Codelivery of High-Molecular-Weight Poly-porphyrins and HIF-1α Inhibitors for In Vivo Synergistic Anticancer Therapy.

Photodynamic therapy (PDT) is showing great potential in the treatment of cancer diseases, and photosensitizers play crucial roles in absorbing the energy of light and generating reactive oxygen species (ROS) during PDT. Most of the photosensitizers bearing macrocyclic structures have strong hydrophobicity and suffer from the π-π interaction and undesired aggregation caused quenching (ACQ), which severely limit the PDT efficacy. Moreover, the continuous oxygen consumption during PDT also leads to the upregulated expression of hypoxia-inducible factor-1α (HIF-1α), which can aggravate the growth of tumors. To overcome the abovementioned problems, polymerized photosensitizers repelled by flexible thioketal linkers were designed and synthesized using a multicomponent polymerization (MCP) method to afford the poly-porphyrins with high molecular weight (Mw > 20 000 g/mol) under room temperature. The ACQ effect could be significantly inhibited by introducing flexible chains and increasing Mw, leading to the improvement in the singlet oxygen quantum yield and phototoxicity simultaneously. An HIF-1α inhibitor, Lificiguat (YC-1) was synthesized as a chemodrug and codelivered with poly-porphyrins to decrease the expression of HIF-1α and inhibit tumor growth under hypoxia. With the synergistic PDT and chemotherapy, poly-porphyrin/YC-1 micelles showed excellent therapeutic antitumor efficacy both in vitro and in vivo.