Cell Membrane-Anchored Click Reaction Enhances Porphyrin Uptake for Highly Efficient Photodynamic Therapy of Breast Tumors

Enhancing cell uptake of drugs for better therapy is a fundamental scientific problem in pharmaceutics. The "hydrophobic-hydrophilic-hydrophobic" structure has shown the potential of enhancing cell uptake of drugs. Thus, cell membrane-anchored formation of this structure should additionally enhance cell uptake of drugs but has not been reported. In this work, we rationally designed acid-deshielding cysteine-PEG-DSPE (<b>DA-Cys-PD</b>) and PE-porphyrin-PEG-CBT (<b>Por-CBT</b>). After <b>DA-Cys-PD</b> anchors on the tumor cell membrane, the weak acidic environment of the cell deshields the anchor to yield Cys-PD, which subsequently click-reacts with <b>Por-CBT</b> to yield <b>Por-Luc-PD</b> with a "hydrophobic-hydrophilic-hydrophobic" structure. This in situ formed structure significantly enhances the cellular uptake of porphyrin and its consequent photodynamic therapeutic effect on breast tumors. Particularly, with the assistance of the cell membrane-anchored click reaction, porphyrin uptake in cancer cells or breast tumors is increased roughly to be 7.8-fold or 3.9-fold of that of the negative control group whose Cys is acid-inactive, respectively. The enhanced porphyrin uptake leads to highly efficient photodynamic therapy of breast tumors with a remarkable tumor growth inhibition rate of 64.1% compared with that of 5.5% of the negative control group. This approach of cell membrane-anchored click reaction provides people with a simple and feasible avenue for enhancing cell uptake of drugs/probes, as well as their therapeutic/diagnostic effects.