Simultaneous release of two drugs from polymer nano-implant inhibits recurrence in glioblastoma spheroids

Local implant-based delivery of rationally selected combination of chemotherapeutics has some major advantages for the treatment of glioblastoma such as: (a) 100 % bio-availability locally in brain can be achieved at the tumor site (b) avoid systemic leakage and associated toxicity, and (c) simultaneous inhibition of multiple, mutually exclusive cancer mechanisms is possible. Here, we report a polymeric brain implant capable of delivering two different drugs in recur-rent glioma cells. We have selected a combination of clinically used DNA alkylating agent, Te-mozolomide, and a DNA mismatch repair protein (Ligase IV) inhibitor, SCR-7, and delivered simultaneously into tumor spheroids formed by rat glioma cells, C6. The dual-drug loaded polymeric wafer, prepared by lyophilization method, could deliver both the drugs in a controlled fashion. To test the efficacy of this system, we have optimized an in vitro recurrent model of glioma spheroids wherein, the implant released both the drugs in a sustained fashion, thereby continuously exposing the cells to DNA methylation while inhibiting the DNA repair pathways. This leads to synergistic toxicity and inhibition of tumor recurrence for extended duration compared to free drug combination.