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• W3204348039 abstract "1272 Purpose: Translocator protein (TSPO) is one of the emerging cancer biomarkers and has been shown to be associated with poor prognosis in a variety of malignancies. However, an appropriate drug delivery system is essential for development of TSPO targeted cancer therapy, as TSPO is also expressed in normal tissues. Herein, we developed a pH-sensitive cancer targeting liposomal nanoplatform containing a photosensitizer (IR780) conjugated imidazopyridine analog (BS333) for effective cancer TSPO targeted photodynamic therapy (PDT). Methods: BS333 was prepared by thiourea ligation of IR780-NH2 and TSPO targeting ligand, CB86 in dimethylformamide at 80℃ for 2 hours. followed by purification of silica-gel column chromatography. The pH-sensitive liposome (pH-lipo) was prepared for endosomal escape by adding pH sensitive lipids (DPPE-Hz-PEG2k). BS333 and IR780 dye were separately loaded in two-type of liposomes (lipo and pH-lipo) by self-assembly method, respectively (named BS333 lipo, BS333 pH-lipo, IR780 lipo, and IR780 pH-lipo) (Figure 1). The BS333 pH-lipo and other control liposomes were characterized by absorbance spectra and dynamic light scattering (DLS) to confirm their size, loading efficiency, stability, and pH sensitivity. Comparison of TSPO specific targeting efficiency, ROS generation, and in vitro PDT effect of four liposomes were conducted using HeLa cells. In vivo imaging was performed with BS333 pH-lipo and BS333 lipo at different time points (0, 4, 15 and 30 hours). Results: BS333 was successfully synthesized and confirmed by nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-mass spectrophotometry (LC-MS). The hydrodynamic size of BS333 pH-lipo was 75.16 ± 27.83 nm (S1c). Loading efficiency of BS333 to pH-lipo was about 75%, which was confirmed by absorbance at 800 nm (S1a, b). BS333 pH-lipo had a high stability for 24 h and degraded at pH 5.5 (S1c, d, e), while BS333 lipo did not, confirming pH-sensitivity of BS333 pH-lipo. The specific binding to TSPO was evaluated by mitochondrial signal quenching in confocal microscopy images, because TSPO is expressed in mitochondria and fluorescence resonance energy transfer (FRET) can take place when IR780 or BS333 is in a close distance with mitotraker (a mitochondria staining dye). The TSPO binding was the highest in BS333 pH-lipo compare to other controls (Figure 2). BS333 pH-lipo demonstrated an efficient ROS production ability under 808-nm laser irradiation. (S3). The cell killing effect of BS333 pH-lipo was enhanced by 20-fold by 808-nm laser irradiation in HeLa cells. The in vitro PDT effect of BS333 pH-lipo was over 6-fold higher than that of IR780 lipo, furthermore, it was over 2-fold higher than those of IR780 pH-lipo and BS333 lipo. These results confirmed that both TSPO targeting photosensitizer (BS333) and pH sensitive liposome were responsible for the enhanced PDT effect (Figure 3). The BS333 pH-lipo had a substantial tumor uptake showing similar targeting efficiency of BS333 lipo, which indicates that pH-lipo was not cleavable during the circulation (Figure 4). Conclusion: We developed an IR780 conjugated TSPO-binding ligand loaded pH-sensitive liposome nanoplatform (BS333 pH-lipo), it demonstrated excellent TSPO specific targeting, pH sensitivity, photodynamic therapeutic effect, and high tumor targeting efficiency." @default.
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• W3204348039 date "2021-05-01" @default.
• W3204348039 modified "2023-09-23" @default.
• W3204348039 title "IR780 Conjugated TSPO-binding Ligand Loaded pH-sensitive Nanoplatform for Effective TSPO Targeted Photodynamic Therapy" @default.
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