Chitosan-phospholipid blend for sustained and localized delivery of docetaxel to the peritoneal cavity.
Localized and sustained delivery of chemotherapeutics presents a "magic bullet" effect by providing high drug concentrations at the target site, extended drug exposure and reduced systemic toxicity. In the present study, an injectable chitosan-phospholipid (PoLi(gel)) blend is put forth as a strategy to achieve sustained and localized delivery of docetaxel (DTX) following intraperitoneal (IP) administration. The stability of the blend was confirmed in vitro, by turbidity measurements and attributed to specific molecular interactions and the organization of the materials within the blend, as evidenced by FTIR analysis and confocal laser scanning microscopy, respectively. The chitosan and phospholipid were found to colocalize in regions surrounding a mean object area of 11.2mum(2) with colocalization coefficients of 43% and 46% for the chitosan and phospholipid, respectively. The PoLi(gel) blend afforded sustained drug release as seen both in vitro (2.4+/-0.7% DTX per day) and in vivo (4.4+/-0.7% DTX per day). Constant concentrations of DTX were observed over a 2-week period in plasma and relevant peritoneal tissues, with no signs of toxicity or inflammation, following IP administration of the blend in healthy CD-1 mice. At DTX doses of 28.8 and 19.2mg/kg, the blend showed significant tumor inhibition of 87.3+/-9.3% and 74.1+/-25.9%, respectively, in a murine xenograft model of human ovarian adenocarcinoma. This localized delivery system has shown excellent potential for sustained IP treatment of cancers, such as ovarian, that reside in the peritoneal cavity.
Zahedi
Payam
P
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, Canada M5S 3M2.
De Souza
Raquel
R
Piquette-Miller
Micheline
M
Allen
Christine
C
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D048271:Chitosan / Q000737:chemistry*; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D000077143:Docetaxel; D004337:Drug Carriers; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D007274:Injections, Intraperitoneal; D051379:Mice; D010743:Phospholipids / Q000737:chemistry*; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D010743:Phospholipids; D043823:Taxoids; D000077143:Docetaxel; D048271:Chitosan