Supramolecularly enabled pH- triggered drug action at tumor microenvironment potentiates nanomedicine efficacy against glioblastoma

The crucial balance of stability in blood-circulation and tumor-specific delivery has been suggested as one the challenges for effective bench-to-bedside translation nanomedicines (NMs). Herein, we developed a supramolecularly enabled tumor-extracellular (Tex) pH-triggered NM that can maintain micellar structure with entrapped-drug during systemic circulation progressively release drug tumor by rightly sensing heterogeneous tumor-pH. Desacetylvinblastine hydrazide (DAVBNH), derivative potent anticancer vinblastine, was conjugated to an aliphatic ketone-functionalized poly(ethylene glycol)–b-poly(amino acid) copolymer hydrolytic derived hydrazone bond efficiently tailored exploiting compartmentalized polymer micelle. We confirmed safe therapeutic application Tex pH-sensitive DAVBNH-loaded micelle (Tex-micelle) orthotopic glioblastoma (GBM) models, extending median survival 1.4 times GBM xenograft 2.6 syngeneic model, compared free DAVBNH. work presented here offers novel chemical insights into molecular design smart NMs correctly Tex-pH via programmed functionalities. practical engineering strategy based on clinically relevant platform, encouraging Tex-micelle GBM, most lethal human cancers, thus suggests potential clinical this system against other types common including GBM.