Hypoxia-Sensitive Zwitterionic Vehicle for Tumor-Specific Drug Delivery through Antifouling-Based Stable Biotransport Alongside PDT-Sensitized Controlled Release

A hypoxia-sensitive zwitterionic vehicle, D-High-PEI-(A+P), with the ability for antifouling-mediated, stable biotransport and a photodynamic therapy (PDT)-sensitized hypoxic response for spatiotemporal controlled drug release, was developed for the tumor-specific delivery of chemotherapeutics and biomacromolecules. The amphiphilic D-High-PEI-(A+P) was constructed from a betaine monomer (DMAAPS), a photosensitizer (PpIX), and an azobenzene-4,4'-dicarboxylic acid-modified polyethylenimine. Herein paditaxel (PTX) was selected as a common model drug to verify the functions of the designed polymer. First, D-High-PEI-(A+P) was demonstrated to spontaneously coassemble with PTX in aqueous solution with high drug loading (>35%). The desirable antifouling ability of D-High-PEI-(A+P) was independently verified by efficient 4T1 endocytosis in serum alongside systemic tumor targeting. Furthermore, PpIX-mediated PDT was verified to aggravate and homogenize a hypoxic microenvironment at the cell and tissue levels for a sharp responsive disassembly of D-High-PEI-(A+P) and thus a robust drug release in a well-controlled manner. As a result, D-High-PEI-(A+P) amplified the therapeutic outcome of PTX on orthotopic 4T1 mouse models with minimal collateral damage. We proposed that D-High-PEI-(A+P) may serve as a tailor-designed universal vehicle for the tumor-specific delivery of drugs with distinct physicochemical properties.

Automated summary

The hypoxia-sensitive zwitterionic vehicle D-High-PEI-(A+P) was developed for tumor-specific delivery of chemotherapeutics and biomacromolecules, with antifouling properties and photodynamic therapy-sensitized hypoxic response to enable controlled drug release. It demonstrated high drug loading, efficient tumor targeting, and responsive drug release, amplifying the therapeutic outcome with minimal collateral damage in orthotopic mouse models. D-High-PEI-(A+P) has the potential to serve as a universal vehicle for the tumor-specific delivery of drugs with diverse physicochemical properties.