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

Autor: Jiacui Xie, Fangke Zhang, Jianhai Chen, Huaying Wen, Qiudi Huang, Yugang Huang, He Wang, Yi Zhou, Peiyin Li, Wenwen Shi, Linghao Qin
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Lung Neoplasms
Cancer therapy
Proton Magnetic Resonance Spectroscopy
Pharmaceutical Science
Medicine (miscellaneous)
Apoptosis
02 engineering and technology
Mitochondrion
Multidrug resistance
Applied Microbiology and Biotechnology
chemistry.chemical_compound
Hyaluronic Acid
Nanomicelles
Micelles
Membrane Potential
Mitochondrial
0303 health sciences
Mice
Inbred BALB C
biology
Chemistry
Cytochrome c
Pinocytosis
Mitochondrial targeting
021001 nanoscience & nanotechnology
Endocytosis
Mitochondria
Paclitaxel
lcsh:R855-855.5
Mitochondrial Membranes
Molecular Medicine
Female
Efflux
0210 nano-technology
Signal Transduction
endocrine system
lcsh:Medical technology
Cell Survival
lcsh:Biotechnology
Biomedical Engineering
Bioengineering
Antineoplastic Agents
Poloxamer
03 medical and health sciences
Inhibitory Concentration 50
Organophosphorus Compounds
lcsh:TP248.13-248.65
Animals
Humans
030304 developmental biology
Research
Molecular medicine
Xenograft Model Antitumor Assays
Multiple drug resistance
A549 Cells
Drug Resistance
Neoplasm
biology.protein
Cancer research
Nanoparticles
Lysosomes
Zdroj: Journal of Nanobiotechnology, Vol 18, Iss 1, Pp 1-21 (2020)
Journal of Nanobiotechnology
ISSN: 1477-3155
Popis: 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.
Databáze: OpenAIRE
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