A rationally designed local delivery platform (OncoPLEX) for sustained docetaxel release to overcome therapeutic barriers in post-resection solid tumors and glioblastoma.

Abstract

e15099 Background: Post-surgical recurrence is a leading cause of treatment failure in solid tumors, particularly glioblastoma (GBM), where the blood-brain barrier (BBB) and infiltrative disease limit the efficacy of systemic chemotherapy. We developed OncoPLEX, a localized, controlled-release formulation of docetaxel (TDX), designed to deliver sustained, high local concentration of bioactive drug to the surgical margin while minimizing systemic exposure and toxicity. Methods: Efficacy was evaluated in multiple models, including post-partial resection of subcutaneous colorectal carcinoma model (CT-26) and non-resected orthotopic intracranial 9L gliosarcoma. Outcomes included tumor regrowth, overall survival (OS), systemic toxicity, and 16-week intracranial safety. Plasma pharmacokinetics (PK) were measured and compared with intravenous (IV) DTX administration. Results: OncoPLEX demonstrated enhanced potency with a 50.3% lower IC50 in the CT-26 cells relative to free DTX. In CT-26 post-resection model, OncoPLEX achieved near-complete growth inhibition and significantly extended survival (p < 0.05). In non-resected orthotopic gliosarcoma, a single intracranial dose of OncoPLEX (50 mg) produced an OST of 35 days, nearly doubling median OS of the untreated (18 days) and systemic temozolomide (23 days) groups. PK analysis confirmed a 13-fold lower Cmax compared with IV administration (67 vs. 881 ng/mL) while maintaining comparable total exposure (AUC). No permanent neurotoxicity or systemic decline was observed over 16 weeks. Antitumor activity demonstrated distal radial diffusion from the site of administration into the tumor mass. Conclusions: Localized, controlled, and prolonged DTX delivery via OncoPLEX enables superior outcomes by bypassing the BBB, overcoming chemoresistance, and potentially providing extended tissue penetration depth. Unlike systemic nanoparticle-based delivery systems, this platform provides a sustained, high-concentration local therapeutic effect with improved safety. OncoPLEX represents a highly translatable strategy for improving outcomes in high-risk solid tumors and aggressive CNS malignancies.