Tumor- and mitochondria-targeted nanoparticles eradicate drug resistant lung cancer through mitochondrial pathway of apoptosis

  • J Nanobiotechnology. 2020 Jan 9;18(1):8. doi: 10.1186/s12951-019-0562-3.
He Wang  1  2 ,  Fangke Zhang  1 ,  Huaying Wen  1 ,  Wenwen Shi  1 ,  Qiudi Huang  1 ,  Yugang Huang  1 ,  Jiacui Xie  1 ,  Peiyin Li  1 ,  Jianhai Chen  3 ,  Linghao Qin  4 ,  Yi Zhou  5
Affiliations
  • 1. Key Laboratory of Molecular Clinical Pharmacology & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China.
  • 2. Center of Cancer Research, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, Guangdong, China.
  • 3. Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.
  • 4. School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, China. [email protected].
  • 5. Key Laboratory of Molecular Clinical Pharmacology & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China. [email protected].
PMID: 31918714 DOI: 10.1186/s12951-019-0562-3
Abstract

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.

Keywords
Cancer therapy; Mitochondrial targeting; Multidrug resistance; Nanomicelles; Paclitaxel.