(527g) Controlled Delivery of Paclitaxel from Electrohydrodynamically Atomized Microparticles and from Micro-Porous Foams for the Post-Surgical Treatment of Glioblastoma Multiforme

Glioblastoma multiforme is the most common and most aggressive primary malignant brain tumor. The highly invasive nature of glioblastoma, as well as the fact that few cells are actively replicating at any given time, means that therapies need to act in areas of the brain distant from the site of the tumor origin and for long periods of time after their introduction. This criterion negates established treatments such as surgery, radiation, and conventional chemotherapy which have not significantly altered the median survival of glioblastoma [1]. The use of controlled chemotherapeutic release from implants as an adjunct treatment to mandatory tumor debulking surgery continues to look promising as it allows high drug localization and ensures a sustained release over a long period of time. Implantation in the cavity following a tumor debulking procedure, has been shown to improve drug distribution over the site of action due to high pressure build up in the cavity from edema effects and the higher interstitial tumor pressure present. In the first part of this study, microparticles were fabricated by subjecting a solution of Poly (DL-lactic-co-glycolic acid 50:50) (Mol. Wt. 40,000 ? 75,000) and Paclitaxel to Electro-Hydrodynamic Atomization (EHDA). This generated particles 15.0 ìm in diameter, with a small standard deviation of 1.7 ìm, and 10% to 20% w/w drug loading. The particles are shown to provide a nearly linear release of 1.27-1.38% of the encapsulated Paclitaxel/day, after an initial burst, for more than 30 days. In a study with the Balb/c nude mice subcutaneous model, the experimental group showed tumor volume reductions of 73% over the placebo blank group for 20% drug-loaded microparticles. Drug penetration profiles after 7, 14, and 21 days in Wistar rats, as determined by immuno-staining, after 7, 14 and 21 days will also be presented. The biodistribution profile of the drug over a duration of 21 days has been able to achieve a significant reduction in tumor volume by this treatment, as compared to placebo groups. In the second part of this study, a new implant formulation using micro-porous foams was developed for surgical experiments. Paclitaxel-loaded Poly (DL-lactic-co-glycolic acid 85:15) (Mol. Wt. 50,000 ? 75,000) foams were prepared by a high pressure CO2 quenching method. Under high pressure CO2, the glass transition temperature (Tg) of PLGA is depressed and a polymer melt may be formed at temperatures of 35o or 40o with large amounts of dissolved CO2. Upon rapid depressurization, CO2 nuclei form in the polymer matrix and dissolved CO2 diffuses to these nuclei. The pore size, porosity and structure of the polymer are dependent upon the amount of dissolved gas and the rate of depressurization. In vitro studies for the paclitaxel-encapsulated foams at 1-5 w/w% drug loading show nearly zero order release for the first week. The increased surface area from the network of micro-sized pores greatly improved the release of paclitaxel and the structural integrity of the foam makes it a suitable candidate for implantation studies. By using supercritical CO2 as a foaming agent, the use of organic solvent may be minimized or even eliminated in the production of PLGA foams.

[1] Aghi, M. and S. Rabkin (2005).Curr Opin Mol Ther 7(5): 419-3.