(524g) Local Intracranial Drug Delivery Using Biodegradable PLGA-Paclitaxel Micro/Nano-Fiber Implants to Treat Malignant Brain Tumors

Authors: 
Ranganath, S. H. - Presenter, National University of Singapore
Wang, C. - Presenter, National University of Singapore


Malignant brain tumors (gliomas) characterized by aggressive proliferation, inexorable local recurrence and invasive nature are among the most recalcitrant cancers to treat in the human body. This necessitates the urgent need for the development of implantable, biocompatible and biodegradable delivery devices carrying cytotoxic and radiosensitizing drugs for post-surgical synergetic chemo-radiotherapy against malignant gliomas. Most of the polymeric implants delivering paclitaxel (a cytotoxic and radiosensitizing drug) developed are either micro/nano-particles, compressed micro/nano-particle discs or wafers. However, due to very high interstitial pressure in the brain/tumor, intratumoral injection of drug loaded microparticles will always run the risk of being expelled out of the target site thus negating the advantages of local delivery. The other disadvantage of using microparticles is the high initial burst due to the presence of the drug on the surface which might lead to undesired neurotoxicity. On the other hand, drug loaded compressed discs and wafers have low surface area to volume ratio available for polymer degradation and drug diffusion and hence would result in low drug release rates and undesired secondary burst.

In an effort to improve local therapy against glioma by avoiding high initial burst and providing drug release sustainability and implantability, we have developed poly (D,L-lactide-co-glycolide) (PLGA) micro/nano-fiber implants bearing paclitaxel by Electrohydrodynamic Atomization process (EHDA). The fibrous matrices not only provided greater surface area to volume ratio for effective drug release rates but also gave the much needed implantability into tumor resected cavity in post-surgical glioma chemotherapy. Paclitaxel release from the implants was engineered by varying the PLGA co-polymer (PLGA 85:15 and PLGA 50:50) and fiber diameter (micro, sub-micro and nano) and then evaluated. The performance of the formulations in sustaining drug release and cytotoxicity were also evaluated in vitro through apoptosis study on C6 glioma cells. In addition, the formulations were tested against subcutaneous C6 glioma tumors in BALB/c nude mice. Additional evaluations of the implants in terms of drug bio-distribution in the brain, survivability analysis in C6 glioma intracranial model using bio-imaging are ongoing and will be discussed in the presentation.

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