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 poly(L-lactic acid) to provide local delivery to the peritoneal cavity. Microspheres were made in 1-40 and 30-120 microm size ranges. In an in vitro release study, 30-120 microm microspheres loaded with 10, 20 and 30% paclitaxel exhibited a burst phase of release for 3 days followed by an apparently zero-order phase of release. At all loadings, 20-25% of the original load of paclitaxel was released after 30 days. The effect of microsphere size on retention in the peritoneal cavity was assessed. Control 1-40 microm microspheres were injected intraperitoneally in rats. The rats received either insufflation of the peritoneal cavity using 11 mmHg CO2 or no further treatment. After sacrifice, microspheres with diameters less than 24 microm 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 were carried out using 30-120 microm 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 microm 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 evident tumor growth was observed on any peritoneal surfaces or in the surgical wound site. Rats receiving control microspheres all showed tumor cell implantation and growth after 2 weeks.
Liggins
R T
RT
Angiotech Pharmaceuticals Inc., Vancouver BC, Canada.
D'Amours
S
S
Demetrick
J S
JS
Machan
L S
LS
Burt
H M
HM
D000818:Animals; D002245:Carbon Dioxide / Q000008:administration & dosage; D002432:Cecum / Q000473:pathology* / Q000601:surgery*; D016503:Drug Delivery Systems; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology*; D007327:Insufflation; D007431:Intraoperative Complications; D019344:Lactic Acid; D008297:Male; D008863:Microspheres; D017239:Paclitaxel / Q000008:administration & dosage* / Q000627:therapeutic use; D010529:Peritoneal Cavity; D011091:Polyesters; D011108:Polymers; D051381:Rats; D017208:Rats, Wistar
D011091:Polyesters; D011108:Polymers; D002245:Carbon Dioxide; D019344:Lactic Acid; C033616:poly(lactide); D017239:Paclitaxel