Targeting Platelets Containing Electro-encapsulated lloprost to Balloon Injured Aorta in Rats

Summary

Drugs can be electro-encapsulated within platelets and targeted to damaged blood vessels by exploiting the platelet’s natural haemostatic properties to adhere to collagen and other vessel wall constituents revealed by injury. A rat aorta balloon angioplasty model has been used to study the effect on platelet deposition of giving iloprost loaded platelets i.v. during the balloon injury. After labelling the circulating platelets with ¹¹¹-Indium before balloon injury, time course studies showed maximum platelet deposition on the injured aorta occurred at about 1 h post-injury and the deposition remained stable over the next 2-3 h. When iloprost-loaded platelets were given i.v. during injury and the circulating platelet pool labelled with ¹¹¹-Indium 30 min later, platelet deposition, measured at 2 h postinjury, was substantially and significantly reduced compared with control platelet treatment. Some antiproliferative effects of iloprost-loaded platelets given i.v. during injury have also been observed. Whereas the incorporation of [³H]-thymidine into aorta intima-media DNA at 3 days post injury was 62-fold higher in balloon injured rats than in control sham operated rats, thymidine incorporation into intima/media of rats which had received iloprost loaded platelets during injury was reduced as compared with rats subjected only to the injury procedure. The reduction was only of near significance, however, but at 14 days after injury the total DNA content of the aorta intima/media of rats given iloprost loaded platelets during injury was significantly reduced. Although iloprost loaded platelets can clearly inhibit excessive platelet deposition, other encapsulated agents may have greater anti-proliferative effects. These studies have shown that drug loaded platelets can be targeted to injured arteries, where they may be retained as depots for local release. We believe this novel drug delivery protocol may have therapeutic potential in reducing the incidence of occlusion and restenosis after angioplasty and thrombolysis treatment. Electro-encapsulation of drugs into platelets is a simple procedure and, using autologous and fully biocompatible and biodegradable platelets as delivery vehicles, might overcome some of the immunological and toxicological problems which have been encountered with other delivery vectors such as liposomes, microbeads, synthetic microcapsules and antibodies.

• References

• 1 Nicod P, Scherrer U. Explosive growth of coronary angioplasty: Success story of a less than perfect procedure (Editorial comment). Circulation 1993; 87: 1749-1751
• 2 Fuster V. Post PTCA restenosis: Overview. In: Restenosis Summit IV, Cleveland Clinic Foundation. Ohio, USA: 1992. pp 28-33
• 3 Kent KM. Restenosis after percutaneous transluminal coronary angioplasty. Amer J Cardiol 1988; 61: 67-70
• 4 Liu MW, Roubin GS, King SB. Restenosis after coronary angioplasty: Potential biological determinants and role of intimal hyperplasia. Circulation 1989; 79: 1374-1387
• 5 Ross R. The pathogenesis of atherosclerosis: An update. J Am Coll Cardiol 1986; 14: 813-836
• 6 Ross R, Masuda J, Raines E. Cellular interactions, growth factors and smooth muscle cell proliferation in atherogenesis. Ann NY Acad Sci 1990; 598: 102-112
• 7 Forester JS, Fishbein M, Helfant R, Fagin J. A paradigm for restenosis based upon cell biology: Clues for the development of new preventive therapies. In: The practice of interventional cardiology (92nd Edition). Vogel JH K, King SB. eds Mosby Year Book Inc; St Louis: 1993. pp 495-508
• 8 Popma JJ, Topol EJ. Factors influencing restenosis after coronary angioplasty. Amer J Med 1990; 88: 1N-16N
• 9 Fingerle J, Johnson R, Clowes R, Majesky MW, Reidy MA. Role of platelets in smooth muscle cell proliferation and migration after vascular injury in rat carotid artery. Proc Natl Acad Sci USA 1989; 8: 8412-8416
• 10 De Servi S, Mazzone A, Ricevut G, Fiorvantia E, Angoli Secchia G, Angoli L, Stefano G, Specchia G. Granulocyte activation after coronary angioplasty in humans. Circulation 1990; 82 (140) 1476-1482
• 11 Newby AC, George SJ. Proposed roles of growth factors in mediating smooth muscle cell proliferation in vascular pathologies. Cardiovasc Res 1993; 27: 1173-1183
• 12 Reidy MA, Bowyer DE. Control of arterial smooth muscle cell proliferation, Current Opinions in Lipidology. 1993; 4: 349-355
• 13 Hermans WR M, Rensing BJ, deFeyter P, Serruys PW. Pharmacologic therapy in the prevention of restenosis after percutaneous transluminal angioplasty. In: The practice of interventional cardiology. Vogel JH K, King SB. eds Mosby Year Book Inc; St Louis, USA : 1981. pp 547-571
• 14 Wolinsky RL, Thung SN. Use of a porous balloon catheter to deliver concentrated heparin into the wall of the normal canine artery. J Amer Coll Cardiol 1990; 15: 475-481
• 15 Lambert CR, Leone JE, Rowland SM. Local drug delivery catheters: Functional competence of porous and microporous designs. Coronary Artery Disease 1993; 4: 469-475
• 16 Wilensky RL, March Kl, Gradus-Pizlo I, Speady AJ, Hathaway DR. Methods and devices for local drug delivery in coronary and peripheral arteries. Cardiovasc Med 1993; 3: 163-170
• 17 Wilensky RL. The problems and the promise of local drug delivery. In: Restenosis Summit VI, Cleveland Clinic Foundation. Ohio, USA: 1994. pp 352-356
• 18 Hughes K, Crawford N. Reversible electropermeabilisation of human and rat platelets: Evaluation of morphological and functional integrity “in vitro” and “in vivo”. Biochim Biophys Acta 1989; 981: 277-287
• 19 Hughes K, Crawford N. Reversibly electro-permeabilised platelets: Potential use as vehicles for drug delivery. Biochem Soc Trans 1990; 18: 871-873
• 20 El Gamal BA B, Pfliegler G, Crawford N. Effect of platelet encapsulated iloprost on platelet aggregation and adhesion to collagen and injured blood vessels “in vivo”. Thromb Haemost 1992; 68: 606-614
• 21 Fisher CA, Kappa JR, Sinha AK, Cottrell ED, Reiser MJ, Addonizio VP. Comparison of equimolar concentrations of iloprost, prostacyclin and prostaglandin E₁ on human platelet function. J Lab Clin Med 1988; 110: 706-718
• 22 Pfliegler G, El Gamal BA B, Badimon JJ, Badimon L, Crawford N. Inhibition of platelet recruitment to arterial lesions by predeposition of platelets containing encapsulated iloprost. Thromb Haemost 1994; 72: 604-610
• 23 Capron L, Jarnet J, Kazandjian S, Housset E. Growth-promoting effects of diabetes and insulin on arteries: An in vivo study of rat aorta. Diabetes 1986; 35: 973-978
• 24 Goldberg L, Sternermann MB, Schnipper LE, Ransil BJ, Crooks GW, Fuhro RL. Vascular smooth muscle cell kinetics: A new assay for studying patterns of cellular proliferation in vivo. Science 1979; 205: 920-922
• 25 Vehara Y, Ishimitsu T, Kimura MI, Ishii M, Ikeda T, Sugimoto T. Regulatory effects of eicosanoids on thymidine uptake by vascular smooth muscle cells of rats. Prostaglandins 1988; 36: 847-859