Novel biocompatible intraperitoneal drug delivery system increases tolerability and therapeutic efficacy of paclitaxel in a human ovarian cancer xenograft model.
OBJECTIVE
We compared the safety, toxicity, biocompatibility and anti-tumour efficacy of a novel chitosan-egg phosphatidylcholine (ePC) implantable drug delivery system that provides controlled and sustained release of paclitaxel (PTX(ePC)) versus commercial paclitaxel formulated in Cremophor EL (PTX(CrEL)).


METHODS
Toxicity studies were conducted in healthy CD-1 female mice, whereas efficacy studies were performed in the SKOV-3 xenograft model of ovarian cancer. Treatments consisted of intraperitoneal (IP) implantation of drug-free or PTX(ePC) formulations, IP bolus PTX(CrEL), or Cremophor EL (CrEL) vehicle. Toxicity was assessed as number of deaths, weight loss, serum hepatic enzyme levels and histopathological changes.


RESULTS
Mice implanted with drug-free or PTX(ePC) formulations did not exhibit observable toxicities, local inflammation or fibrous encapsulation of the implant. In contrast, mice receiving PTX(CrEL) or CrEL encountered significant toxicity, lethality, abnormal peritoneal organ morphology and hepatic inflammation. The maximum tolerable dose (MTD) of PTX(CrEL) was 20 mg/kg/week, whereas PTX doses of up to 280 mg/kg/week were well tolerated when administered as PTX(ePC). Enhanced anti-tumour efficacy was achieved with PTX(ePC) in contrast to PTX(CrEL) with the same total dose of 60 mg/kg PTX.


CONCLUSIONS
The novel PTX(ePC) formulation is a safer and better tolerated method for PTX administration, with significant increase in MTD and enhanced anti-tumour efficacy, suggesting improved therapeutic index with possible clinical implications in the treatment of ovarian tumours.
Vassileva
Vessela
V
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Rm. 1003, M5S 3M2, Toronto, ON, Canada.
Grant
Justin
J
De Souza
Raquel
R
Allen
Christine
C
Piquette-Miller
Micheline
M
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001672:Biocompatible Materials / Q000737:chemistry; D048271:Chitosan / Q000737:chemistry; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000737:chemistry*; D004343:Drug Implants / Q000737:chemistry*; D004531:Eggs; D005260:Female; D005990:Glycerol / Q000031:analogs & derivatives / Q000737:chemistry; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D010713:Phosphatidylcholines / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D001672:Biocompatible Materials; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004343:Drug Implants; D010713:Phosphatidylcholines; C000515:cremophor EL; D048271:Chitosan; D017239:Paclitaxel; D005990:Glycerol