Glioblastoma multiforme (GBM) is the most aggressive brain tumor with > 90 % recurrence rate and short median survival time (< 15 months). Because GBM recurrence mostly occurs within ~2 cm of the original lesion, a locally diffusing treatment should be very effective to significantly extend median survival. Currently, carmustine (bis-chloroethyl-nitrosourea - BCNU) loaded discs (Gliadel) provide local drug delivery, implanted into the cavity created after tumor resection. However, there are limitations including a short effective release period (~5-7 days) and non-conformity to the resection cavity due to stiff, unmalleable polymeric disc form. The long-term goal of this proposal is to develop improved methods for controlled, local drug delivery for treating GBM. The objective of this application is to investigate the use of complex, multi-layered fiber membranes as an optimized vehicle for drug delivery. The central hypothesis of this grant, based on successful preliminary animal trial data (with >150-day survival), is that core-sheath fibers formed by coaxial electrospinning can provide a superior drug release profile with controlled initial release and extended long term drug delivery. The core-sheath fiber construct also lends itself to multiple drug release due to its composition of two or more individual components. Multi-layered porous membrane discs and pouches can provide designed (?programmed?) release of drug molecules for ?cocktail? therapy. The project consists of three specific aims: (1) Fabricate core-sheath fiber membranes with various polymer hosts for optimum mechanical strength, flexibility, biocompatibility, and ability to incorporate specific drug molecules. Transform planar (thin, large area) membranes into 3-D formulations (discs and pouches) for surgical implantation. (2) Investigate drug release mechanisms from planar membranes, discs and pouches in order to realize programmable long-term (months) drug delivery. Investigate in detail controlled dual drug release from multi-layered core-sheath fiber membrane discs. Sequential drug release was recently demonstrated using TMZ or BCNU and acriflavine (ACF) by embedding ACF-incorporated discs within TMZ or BCNU-incorporated membranes. Combinations of current anti-cancer drugs (BCNU, TMZ, paclitaxel) and potential new drug candidates (ACF, disulfiram) will be investigated to obtain the most synergistic combination for localized cocktail chemotherapy. (3) Demonstrate (a) improved inhibition of cancer cell growth in vitro and (b) extended survival rate using established in vivo animal models. This study proposes the innovative use of complex multi-layered fibers for controlled release of incorporated drug molecules for the treatment of GBM. The project has the potential to provide significant improvement in the outcome of patients with GBM by developing a novel material system for drug delivery in a bioavailable, biocompatible form.
Despite recent technological advancements and promising preclinical experiments, patients with brain tumors are still met with limited treatment options. Barriers to clinical improvements include effective drug delivery across the blood-brain barrier to reach the tumor efficiently and selectively, and successfully achieving the balance between maximizing anti-tumor efficacy and minimizing risks of toxicity. Given our promising early results and our strong and complementary team, the proposed core-sheath fiber constructs could pave the way for the development of nano- and bio- medical platforms that provide highly tuned local delivery of therapeutics to the brain in order to suppress glioblastoma recurrence.
