期刊
JOURNAL OF NANOBIOTECHNOLOGY
卷 18, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s12951-019-0562-3
关键词
Mitochondrial targeting; Paclitaxel; Nanomicelles; Multidrug resistance; Cancer therapy
资金
- 2018 High-level university academic backbone and training program in Guangzhou Medical University [B185004199]
- 2018 Guangdong Key discipline construction project of pharmacy [Q185031010]
- 2019 Undergraduate laboratory open project [C195015003]
- 2018 Construction of scientific research teaching and academic improvement project in Guangzhou Medical University [B185004025]
- Scientific Research Projects of Guangzhou [201707010329]
- 2017 University innovation and strengthening program [Q17024031]
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.
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