Local delivery of SN-38 for the treatment of glioblastoma: Engineering precision chemotherapy beyond the blood-brain barrier.

Glioblastoma (GBM) is characterized by near-universal local recurrence despite maximal surgical resection and systemic therapy, a failure largely driven by infiltrative tumor margins and the restrictive blood-brain barrier (BBB). The topoisomerase I inhibitor SN-38, active metabolite of irinotecan, has emerged as a promising therapeutic alternative for GBM management, offering 100- to 1000-fold greater cytotoxicity than its prodrug and a lack of cross-resistance with temozolomide (TMZ). However, the clinical utility of SN-38 is severely constrained by its poor aqueous solubility, rapid physiological inactivation via lactone-to-carboxylate interconversion, and dose-limiting systemic toxicities. While local drug delivery systems (LDDS) offer a strategic bypass of the BBB, their clinical translation remains limited and therapeutic outcomes inconsistent. In this review, we reframe local SN-38 therapy as an engineering challenge defined by the coupled constraints of chemical stability, parenchymal transport, and release kinetics. We critically evaluate current delivery platforms - including polymeric depots, hydrogels, nanoparticles, and convection-enhanced delivery (CED) - based on their capacity to satisfy four essential design criteria: (i) sustained drug exposure at infiltrative margins, (ii) stabilization of the active lactone form, (iii) expansive spatial distribution beyond the resection margin, and (iv) mechanical and geometric compatibility with the soft brain parenchyma. Based on this analysis, we provide a clear set of requirements for next-generation SN-38 or irinotecan delivery systems. This perspective highlights the need for integrated strategies combining controlled release with enhanced transport and provides a roadmap for the rational development of locally delivered treatments for GBM.