Local delivery of SN-38 using a biodegradable implantable membrane for treatment of glioblastoma.

Abstract

e14100 Background: Glioblastoma (GBM) remains a lethal disease with high rates of local recurrence despite maximal surgical resection and standard chemoradiotherapy. Systemic delivery of cytotoxic agents is limited by the blood–brain barrier and dose-limiting toxicity. CEB-01 is a biodegradable nanofiber membrane designed for local delivery of SN-38, a potent topoisomerase I inhibitor, directly to the surgical cavity. This study evaluated the preclinical efficacy, potency, and local tolerability of CEB-01 in GBM models. Methods: The antitumor activity of SN-38 was assessed in glioblastoma cell lines, including temozolomide-resistant and MGMT-positive and -negative models (GBM cell line panel Sanger Institute). In vivo efficacy and local tolerability of CEB-01 were evaluated in rodent intracranial models following surgical implantation in the brain. Tumor growth, histopathology, and neurological tolerance were assessed. External preclinical data were used to contextualize local SN-38 dose ranges and exposure relative to previously reported delivery strategies. Results: SN-38 demonstrated markedly higher in vitro potency compared with temozolomide and carmustine, with IC50 values approximately 1,000-fold lower across GBM cell lines and preserved activity in MGMT-positive and temozolomide-resistant models. In vivo implantation of CEB-01 showed good local tolerability, with no significant behavioral toxicity, weight loss, or fibrosis observed during long-term follow-up. Histological evaluation revealed only localized cortical changes related to surgery and implantation, comparable to incision controls. Dose-scaling analyses indicated that local SN-38 delivery in the low milligram range is pharmacologically plausible while minimizing systemic exposure, supporting further translational development. Conclusions: These preclinical data support CEB-01 as a promising local drug-delivery strategy for glioblastoma, combining high antitumor potency of SN-38 with acceptable local tolerability. Localized sustained delivery of SN-38 may overcome key limitations of systemic chemotherapy in GBM and warrants further translational and clinical investigation.