Intracranially Injectable Nano Microparticle gel for The Treatment of Glioblastoma

Abstract

Sustained delivery of chemodrugs is essential for the treatment and prolonged inhibition of Glioblastoma Multiforme (GBM), a grade-4 brain tumor with a limited median survival of 12 - 13 months. Even with the current clinical regimen of systemic intravenous or oral delivery of chemodrug, Temozolomide (Temodar®), and adjuvant radiation, the overall survival did not increase significantly. With the invention of GliadelTM, the sole FDA-approved intracranial drug delivery system for brain tumors, which is loaded with an alkylating agent, Carmustine or BCNU (1,3-bis(2-chloroethyl)-N-nitrosourea), we expected a better outcome. However, treatment of patients with GliadelTM resulted in a marginal improvement of median survival for upto 2 - 3 months. In examining the challenges of drug delivery using GliadelTM, it was found that (i) almost complete release of drug payload occurred within 7 days of implantation and (ii) the released drug could penetrate only upto ~ 5mm in the brain tissue. It was reported that GBM patients develop recurrence post-treatment owing to the fact that tumors recur 2 - 3cm from the boundary of tumor resected cavity. This indicates that it is critical for the drugs to diffuse 2 - 3cm deep from the tumor resected margin. In addition, we also need to sustain the drug release for gt 7 days for a better survival outcome. Keeping these critical challenges as objectives, this thesis aims at the development and in vivo testing of nano / microparticle containing gel, loaded with chemodrug BCNU, that can be injected locally in the brain and perform dual functions of sustained release upto 7 - 15 days, and increased diffusion of 2 - 3cm. To achieve this objective, we designed a unique nanoatmicro system wherein the drug is primarily loaded into larger 250nm sized nanoparticles (BCNU-NP-250) or 3000nm sized microparticles (BCNU-NP-3000), which is dispersed in a Polyethylene glycol (PEG) gel (mol.wt. 400Da), and once the drug is released, it will complex with the outer layer of PEG to form ~ 33nm sized PEG-drug