Paclitaxel loaded poly(L-lactic acid) microspheres for the prevention of intraperitoneal carcinomatosis after a surgical repair and tumor cell spill

A controlled release delivery system for paclitaxel was developed using pol y(L-lactic acid) to provide local delivery to the peritoneal cavity. Micros pheres were made in 1-40 and 30-120 mu m size ranges. In an in vitro releas e study, 30-120 mu m microspheres loaded with 10, 20 and 30% paclitaxel exh ibited a burst phase of release for 3 days followed by an apparently zero-o rder phase of release. At all loadings, 20-25% of the original load of pacl itaxel was released after 30 days. The effect of microsphere size on retent ion in the peritoneal cavity was assessed. Control 1-40 Crm microspheres we re injected intraperitoneally in rats. The rats received either insufflatio n of the peritoneal cavity using 11 mmHg CO2 or no further treatment. After sacrifice, microspheres with diameters less than 24 mu m were observed in the lymphatic system after being cleared from the peritoneal cavity through fenestrations in the diaphragm. Insufflation of the peritoneal cavity had no effect on the size of microspheres that were cleared. Efficacy studies w ere carried out using 30-120 mu m microspheres that were of sufficient size to be retained in the peritoneal cavity. In a model of a tumor cell spill after a cecotomy repair, 100 mg of 30-120 mu m microspheres containing 30% paclitaxel were effective in preventing growth of tumors in the peritoneal cavity at both 2 and 6 weeks post-surgery. No gross or histologically evide nt tumor growth was observed on any peritoneal surfaces or in the surgical wound site. Rats receiving control microspheres all showed tumor cell impla ntation and growth after 2 weeks. (C) 2000 Elsevier Science Ltd. All rights reserved.