Overcoming Chemo-Resistance in Glioma-Bearing Rats by Using Sequential and Biodegradable Multidrug-Loaded Nanofibrous Membranes

Glioblastoma multiforme (GBM) is the most common and most aggressive malignant primary brain tumor in humans. Standard treatment consists of maximal surgical resection, radiotherapy, and concomitant and adjuvant chemotherapy. Despite 30 years of intensive efforts to find an effective chemotherapy regimen for GBM, the prognosis of the patients afflicted with these tumors has been historically dismal, with progressive neurologic impairment and imminent death. Although drug delivery may limit the intracerebral delivery of chemotherapies, the major cause of treatment failure is primary tumor resistance to chemotherapy. Resistance to nitrourease (e.g., carmustine[BCNU]) and methylating agents (e.g., temozolomide), which damage DNA, can be mediated by a DNA repair protein, O6-alkyltransferase (AGAT). Depletion of this protein with ankylguanines or methylating agents, however, restore tumor cell sensitivity to the cytotoxicity of nitrourease and methylating agents. By using co-axial electrospinning techniques, we loaded temozolomide onto 50:50 PLGA nanofibers and developed novel core-sheath structured to load O6-BG. The carmustine was loaded onto 75:25 PLGA nanofibers by electrospinning. The double layered nanofibrous membranes were surgically implanted onto the brain surfaces of healthy rats for conducting pharmacodynamic studies and onto D-456 MG glioma-bearing rats for estimating the therapeutic efficacy. The O6-BG were rapidly released from the 50:50 PLGA nanofibres after implantation, followed by the release of chemotherapeutic agents (carmustine & temozolomide) from the 75:25 PLGA nanofibres. All drug concentrations were estimated by HPLC and ELISA analysis for 12 weeks. Then the double layered nanofiberous membranes were surgically implanted onto brain surface of tumor-beraing rats to evaluated the therapeutic efficacy. The experimental results, including attenuated malignancy (evaluated by immunohistolchemistry and pathologic examinations), retarded tumour growth (evaluated tumor volumes by regularly followed MRIs), and prolonged survival in tumour-bearing rats were used to evaluat the efficacy of the double layed nanofibrous membranes for treatment of GBM. The study purpose is to demonstrated the novel structured core-sheath 50:50 PLGA nanofibers can provided sustained release of O6-BG into brain parenchyma. Following the O6-BG releasing from the 50:50 PLGA, the two chemotherapeutic agents (BCNU and temozolomide) releasing from 75:25 PLGA nanofibers. O6-BG released prior to chemotherapeutic agents can restore the sensitivity to ankylating agents and increase the therapeutic activity. The results to evaluate potential of nanofibrous membranes for the long-term deliveries of combined chemotherapy agents to treatment GBM clinically.