Intracranial Nanogel Pellets Carrying Temozolomide and Paclitaxel for Adjuvant Brain Cancer Therapy.

Abstract

Glioblastoma multiforme is the most frequently diagnosed primary malignant brain tumor. Despite multimodal therapy with surgical resection, radiation therapy, and chemotherapy, recurrence of the tumor is almost always guaranteed due to the infiltrative nature of the disease. Moreover, the blood brain barrier imparts an additional layer of complexity by impeding the delivery of therapeutic agents to the tumor, hence limiting the efficacy of systemically delivered drugs. Hence, to overcome this obstacle and avoid treatment resistance, the local delivery of combination therapies has risen as an appealing adjuvant treatment. The present study describes the creation of a novel PLGA-PEG-PLGA-based nanogel pellet system for the interstitial delivery of Temozolomide (TMZ) and paclitaxel (PTX) to the brain. The nanogel pellet was shown to be stable as a pellet at ambient temperature, absorb water, change to a gel formulation at physiological temperature, and achieve gradual long-term release of TMZ and PTX in vitro. Additionally, in vivo testing of the TMZ/PTX-loaded nanogel pellets in an orthotopic CT2A mouse model and an orthotopic 9L rat model has shown an acceptable safety profile when implanted intracranially and a significant improvement in overall survival.