Introduction: Glioblastoma, the most common and lethal brain malignancy in humans, is highly resistant to chemotherapy and shielded from it by the blood brain barrier (1). In order to overcome this physical obstacle, local drug delivery by means of a novel wafer based on coaxial fibers with poly[bis (p-carboxyphenoxy)propane] anhydride-sebacic acid (PCPP-SA)/BCNU core and poly(e-caprolactone) (PCL) sheath was tested on a rodent 9L gliosarcoma model. Coaxial fibers allow a longer and more gradual release of BCNU inside the tumor resection cavity, decreasing the rate of drug diffusion in the first hours post-implantation (2).

Methods: Wafers using two different electrospun coaxial fibers and loaded with 5-8% BCNU were implanted in female F344 rats bearing intracranial 9L gliosarcoma. Animals were treated with either an empty polymer or two variants of BCNU-loaded electrospun membranes. Two rats were euthanized at day 45 post-implantation, and histologic evaluation was performed.

Results: Intracranially implanted electrospun membranes were tolerable with no signs of toxicity or adverse reactions observed. The membranes led to statistically significant improvements in median survival in the highly aggressive tumor model tested. The group that received no treatment(n=6) and the group that received the blank construct (n=5) both had a median survival of 12 days. The two groups(n=10; n=10) that received varying doses of the fiber construct delivering BCNU had not reached median survival by Day 70 with 100% (p=0.0001) and 90% (p=0.0021) of the animals surviving, respectively. The survival data were confirmed by histological analysis showing abscence of malignant cells 45 days post-implantation.

Conclusions: Interstitial chemotherapy by means of biodegradable polymeric electrospun coaxial fibers is capable of delivering an effective dose of cytotoxic agents in a more constant and prolonged fashion. The drug-impregnated core, shielded by a polymeric layer, enables the disc to degrade over a period of months allowing an efficient intracranial diffusion of therapeutics.

Patient Care: This novel combination of BCNU and electrospun membranes can efficiently and safely deliver high doses of chemotherapeutics to the brain, without causing significant side effects. Active compounds can be constantly released for periods of time that are significantly longer than those achieved with other polymers.

Learning Objectives: By the conclusion of this session, participants should be able to: 1) Describe the importance of new strategies of drug delivery for the treatment of glioblastoma multiforme, 2) Discuss, in small groups the clinical implications of this highly tolerable formulation, 3) Identify an effective treatment for patients with high-grade gliomas.

References: (1) B. Engelhardt, L. Sorokin. The blood–brain and the blood–cerebrospinal fluid barriers: function and dysfunction. Semin. Immunopathol. 31, 497– 511, (2009). (2) Han, D. et al., In-vitro evaluation of MPA-loaded electrospun coaxial fiber membranes for local treatment of glioblastoma tumor cells. J. Drug Deliv. Sci. Technol. 40, 45–50, (2017).