期刊
BIOCONJUGATE CHEMISTRY
卷 30, 期 5, 页码 1451-1458出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.bioconjchem.9b00192
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资金
- Mr. and Mrs. Spencer T. Olin Fellowship for Women in Graduate Study
- National Institutes of Health [R01 CA171651, U54 CA199092, R01 EB021048, P50 CA094056, P30 CA091842, S10 OD016237, S10 RR031625, S10 OD020129]
- Department of Defense Breast Cancer Research Program [W81XWH-16-1-0286]
- Alvin J. Siteman Cancer Research Fund [11-FY16-01]
Photodynamic therapy (PDT) is often used in preclinical and clinical treatment regimens. Reactive oxygen species (ROS) generated by photosensitizers (PSs) upon exposure to light induce cell death via diverse mechanisms. PSs can exert therapeutic effects in different cellular organelles, although the efficacy of organelle-specific PDT has yet to be determined as most previous studies use different PSs in different organelles. Here, we explored how a single PS, chlorin e6 (Ce6), targeted to different organelles altered the effectiveness of PDT. Ce6 intrinsically localizes to the ER after 4 h of incubation. Modification of Ce6 via conjugation with an octapeptide (LS765), a monosubstituted triphenylphosphonium (TPP) derivative (LS897), or a disubstituted TPP derivative (LS909) altered the intrinsic localization. We determined that LS765 and LS9897 predominantly accumulated in the lysosomes, but LS909 trafficked equally to both the mitochondria and the lysosomes. Moreover, the conjugation altered the type of ROS produced by Ce6, increasing the ratio of hydrogen peroxide to hydroxyl radicals. Irradiation of identical concentrations of the PSs in solution with 650 nm, 0.84 mW/cm(2) light for 10 min showed that the TPP conjugates nearly doubled the hydrogen peroxide production from similar to 0.2 mu M for Ce6 and LS765 to similar to 0.37 mu M for LS897 and LS909. In contrast, Ce6 produced similar to 1.5-fold higher hydroxyl radicals than its conjugates. To compare the effect of each PS on cell death, we normalized the intracellular concentration of each PS. Hydrogen peroxide-producing PSs are effective PDT agents in the lysosomes while the hydroxyl-generating PSs are very effective in the ER Compared to the PSs that accumulated in the lysosomes, only the ER-targeted Ce6 exerted >50% cell death at either low light power or low intracellular concentration. By delineating the contributions of cellular organelles and types of ROS produced, our work suggests that targeting hydroxyl radical-producing PSs to the ER is an exciting strategy to improve the therapeutic outcome of PDT.
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