(332g) Implantable Hydrogel Beads Entrapping PLGA-Paclitaxel Microspheres: Exploring the Effects of near-Zero Order Drug Release for Intracranial Chemotherapy

Local intracranial chemotherapy using drug-loaded microspheres has shown considerable potential in many pre-clinical studies. However, its translation into clinical trials has been hindered by two major disadvantages: implantability and excessively high initial drug release. Intra-tumoral injection of microspheres (suspended in saline) reduces the efficiency of implantation due to the expelling of microspheres from the target site because of high interstitial pressure in the tumor. Also, owing to the concentration of drug near the surface, the microspheres exhibit a high initial drug release that can cause neurotoxicity. In an effort to overcome these limitations, we have developed alginate hydrogel beads that entrap PLGA-paclitaxel microspheres.

Highly monodisperse and smooth PLGA-paclitaxel microspheres were fabricated using the Electrohydrodynamic Atomization (EHDA) process. The microspheres were then entrapped by dripping microsphere-sodium alginate suspension into calcium chloride solution and forming an alginate matrix by ionotropic gelation. This system offers the combination of sustained paclitaxel release from the PLGA-paclitaxel microspheres with structural and containment advantages from the alginate hydrogel matrix. Its application as an implant into the intracranial tumor resection cavity in the brain for post-surgical chemotherapy against malignant brain tumors has been evaluated in this study.

The beads were prepared using two types of dripping methods, manual dripping (MD) and electrospray dripping (ED), after which they were characterized and compared. Manual dripping yielded polydisperse non-spherical beads with a non-uniform distribution of the microspheres within them. In the ED method, a highly viscous suspension of alginate and PLGA-paclitaxel microspheres were dripped through a nozzle under a high voltage difference (~ 12 kV) into a calcium chloride solution. This yielded highly monodisperse and spherical beads with a uniform microsphere distribution within them. Hence, for further studies, beads fabricated using the ED method were used. The hydrogel bead disintegration and drug release were evaluated to study the effect of various process parameters such as the CaCl2 concentration, gelation time and microsphere loading. In vitro release of paclitaxel from this system was also investigated. The use of IC50 (drug concentration needed to inhibit cancer cell concentration to 50% in vitro) for various formulations in comparison with systemic Taxol® against C6 glioma cells in vitro was also evaluated to elucidate the sustainability of drug release. In vivo intracranial studies focused on paclitaxel bio-distribution in the brain, survivability analysis and tumor volume through bio-imaging are ongoing and will be discussed in the presentation.