Original Article

Cancer Chemotherapy and Pharmacology

, Volume 60, Issue 6, pp 907-914

Novel biocompatible intraperitoneal drug delivery system increases tolerability and therapeutic efficacy of paclitaxel in a human ovarian cancer xenograft model

  • Vessela VassilevaAffiliated withDepartment of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto
  • , Justin GrantAffiliated withDepartment of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto
  • , Raquel De SouzaAffiliated withDepartment of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto
  • , Christine AllenAffiliated withDepartment of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto
  • , Micheline Piquette-MillerAffiliated withDepartment of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto Email author 

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Abstract

Purpose

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 (PTXePC) versus commercial paclitaxel formulated in Cremophor EL (PTXCrEL).

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

Conclusions

The novel PTXePC 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.

Keywords

Paclitaxel Maximum tolerable dose Biocompatible implantable drug delivery system Controlled release Intaperitoneal therapy Anti-tumour efficacy