Injectable chemotherapeutic microspheres and glioma II: Enhanced survival following implantation into deep inoperable tumors

Purpose. Delivery of chemotherapeutics using implantable, biodegradable polymers provides a potentially powerful method of treating brain tumors. The present studies examined the ability of injectable microspheres, formulated to release carboplatin or BCNU for 2-3 weeks, to enhance survival in a rodent model of deep, inoperable glioma. Methods. Rat glioma (RG2) cells were implanted into the striatum of rats. In a first experiment, the tumors were allowed to grow for 3 days, followed by either no treatment, bolus chemotherapy (100 mu g), or implantation of microspheres containing 10, 50, or 100 mu g of carboplatin. The microspheres were implanted, via hypodermic injection, directly into the center of the small, 3-day-old tumors. In a second experiment, tumors grew for 8 days prior to treatment with either carboplatin- or BCNU-loaded microspheres. The microspheres were then injected either directly into the center of these larger tumors or into three sites along the perimeter of the tumor. Separate sets of animals received bolus chemotherapy (100 mu g) into either the tumor center or around the tumor perimeter. Results. Injection of carboplatin-loaded microspheres into the center of the small 3 day old, tumors produced dose-related increases in survival. When injections of carboplatin- or BCNU-loaded microspheres were made into the center of the larger, 8-day-old tumors, survival was not enhanced. However, when the microspheres were injected along the perimeter of the larger tumors, sustained-release chemotherapy did significantly prolong survival. Bolus chemotherapy was less effective than sustained release chemotherapy. Conclusions. Together, these data: (1) demonstrate that sustained delivery of chemotherapy in or near the tumor site is superior to equipotent bolus doses in inoperable tumors, (2) demonstrate that injection of sustained release microspheres into the tissue surrounding a growing tumor may provide superior effects over injections directly into the tumor mass, and (3) suggest that this approach may provide a useful means of selectively delivering chemotherapeutics to tumors or portions of tumors that cannot otherwise be treated with conventional surgical approaches.