Janus macromolecular brushes for synergistic cascade-amplified photodynamic therapy and enhanced chemotherapy.

The aggregation-caused quenching (ACQ) effect of photosensitizers and multidrug resistance are the major obstacles in photodynamic therapy (PDT) and chemotherapy, respectively. Synergistic photo-chemotherapy is a promising cancer treatment to overcome the short boards of each single therapy. However, the fabrication of nanocarriers acting as both photosensitizers in PDT and the vehicle of drug release is a key challenge. Herein, we constructed a well-defined porphyrin-containing Janus macromolecular brush and used it as both a photosensitizer and a pH-responsive vehicle for DOX release. The Janus macromolecular brush with pH-responsive side chains and porphyrin units linked covalently in each repeat unit was synthesized by the combination of reversible addition-fragmentation chain transfer (RAFT) polymerization and click chemistry. The high grafting content of porphyrin units in the macromolecular brush improved the DOX loading capability by π-π stacking and therefore reduced the total treatment dose of DOX-loaded macromolecular brush nanoparticles (NPs). The pH-responsive side chains played triple roles in synergistic cascade-amplified PDT and enhanced chemotherapy including an executor of controlled drug release, a ligand with a mitochondria-targeting feature, and a barrier to reduce the ACQ effect of porphyrin units. In vitro and in vivo studies confirmed that the DOX-loaded macromolecular brush NPs exhibited high phototoxicity and significant tumor inhibition efficacy. STATEMENT OF SIGNIFICANCE: Synergistic photodynamic therapy (PDT) and chemotherapy has emerged as a promising cancer treatment to overcome the challenges of a single modality. Herein, we constructed new pH-responsive vesicles using porphyrin-containing Janus macromolecular brushes as theranostic nanocarriers to encapsulate high-loading doxorubicin (DOX) for synergistic cascade-amplified PDT and enhanced chemotherapy. The high grafting content of porphyrin units in Janus macromolecular brushes improved DOX loading capability by π-π stacking for enhanced chemotherapy. Moreover, pH-responsive side chains subsequently enhanced the suppression of the aggregation-caused quenching (ACQ) effect of porphyrins for cascade-amplified PDT. In vitro and in vivo studies confirmed that DOX-loaded macromolecular brush nanoparticles exhibited high phototoxicity and significant tumor inhibition efficacy.