Predicting In Vivo Efficacy of Potential Restenosis Therapies by Cell Culture Studies: Species-Dependent Susceptibility of Vascular Smooth Muscle Cells

Hila Epstein1, Laura Rabinovich1, Shmuel Banai2, Vicktoria Elazar1, Jianchuan Gao1, Michael Chorny1, Haim D Danenebrg3, Gershon Golomb*, 1
1 Dept. of Pharmaceutics, School of Pharmacy
2 Dept. of Cardiology, Bikur Cholim Hospital
3 Dept. of Cardiology, Hadassah Hospital, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel

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* Address correspondence to this author at the Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, the Hebrew University of Jerusalem, POB 12065, Jerusalem 91120, Israel; Tel: 972-2-6757504; Fax: 972-2-6757503; E-mail:


Although drug-eluting stents (DES) are successfully utilized for restenosis therapy, the development of local and systemic therapeutic means including nanoparticles (NP) continues. Lack of correlation between in vitro and in vivo studies is one of the major drawbacks in developing new drug delivery systems. The present study was designed to examine the applicability of the arterial explant outgrowth model, and of smooth muscle cells (SMC) cultures for prescreening of possible drugs. Elucidation of different species sensitivity (rat, rabbit, porcine and human) to diverse drugs (tyrphostins, heparin and bisphsophonates) and a delivery system (nanoparticles) could provide a valuable screening tool for further in vivo studies. The anticipated sensitivity ranking from the explant outgrowth model and SMC mitotic rates (porcine>rat>>rabbit>human) do not correlate with the observed relative sensitivity of those animals to antiproliferative therapy in restenosis models (rat≥rabbit>porcine>human). Similarly, the inhibitory profile of the various antirestenotic drugs in SMC cultures (rabbit>porcine>rat>>human) do not correlate with animal studies, the rabbit- and porcine-derived SMC being highly sensitive. The validity of in vitro culture studies for the screening of controlled release delivery systems such as nanoparticles is limited. It is suggested that prescreening studies of possible drug candidates for restenosis therapy should include both SMC cell cultures of rat and human, appropriately designed with a suitable serum.

Key Words: Angioplasty/coronary intervention, cell culture / isolation, restenosis, smooth muscle cells.