Precise Molecular Engineering of Heptamethine Cyanine‐Based Near‐Infrared Type‐I Photosensitizers for Pro‐Death Autophagy and Hypoxia‐Tolerant Antitumor Treatment
Fuping Han, Mengya Guo, Xiao Zhou, Zhenyu Zhang, Hongyi Zhang, Lihan Cai, Xin Li, Tiancong Shi, Saran Long, Wen Sun, Jianjun Du, Jiangli Fan, Xiaojun Peng
Abstract
Heptamethine cyanine (Cy7) dyes have excellent near-infrared (NIR) fluorescence imaging capability but competitively inhibit the photodynamic therapy (PDT) effect, especially in hypoxic solid tumors. In this study, a series of aryl-ketone-modified Cy7 derivatives (ACy) were constructed to transform Cy7 into a type-I photosensitizer capable of both hydrogen (H)-abstraction and electron transfer for the first time. The introduction of an aryl-ketone group at the C3 position of Cy7 imparted it with H-abstraction capability and enhanced its intersystem crossing efficiency. Moreover, an increase in the steric hindrance of the aryl-ketone group promoted the efficiency of the H-abstraction reaction and electron transfer process. Optimized molecules, 3ACy-3ipr, not only exhibited bright fluorescence but also generated hydroxyl and alkyl radicals upon NIR light irradiation. These radicals induced mitochondrial autophagy in hypoxic tumor cells, eventually leading to necrosis and ferroptosis. Tumor targeting peptide modified liposomes were used to construct nanocarriers to improve the biocompatibility and tumor retention of 3ACy-3ipr, which fluoresces at the tumor site and significantly inhibited the growth of solid tumors via PDT. This study provides an excellent platform for the precise development and clinical utilization of NIR theranostic agents.