| Poly (Ethylene Oxide)-Poly (ε-Caprolactone) Micelles In Different Morphologies: Advantages Of Worm-Like Micelles For Paclitaxel Delivery In Lung Cancer Therapy | ||
| Shenshen Cai1, Tamara Minko2 and Dennis E. Discher1, (1)University of Pennsylvania, 220 South 33rd Street, Room 112 Towne Bldg., Philadelphia, PA 19104-6391, (2)Ernest Mario School of Pharmacy, Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 Purpose: To develop and evaluate worm-like polymeric micelles as a novel drug delivery system with increased drug loading capacity, extended blood circulation and enhanced dose tolerance compared to conventional spherical micelles. Methods: Both worm-like and spherical micelles were prepared from the diblock polymer poly (ethylene oxide)-poly (ε-caprolactone) (PEO-PCL, or OCL3). Paclitaxel (TAX) was loaded and the loading capacity and efficiency were determined using HPLC instrumentation. Micelle stability and degradability were also evaluated. Human lung carcinoma A549 cells were used for in vitro cytotoxicity studies, with currently used Cremophor® EL TAX formulation as a benchmark. Tumor shrinkage studies in female athymic mice implanted with A549 tumors were performed with micelle-encapsulated TAX at the maximum tolerance dose (MTD). Circulation and biodistribution after 24 hrs were also performed for blood and non-tumor organs. Results: Worm-like micelles have an average length of 6-7 μm, and similar radius to spherical micelles made from the same OCL3 copolymer. Loaded with TAX, OCL3 micelles in both morphologies showed 5 fold lower IC50 than Cremophor® EL TAX and 13 fold lower IC50 than free TAX against A549 cells in vitro. In drug encapsulation studies, due to their cylindrical structure, worm-like micelles demonstrated a 100% higher TAX loading capacity than spherical micelles made of same amount of polymer. Furthermore, worm-like micelles also showed a higher (nearly 2-fold) MTD in mice than spherical micelles, which is probably due to the extended circulation in blood and thus the retarded distribution into major organs. The increased MTD allowed the improved tumor shrinkage with higher administrated TAX doses in in vivo studies. TAX circulation, biodistribution and apoptosis studies showed the enhanced circulation in blood and EPR-based accumulation in tumor, and much reduced toxicity in other major organs (p < 0.05) associated with worm micelles compared to spheres. Conclusion: OCL3 polymeric micelles could be used as a improved TAX carrier with enhanced drug potency and reduced toxicity compared to Cremophor® EL. Especially, OCL3 worm-like micelles have shown greater potential than spherical micelles of their ability to increase drug loading capacity, MTD, circulation in blood and accumulation in the tumor site, while reducing toxicity to other major organs. Extended Abstract Status: Not Uploaded | ||