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

• Published in: Nanoscale 2021-01, Vol.13 (2), p.1195-125
• Main Authors: Wang, Chao, Zhao, Xianhao, Jiang, Haoyu, Wang, Jiaxin, Zhong, Weixiu, Xue, Ke, Zhu, Chunlei
• Format: Article
• Language: English
• Subjects: Apoptosis; Biocompatibility; Biodegradability; Cancer; Charge transfer; Density; Emission analysis; Fatty acids; Feedback; Fluorescence; Light irradiation; Lipids; Lipoproteins; Lipoproteins, LDL; Mitochondria; Morphology; Neoplasms - drug therapy; Particle size distribution; Photochemotherapy; Photodynamic therapy; Photosensitizing Agents - pharmacology; Photosensitizing Agents - therapeutic use; Real time; Sensitizing
• ISSN: 2040-3364; 2040-3372
• DOI: 10.1039/d0nr07342c

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. Low-density lipoproteins (LDLs) reconstituted with a multifunctional mitochondrion-targeting photosensitizer are able to achieve fluorescence-feedback photodynamic therapy of LDL receptor-overexpressing cancer cells.