Porphyrin-lipid assemblies and nanovesicles overcome ABC transporter-mediated photodynamic therapy resistance in cancer cells
Porphyrin-lipid assemblies and nanovesicles overcome ABC transporter-mediated photodynamic therapy resistance in cancer cells
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DOI：
10.1016/j.canlet.2019.04.037
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发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Huang, Huang-Chian
中科院分区：
文献类型：
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作者：
Baglo, Yan;Liang, Barry J.;Huang, Huang-Chian
光动力疗法（PDT）涉及光敏剂的光活化以产生诱导细胞调节或死亡的反应性分子种类。基于早期的研究结果表明光敏剂苯并卟啉衍生物（BPD）是乳腺癌耐药蛋白（ABCG 2）的底物，我们研究了P-糖蛋白（P-gp）和多药耐药相关蛋白1（MRP 1）转运BPD的能力。在一组过表达P-gp、MRP 1或ABCG 2的乳腺癌细胞系中，BPD转运仅发生在过表达P-gp和ABCG 2的细胞中。细胞内BPD荧光不受MRP 1的影响，如通过流式细胞术测定的。为了绕过P-gp和ABCG 2介导的BPD外排，我们引入了脂化策略以产生不再是P-gp和ABCG 2底物的BPD衍生物。磷脂结合的BPD及其纳米脂质体制剂逃避P-gp和ABCG 2介导的转运。在细胞毒性试验中，脂化BPD及其纳米脂质体制剂消除了P-gp和ABCG 2介导的PDT抗性。我们证实，P-gp，像ABCG 2，在BPD转运和BPD-PDT抗性中起作用。此外，我们引入卟啉脂质纳米囊泡作为逃避P-gp和ABCG 2介导的BPD外排的新策略，以改善两种乳腺癌细胞系的PDT结果。
Photodynamic therapy (PDT) involves light activation of the photosensitizer to generate reactive molecular species that induce cell modulation or death. Based on earlier findings showing that the photosensitizer benzoporphyrin derivative (BPD) is a breast cancer resistance protein (ABCG2) substrate, we investigated the ability of the P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) to transport BPD. In a panel of breast cancer cell lines overexpressing P-gp, MRP1, or ABCG2, BPD transport occurs only in cells overexpressing P-gp and ABCG2. Intracellular BPD fluorescence is not affected by MRP1, as determined by flow cytometry. To bypass P-gp- and ABCG2-mediated efflux of BPD, we introduce a lipidation strategy to create BPD derivatives that are no longer P-gp and ABCG2 substrates. The phospholipid-conjugated BPD and its nanoliposomal formulation evade both P-gp- and ABCG2-mediated transport. In cytotoxicity assays, lipidated BPD and its nanoliposomal formulation abrogate P-gp- and ABCG2-mediated PDT resistance. We verify that P-gp, like ABCG2, plays a role in BPD transport and BPD-PDT resistance. Furthermore, we introduce porphyrin-lipid nanovesicles as a new strategy to escape P-gp and ABCG2-mediated efflux of BPD for improved PDT outcomes in two breast cancer cell lines.