Release kinetics of imatinib mesylate from a thermosensitive polymer and its effect on vascular smooth muscle cells

Proliferating smooth muscle cells can cause hemodialysis vascular access stenosis. Applying antiproliferative drugs like imatinib mesylate that inhibit growth factors using a delivery system that keeps these agents at the site of stenosis could inhibit these proliferating cells. The aim of the study was to understand the release kinetics of imatinib from an injectable gel and the effect of imatinib on inhibiting proliferation of vascular smooth muscle cells. Imatinib mesylate was obtained from capsules or tablets and mixed with ReGel™. The release profile of imatinib from ReGel™ was studied in a release medium under both sink and nonsink conditions. Freebase of imatinib was also extracted and characterized by RP-HPLC and its release profile was studied under sink and nonsink conditions. The free base of imatinib was incubated with porcine smooth muscle cells to study the effect of the drug on its proliferative properties using the BrdU assay. The results show that the release rates of imatinib mesylate or free base from ReGel™ were similar in sink and nonsink conditions. Imatinib salt or its free base released from the ReGel™ within 2-4 days. The concentrations required to inhibit 50% porcine vascular smooth muscle cells with free base was between 0.5-5 μM. Imatinib release from ReGel™ is quick so its use for the prevention of hemodialysis vascular access stenosis would be limited. The quick release could interfere with the healing process after initial graft implantation and it would require frequent readministrations. Imatinib release from ReGel™ therefore, needs to be prolonged by changing the delivery system to make this approach feasible before further evaluation for this application.