జర్నల్ ఆఫ్ బయోక్వివలెన్స్ & బయోఎవైలబిలిటీ

నైరూప్య

In-vitro Release of Rapamycin from a Thermosensitive Polymer for the Inhibition of Vascular Smooth Muscle Cell Proliferation

Weiwei Zhu, Takahisa Masaki, Alfred K. Cheung and Steven E. Kern

Hemodialysis arteriovenous grafts are often plagued by stenosis at the anastomosis, which is due to th e prolifera- tion of vascular smooth muscle cells (SMCs). To pre vent the stenosis, we have been developing a strate gy for the sustained perivascular delivery of an antiprolifera tive agent, rapamycin, using an injectable biodegra dable polymer, ReGel ® . In this study we examined the in-vitro kinetics of rapamycin released from ReGel and its efficacy for inhibit- ing the proliferation of human and porcine venous a nd arterial SMCs. To study the release from ReGel, rapamycin was mixed with ReGel and incubated at 37 ° C in a release medium. The release medium was perio dically sampled and assayed for rapamycin concentration by UV. Cellular uptake and release of rapamycin were examined by i ncubating SMCs with rapamycin for various durations. Intracel lular drug was extracted and measured by HPLC. Antiproliferative effects and cytotoxicity of stock rapamycin and that released from ReGel were examin ed using cell counting and lactate dehydrogenase (LDH)-release as say, respectively. Rapamycin exhibited a sustained- release pat- tern from ReGel for 52 days. The kinetics of rapamy cin transport through the cell membrane was compati ble with a passive diffusion mechanism. Rapamycin released fro m ReGel exhibited antiproliferative activity simila r to the free drug. Our results support the concept of sustained delivery of rapamycin using ReGel as a promising s trategy to inhibit SMC proliferation for the prevention of hem odialysis arteriovenous graft stenosis.