Smooth muscle cell proliferation plays a major role in the genesisof restenosis after angioplasty or vascular injury. Local delivery of agents capable of modulating vascular responses, have the potential to prevent restenosis. However, the development of injectable microspheres for sustained drug delivery to the arterial wall is a major challenge. We demonstrated the possibility of entrapping an antiproliferative agent, cisplatin, in a series of surface coated biodegradable microspheres composed of poly(lactic acid)– poly(caprolactone) blends, with a mean diameter of 2–10 mm. The microspheres were surface coated with poly ethylene glycol (PEG), chitosan (Chit), or alginate (Alg). A solution of cisplatin and a 50: 50 blend of polylactic acid (PLA)– polycaprolactone (PCL) dissolved in acetone–dichloromethane mixture was poured into an aqueous solution of PEG (or polyvinyl alcohol or Chit or Alg) with stirring using a high speedhomogenizer, for the formation of microspheres. Cisplatin recovery inmicrospheres ranged from 25–45% depending on the emulsification system used for the preparations. Scanning electron microscopy revealed that the PLA–PCL microspheres were spherical in shape and had a smooth surface texture. The amount of drug release was much higher initially (20–30%), this was followed by a constant slow-release profile for a 30-day period of study. It has been found that drugrelease depends on the amount of entrapped drug, on the presence of extra cisplatin in the dispensing phase, and on the polymer coatings.This PEG or Alg-coated PLA/PCL microsphere formulation may have potential for the targeted delivery of antiproliferative agents to treat restenosis.
1. Faxon, D.P. and Currier, J.W. (1995). Prevention of post PTCA restenosis. Ann. N.Y. Acad. Sci., 748: 419–428.
2.
2. Ross, R. (1993). The pathiogenesis of atherosclerosis: a perspectivefor the 1990s. Nature, 362: 801–809.
3.
3. Davies, M.G. and Hagen, P.O. (1994). Pathobiology of intimal hyperplasia. Br. J. Surg, 81: 1254–1269.
4.
4. Lincoff, A.M., Furst, J.G., Ellis, S.G. and Topol, E.J. (1994). Sustained local drug delivery by a novel intravascular eluting stent toprevent restenosis in the porcine coronary artery. J. Am. Coll. Cardiol, 23(18A).
5.
5. Edleman, R.E. and Karnovsky, M.J. (1994). Contrasting effects of the intermittent and continuous administration of heparin in experimental restenosis. Circulation, 89: 770–776.
6.
6. Wilensky, R.L., March, K.L. and Hathaway, D.R. (1991). Direct intraarterial, wall injection of microparticles via a catheter: a potential drug delivery strategy following angioplasty. Am. Heart. J., 122: 1136–1140.
7.
7. Dev, V., Eigler, N., Fishbein, M.C., Tian Y., Hickey, A., Rechavia, E., Forrester, J.S. and Litvack, F. (1997). Sustained local delivery to the arterial wall via biodegradable microspheres. Cardiovasc. Diagn, 41: 324–332.
8.
8. Muller, D.W.M., Ellis, S.G. and Topol, E.J. (1991). Colchicine and antineoplastic therapy for the prevention of restenosis following percutaneous coronary interventions. J. Am. Coll. Cardiol.17Suppl.(B): 126B–131B.
9.
9. Schwartz, R.S., Holmes, D.R.J. and Topol, E.J. (1992). The restenosis paradigm revisited: an alternative proposal for cellular mechanisms. J. Am. Cell. Cardiol, 20: 1284–1293.
10.
10. Heller, J. (1980). Controlled release of biologically active compounds from bioerodible polymers. Biomaterials, 1: 51–57.
11.
11. Nihant, N., Grandfils, C., Jerome, R. and Teyssie, P. (1995). Microencapsulation by coacervation of poly(lactic-co-glycolide) IV. Effect of the processing parameters on coacervation and encapsulation. J.Control. Release, 35: 117–125.
12.
12. Engelberg, I. and Kohn, J. (1991). Physico-mechanical properties of degradable polymers used in medical applications. Biomaterials, 12: 292–300.
13.
13. Bazile, D., Prudhomme, C., Bassoullet, M.T., Marlard, M., Spenlenhauer, G. and Veillard, M. (1995). Stealth Me-PEG-PL Ananoparticles avoid uptake by the mononuclear phagocyte system. J. Pharm. Sci., 84: 493–498.
14.
14. Quellec, P., Gref, R., Perrin, L., Dellacherie, E., Sommer, F., Verbavatz, J.M. and Alonso, M.J. (1998). Protein, encapsulation within polyethylene glycol-coated nanosphertes I: Physicochemical characterization. J. Biomed. Mater. Res., 42: 45–54.
15.
15. Das, G.S., Rao, G.H.R., Wilson, R.F. and Chandy, T. (2000). Colchicine encapsulation within poly(ethylene glycol)-coated poly(lactic acid)/poly ("-caprolactone) microspheres-controlled release studies. Drug Delivery, 7: 1–10.
16.
16. Markman, M., Cleary, S. and Howell, S.B. (1985). Nephrotoxicity of high-dose intracavitary cisplatin with intravenous thiosulfate protection. Eur. J. Cancer. Clin. Oncol., 21: 1015–1018.
17.
17. Fujii, M., Kiura, K., Okabe, K. and Toki, H. (1986). Intrapleural chemotherapy with cisplatin and adriamycin for lung cancer with carcinomatous pleuritis. Jpn. J. Cancer. Chemother., 13: 3203–3206.
18.
18. Ike, O., Shimizu, Y., Wada, R., Hyon, S.H. and Ikada, Y. (1992). Controlled cisplatin delivery system using poly(D, L-lactic acid). Biomaterials, 13: 230–234.
19.
19. Yoshida, M., Asano, M. and Morita, Y. (1989). In vitro release of cisplatin from a needle type copolymer formation implanted inrat kidney. Biomaterials, 10: 16–22.
20.
20. Thacharodi, D. and Rao, K.P. (1995). Development and in vitro evaluation of chitosan-based transdermal drug delivery systems for the controlled delivery of propanolol hydrochloride. Biomaterials, 16: 145–148.
21.
21. Chandy, T. and Sharma, C.P. (1992). Chitosan, beads and granules for oral sustained delivery of nifedipine in vitro studies. Biomaterials, 13: 949–952.
22.
22. Chandy, T., Das, G.S. and Rao, G.H.R. (2000). 5-Fluorouracil-loaded chitosan coated polylactic acid microspheres as biodegradable drugcarriers for cerebraltumours. J. Microencapsulation, 17: 625–638.
23.
23. Chandy, T., Mooradian, D.L. and Rao, G.H.R. (1998). Chitosan/polyethylene glycol-alginate microcapsules for oral delivery of hirudin. J. Applied. Polymer. Sci., 70: 2143–2153.
24.
24. Hari, P.R., Chandy, T. and Sharma, C.P. (1996). Chitosan/calcium alginate beads for oral delivery of insulin. J. Applied. Polymer. Sci., 59: 1795–1801.
25.
25. Song, C.X., Labhasetwar, V., Murphy, H., Qu, X., Humphrey, W.R., Shebuski, R. and Levy, R.J. (1997). Formulation, and characterization of biodegradable nanoparticles for intravascular local drug delivery. J. Control. Release, 43: 197–212.
26.
26. Spenlehauer, G., Vert, M., Benoit, J.P., Chabot, F. and Veillard, M. (1988). Biodegradable cisplatin microspheres prepared by the solvente vaporation method: Morphology and release characteristics. J. Controlled release, 7: 217–229.
27.
27. Frazza, E.J. and Schmitt, E.E. (1971). New absorbable suture. J. Biomed. Mater. Res. Symp., 1: 43–58.
28.
28. Pitt, C.G., Gratzi, M.M., Jeffcoat, A.R., Zweidinger, R. and Schindler, A.(1979). Sustained drug delivery system II. Factors affectingrelease rates from poly(caprolactone) and related biodegradable polyester. J. Pharm. Sci., 68: 1534–1538.
29.
29. Cleland, J.L. (1997). Protein delivery from biodegradable microspheres. Pharmaceutical Biotech., 10: 1–43.
30.
30. Bodmeier, R., Oh, K.H. and Chen, H. (1989). The effect of the addition of low molecular weight poly(DL-lactide) on drug releasefrom biodegradable poly(DL-lactide) drug delivery systems. Int. J. Pharmaceutics, 51: 1–8.
31.
31. Yoshikawa, H. and Seebach, S. (1996). Lymphotropic delivery of cyclosporin A by intramuscular injection of biodegradable microspheres in mice, Biological & Pharmaceu. Bull., 19: 1527–1529.
32.
32. Kamei, S., Okada, H., Inoue, Y., Yoshioka, T., Ogawa, Y. and Toguchi, H.(1993). Antitumor effects of angiogenesis inhibitor TNP-470 inrabbits bearing VX-2 carcinoma by arterial administration of microspheres and oil solution. J. Pharmacol. Exp. Ther., 264: 469–474.
33.
33. Okamoto, Y., Konno, A., Togawa, K., Kato, T., Tamakawa, Y. and Amano, Y.(1986). Arterial chemomobilization with cisplatin microspheres. Br. J. Cancer, 53: 369–375.
34.
34. Merril, E. and Salzman, E.W. (1983). Polyethylene, oxide as a biomaterial. J. Am. Soc. Artif. Intern. Organs., 6: 60–64.
35.
35. Nagaoka, S., Mori, Y., Takiuchi, H.K., Yokota, H., Tanzawa and Shiumi, S.N. (1984). Interaction between blood components and hydrogels with poly(oxyethylene) chains. In: Shalaby, S.W., Hoffman, A.S., Ratner, B.D. and Horbett T.A. (eds.), Polymers as Biomaterials. New York, USA: Plenum. pp. 361–375.
36.
36. Vasudev, S.C. and Chandy, T. (1997). Effect of alternative crosslinking techniques on the enzymatic degradation of bovine pericardium and their calcification. J. Biomed. Mater. Res., 35:357–369.
37.
37. Vasudev, S.C., Chandy, T. and Sharma, C.P. (1997). Influence of polyethylene glycol graftings on the in vitro degradation and calcification of bovine pericardium. J. of Biomat. Applns, 11: 430–452.
