Tumor-acidity triggered detachment of surface coatings and charge-reversal of fluorinated polymeric micelles to boost photodynamic cancer therapy

Abstract

Photodynamic therapy efficiency is constrained by tumor hypoxia and insufficient photosensitizer accumulation. To address these limitations, an oxygen-supplying nanoplatform was developed through function-oriented polymer design. Briefly, an amphiphilic copolymer (PFOC-PEI) was firstly synthesized through chemical conjugation of perfluorooctanoic acid with branched polyethyleneimine, forming micelles capable of encapsulating chlorin e6, while alleviating hypoxia via fluorocarbon-mediated oxygen delivery. To enhance tumor-selective delivery for biocompatibility, a pH-responsive polyanion (PEI-DMMA) derived from 2,3-dimethylmaleic anhydride modification was integrated, yielding composite micelles (Ce6-PFOC-PEI/PEI-DMMA) with tumor stimulus responsiveness charge reversal and oxygen carrying capabilities. The nanocarrier maintained negative surface charge under physiological conditions to prolong blood circulation, while switching to positive charge at tumor sites through microenvironmental-triggered cleavage of acid-labile amide bonds, thereby enhancing tumor accumulation. In vitro studies demonstrated 1.5-fold higher cellular uptake of Ce6-PFOC-PEI/PEI-DMMA under acidic conditions compared to non-hydrolytic controls (Ce6-PFOC-PEI/PEI-SA), correlating with enhanced ROS generation in C6 glioma cells. The improved phototoxicity was evidenced by lower IC50 values against C6 cells. In vivo evaluation revealed 87% tumor growth inhibition in C6 tumor-bearing nude mice of Ce6-PFOC-PEI/PEI-DMMA, which is superior to those of Ce6-PFOC-PEI/PEI-SA (69%) and Ce6-PFOC-PEI (73%). This oxygen self-supplying platform integrates fluorocarbon-mediated oxygenation with pH-responsive charge reversal, demonstrating enhanced PDT efficacy while maintaining favorable biosafety.