Brain implantable nano fibrous wafer for prolonged drug delivery against recurrent glioma

Abstract

Delivery of therapeutic agents at clinically relevant doses is very critical in achieving desired treatment response in chemotherapy. Drug delivery to central nervous system tumors, like glioblastoma multiforme (GBM) faces serious challenges due to existence of blood brain barrier, short drug half-life, fast clearance, high plasma protein binding and non-specific biodistribution. Administration of high doses of drugs to overcome these limitations ultimately leads to dose limiting toxicities. This necessitates alternative strategies to attain required dose of drug locally at the tumor site. Local drug delivery methods can overcome most of the above challenges. For the past two decades, there is one only local drug delivery system (Gliadel ) approved by FDA for treating glioblastoma. Gliadel delivers a chemotherapeutic agent, carmustine, in the tumor resected cavity for nearly 6-7 days. Although Gliadel improves patient survival by 2-3 months, recurrence of tumor from 1-2 cm region of resected margin was reported. This is attributed to: i) the inability of implant to release drug for more than 7-14 days, ii) short-half life and fast clearance of carmustine resulting in poor drug-retention and iii) low tissue penetration of the drug. A number of studies have reported the use of alternative implant systems for the localized delivery of various anti-cancer drugs. However, sustained in vivo release for up to a month or more remains to be an unmet challenge. This study investigated the possibility of developing low-cost, bulk-eroding, biodegradable polymer implants for the sustained release of anti-glioma drugs in the brain for at least one month. Although it is difficult to achieve constant and sustained release using bulk eroding polymers, we have optimized an innovative method to overcome this challenge.