Transporting mitochondrion-targeting photosensitizers into cancer cells by low-density lipoproteins for fluorescence-feedback photodynamic therapy

作者:Wang, C (Wang, Chao)^{[ 1 ]} ; Zhao, XH (Zhao, Xianhao)^{[ 1 ]} ; Jiang, HY (Jiang, Haoyu)^{[ 1 ]} ; Wang, JX (Wang, Jiaxin)^{[ 1 ]} ; Zhong, WX (Zhong, Weixiu)^{[ 1 ]} ; Xue, K (Xue, Ke)^{[ 1 ]} ; Zhu, CL (Zhu, Chunlei)^{[ 1 ]}

NANOSCALE, 2021, 13(2): 1195-1205

DOI: 10.1039/d0nr07342c

摘要

Low-density lipoproteins (LDLs) are an endogenous nanocarrier to transport lipids in vivo. Owing to their biocompatibility and biodegradability, reduced immunogenicity, and natural tumor-targeting capability, we, for the first time, report the reconstitution of native LDL particles with saturated fatty acids and a mitochondrion-targeting aggregation-induced emission (AIE) photosensitizer for fluorescence-feedback photodynamic therapy (PDT). In particular, a novel AIE photosensitizer (TPA-DPPy) with a donor-acceptor (D-A) structure and a pyridinium salt is designed and synthesized, which possesses typical AIE and twisted intramolecular charge transfer (TICT) characteristics as well as reactive oxygen species (ROS)-sensitizing capability. In view of its prominent photophysical and photochemical properties, TPA-DPPy is encapsulated into LDL particles for photodynamic killing of cancer cells that overexpress LDL receptors (LDLRs). The resultant LDL (rLDL) particles maintain a similar morphology and size distribution to native LDL particles, and are efficiently ingested by cancer cells via LDLR-mediated endocytosis, followed by the release of TPA-DPPy for mitochondrion-targeting. Upon light irradiation, the produced ROS surrounding mitochondria lead to efficient and irreversible cell apoptosis. Interestingly, this process can be fluorescently monitored in a real-time fashion, as reflected by the remarkably enhanced luminescence and blue-shifted emission, indicating the increased mechanical stress during apoptosis. Quantitative cell viability analysis suggests that TPA-DPPy exhibits an outstanding phototoxicity toward LDLR-overexpressing A549 cancer cells, with a killing efficiency of ca. 88%. The rLDL particles are a class of safe and multifunctional nanophototheranostic agents, holding great promise in high-quality PDT by providing real-time fluorescence feedback on the therapeutic outcome.