Effects of carrier on disposition and antitumor activity of intraperitoneal Paclitaxel.
OBJECTIVE
The rationale for intraperitoneal (IP) chemotherapy is to expose peritoneal tumors to high drug concentrations. While multiple phase III trials have established the significant survival advantage by adding IP therapy to intravenous therapy in optimally debulked ovarian cancer patients, the use of IP chemotherapy is limited by the complications associated with indwelling catheters and by the local chemotherapy-related toxicity. The present study evaluated the effects of drug carrier on the disposition and efficacy of IP paclitaxel, for identifying strategies for further development of IP treatment.


METHODS
Three paclitaxel formulations, i.e., Cremophor micelles, Cremophor-free paclitaxel-loaded gelatin nanoparticles and polymeric microparticles, were evaluated for peritoneal targeting advantage and antitumor activity in mice after IP injection. Whole body autoradiography and scanning electron microscopy were used to visualize the spatial drug distribution in tissues. A kinetic model, depicting the multiple processes involved in the peritoneal-to-plasma transfer of paclitaxel and its carriers, was established to determine the mechanisms by which a drug carrier alters the peritoneal targeting advantage.


RESULTS
Autoradiographic results indicated that IP injection yielded much higher paclitaxel concentrations in intestinal tissues relative to intravenous injection. Compared to the Cremophor and nanoparticle formulations, the microparticles showed slower drug clearance from the peritoneal cavity, slower absorption into the systemic circulation, longer residence time, 10- to 45-times greater peritoneal targeting advantage and approximately 2-times longer increase in survival time (p < 0.01 for all parameters).


CONCLUSIONS
Our results indicate the important roles of drug carrier in determining the peritoneal targeting advantage and antitumor activity of IP treatment.
Tsai
Max
M
College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
Lu
Ze
Z
Wang
Jie
J
Yeh
Teng-Kuang
TK
Wientjes
M Guillaume
MG
Au
Jessie L-S
JL
D000042:Absorption; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D004337:Drug Carriers; D005260:Female; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles; D017239:Paclitaxel / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D010316:Particle Size
D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D017239:Paclitaxel