Chemotherapeutic drugs frequently encounter multidrug resistance. ATP from mitochondria helps overexpression of drug efflux pumps to induce multidrug resistance, so mitochondrial delivery as a means of "repurposing'' chemotherapeutic drugs currently used in the clinic appears to be a worthwhile strategy to pursue for the development of new anti-drug-resistant cancer agents. TPP-Pluronic F127-hyaluronic acid (HA) (TPH), with a mitochondria-targeting triphenylphosphine (TPP) head group, was first synthesized through ester bond formation. Paclitaxel (PTX)-loaded TPH (TPH/PTX) nanomicelles exhibited excellent physical properties and significantly inhibited A549/ADR cells. After TPH/PTX nanomicelles entered acidic lysosomes through macropinocytosis, the positively charged TP/PTX nanomicelles that resulted from degradation of HA by hyaluronidase (HAase) in acidic lysosomes were exposed and completed lysosomal escape at 12 h, finally localizing to mitochondria over a period of 24 h in A549/ADR cells. Subsequently, TPH/PTX caused mitochondrial outer membrane permeabilization (MOMP) by inhibiting antiapoptotic Bcl-2, leading to cytochrome C release and activation of caspase-3 and caspase-9. In an A549/ADR xenograft tumor model and a drug-resistant breast cancer-bearing mouse model with lung metastasis, TPH/PTX nanomicelles exhibited obvious tumor targeting and significant antitumor efficacy. This work presents the potential of a single, nontoxic nanoparticle (NP) platform for mitochondria-targeted delivery of therapeutics for diverse drug-resistant cancers.

中文翻译：

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靶向肿瘤和线粒体的纳米颗粒通过细胞凋亡的线粒体途径根除耐药性肺癌。

化疗药物经常会遇到多药耐药性。线粒体中的ATP有助于药物外排泵的过表达，从而引起多药耐药性，因此，目前临床上使用的线粒体药物作为“重新使用”化疗药物的一种手段，似乎是开发新型抗药性药物的一项有价值的策略带有线粒体靶向三苯膦（TPP）头基的TPP-Pluronic F127-透明质酸（HA）（TPH）是首先通过酯键形成而合成的；负载紫杉醇（PTX）的TPH（TPH / PTX）纳米胶束TPH / PTX纳米胶束通过巨胞饮作用进入酸性溶酶体后，表现出优异的物理性能并显着抑制了A549 / ADR细胞。透明质酸酶（HAase）在酸性溶酶体中降解HA导致带正电的TP / PTX纳米胶束暴露，并在12 h完成溶酶体逸出，最终在24小时内在A549 / ADR细胞中定位到线粒体。随后，TPH / PTX通过抑制抗凋亡的Bcl-2引起线粒体外膜通透性（MOMP），导致细胞色素C的释放以及caspase-3和caspase-9的活化。在具有肺转移的A549 / ADR异种移植肿瘤模型和耐药性乳腺癌小鼠模型中，TPH / PTX纳米胶束具有明显的肿瘤靶向性和显着的抗肿瘤功效。这项工作展示了单一，无毒的纳米颗粒（NP）平台针对线粒体靶向治疗多种耐药性癌症的治疗方法的潜力。