Abstract
The objective of this study was to overcome drug resistance upon systemic administration of combination paclitaxel (PTX) and the apoptotic signaling molecule C~6~‐ceramide (CER) in biodegradable poly(ethylene oxide)‐modified poly(epsilon‐caprolactone (PEO‐PCL) nanoparticles. Subcutaneous sensitive (wild‐type) and multidrug resistant (__MDR‐__1 positive) SKOV‐3 human ovarian adenocarcinoma xenografts were established in female Nu/Nu mice. PTX and CER were administered intravenously either as a single agent or in combination in aqueous solution and in PEO‐PCL nanoparticles to the tumor‐bearing mice. There was significant (p< 0.05) tumor growth suppression in both wild‐type SKOV‐3 and multidrug resistant SKOV‐3~TR~ models upon single dose co‐administration of PTX (20 mg/kg) and CER (100 mg/kg) in nanoparticle formulations as compared to the individual agents and administration in aqueous solutions. For instance, in SKOV‐3 wild‐type model, more than 4.3‐fold increase (p < 0.05) in tumor growth delay and 3.6‐fold (p < 0.05) increase in tumor volume doubling time (DT) were observed with the combination treatment in nanoparticles as compared to untreated animals. Similarly, 3‐fold increase (p < 0.05) in tumor growth delay and tumor volume DT was observed in SKOV‐3~TR~ model. Body weight changes and blood cells counts were used as measures of safety and, except for an increase in platelet counts (p < 0.05) in PTX + CER treated animals, there was no difference between various treatment strategies. The results of this study show that combination of PTX and CER in biodegradable polymeric nanoparticles can serve as a very effective therapeutic strategy to overcome drug resistance in ovarian cancer. © 2007 Wiley‐Liss, Inc.