind placebo-controlled trial. Multicenter European Research Trial with Cilazapril after Angioplasty to Prevent Transluminal Coronary Obstruction and Restenosis (MERCATOR) Study Group. [J]. Circulation, 1992. 86(1). 100-110.
35. Weintraub W.S., S.J. Boccuzzi, J.L. Klein, et al., Lack of effect of lovastatin on restenosis after coronary angioplasty. Lovastatin Restenosis Trial Study Group. [J]. N. Engl. J. Med.,1994. 331(20).1331-1337.
36. Serruys P.W., J.P. Herrman, R. Simon, et al., A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty. Helvetica Investigators. [J]. N. Engl. J. Med., 1995. 333(12). 757-763.
37. Sollott S.J., L. Cheng, R.R. Pauly, et al., Taxol inhibits neointimal smooth muscle cell accumulation after angioplasty in the rat. [J]. J. Clin. Invest., 1995.95. 1869-1876.
38. Kim D.W., J.S. Kwon, Y.G. Kim, et al., Novel Oral Formulation of Paclitaxel Inhibits Neointimal Hyperplasia in a Rat CarotidArtery Injury Model [J]. Circulation, 2004.109.1558-1563.
39. Nobuyoshi M., T. Kimura, H. Nosaka, et al., Restenosis after successful percutaneous transluminal angioplasty: serial angiographic follow-up of 229 patients. [J]. J. Am. Coll. Cardiol., 1988.12.616-623.
40. Serruys P.W., H.E. Luijten, K.J. Beatt, et al., Incidence of restenosis after successful coronary angioplasty: a time-related phenomenon: a quantitative angiographic study in 342 consecutive patients at 1, 2, 3, and4 months. [J]. Circulation, 1988.77.361-371.
41. Kimura T., H. Yokoi, Y. Nakagawa, et al., Three-year follow-up after implantation of metallic coronary-artery stents. [J]. N. Engl. J. Med., 1996. 334. 561-566.
42. Freireich E.J., E.A. Gehan, D.P. Rall, et al., Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. [J]. Cancer Chemother. Rep, 1966.50 (4). 219-244.
43. Westedt U., L. Barbu-Tudoran, A.K. Schaper, et al., Effects of different application parameters on penetration characteristics and arterial vessel wall integrity after local nanoparticle delivery using aporous balloon catheter. [J]. Eur J Pharm Biopharm, 2004.58(1). 161-168.
44. Yasuda S., T. Noguchi, M. Gohda, et al., Local delivery of low-dose docetaxel, a novel microtubule polymerizing agent, reduces neointimal hyperplasia in a balloon-injured rabbit iliac artery modeL [J]. Cardiovasc. Res., 2002.53 (2).481-486.
45. Teirstein P.S., and R.E. Kuntz, New frontiers in interventional cardiology: intravascular radiation to prevent restenosis. [J]. Circulation, 2001. 104 (21). 2620-2626.
46. Sousa J.E., M.A. Costa, A. Abizaid, et al., Sirolimus-eluting stent for the treatment of in-stent restenosis: a quantitative coronary angiography and three-dimensional intravascular ultrasound study. [J]. Circulation, 2003.107 (1). 24-27.