Sphingosine 1‐Phosphate Liposomes for Targeted Nitric Oxide Delivery to Mediate Anticancer Effects against Brain Glioma Tumors

Abstract Specifically targeting glioblastoma multiforme (GBM) blood vessels and actively enhancing the permeability of the brain–blood–tumor barrier (BBTB) are two extremely difficult challenges currently hindering the development of effective therapies against GBM. Herein, a liposome drug delivery system (S1P/JS‐K/Lipo) is described, which delivers the nitric oxide (NO) prodrug JS‐K, O₂‐(2,4‐dinitrophenyl) 1‐[(4‐ethoxycarbonyl) piperazin‐1‐yl] diazen‐1‐ium‐1,2‐diolate, to GBM tumors using sphingosine‐1‐phosphate (S1P)‐signaling molecules as active targeting lipid ligands. It is revealed that S1P/JS‐K/Lipo actively penetrates the BBTB, aided by caveolin‐1‐mediated transcytosis, and it is demonstrated that the system specifically interacts with S1P receptors (S1PRs), which are highly expressed on GBM cells. Nondestructive ultrasound imaging in GBM mouse models is also utilized to observe microsized NO bubble production from JS‐K, as catalyzed by the glutathione S‐transferases (GSTs) resident in GBM cells. Given that these NO bubbles strongly promote GBM cell death in vivo, the S1PR‐targeted liposome delivery system—which successfully achieves BBTB penetration and tumor targeted delivery of a complex multicomponent drug regimen—represents a promising approach for targeted therapies against GBM and other carcinomas characterized by elevated S1PR expression.