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Mitochondria-targeted delivery of doxorubicin to enhance antitumor activity with HER-2 peptide-mediated multifunctional pH-sensitive DQAsomes.

ABSTRACT: Multidrug resistance (MDR) of breast cancer is the major challenge to successful chemotherapy while mitochondria-targeting therapy was a promising strategy to overcome MDR.In this study, HER-2 peptide-PEG2000-Schiff base-cholesterol (HPSC) derivate was synthesized successfully and incorporated it on the surface of the doxorubicin (DOX)-loaded dequalinium (DQA) chloride vesicle (HPS-DQAsomes) to treat drug-resistant breast cancer. Evaluations were performed using human breast cancer cell and DOX-resistant breast cancer cell lines (MCF-7 and MCF-7/ADR).The particle size of HPS-DQAsomes was ~110 nm with spherical shape. In vitro cytotoxicity assay indicated that HPS-DQAsomes could increase the cytotoxicity against MCF-7/ADR cell line. Cellular uptake and mitochondria-targeting assay demonstrated that HPS-DQAsomes could target delivering therapeutical agent to mitochondria and inducing mitochondria-driven apoptosis process. In vivo antitumor assay suggested that HPS-DQAsomes could reach favorable antitumor activity due to both tumor targetability and sub-organelles' targetability. Histological assay also indicated that HPS-DQAsomes showed a strong apoptosis-inducing effect. No obvious systematic toxicity of HPS-DQAsomes could be observed.In summary, multifunctional HPS-DQAsomes provide a novel and versatile approach for overcoming MDR via mitochondrial pathway in cancer treatment.

SUBMITTER: Shi M

PROVIDER: S-EPMC6054761 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Mitochondria-targeted delivery of doxorubicin to enhance antitumor activity with HER-2 peptide-mediated multifunctional pH-sensitive DQAsomes.

Shi Menghao M Zhang Jiulong J Li Xiaowei X Pan Shuang S Li Jie J Yang Chunrong C Hu Haiyang H Qiao Mingxi M Chen Dawei D Zhao Xiuli X

International journal of nanomedicine 20180718

<h4>Introduction</h4>Multidrug resistance (MDR) of breast cancer is the major challenge to successful chemotherapy while mitochondria-targeting therapy was a promising strategy to overcome MDR.<h4>Materials and methods</h4>In this study, HER-2 peptide-PEG<sub>2000</sub>-Schiff base-cholesterol (HPSC) derivate was synthesized successfully and incorporated it on the surface of the doxorubicin (DOX)-loaded dequalinium (DQA) chloride vesicle (HPS-DQAsomes) to treat drug-resistant breast cancer. Eval ...[more]

PMID: 30140154

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Project description:In this study, we investigated the potential of a dual-targeted pH-sensitive doxorubicin prodrug-microbubble complex (DPMC) in ultrasound (US)-assisted antitumor therapy. The doxorubicin prodrug (DP) consists of a succinylated-heparin carrier conjugated with doxorubicin (DOX) via hydrazone linkage and decorated with dual targeting ligands, folate and cRGD peptide. Combination of microbubble (MB) and DP, generated via avidin-biotin binding, promoted intracellular accumulation and improved therapeutic efficiency assisted by US cavitation and sonoporation. Aggregates of prepared DP were observed with an inhomogeneous size distribution (average diameters: 149.6±29.8 nm and 1036.2±38.8 nm, PDI: 1.0) while DPMC exhibited a uniform distribution (average diameter: 5.804±2.1 μm), facilitating its usage for drug delivery. Notably, upon US exposure, DPMC was disrupted and aggregated DP dispersed into homogeneous small-sized nanoparticles (average diameter: 128.6±42.3 nm, PDI: 0.21). DPMC could target to angiogenic endothelial cells in tumor region via αvβ3-mediated recognition and subsequently facilitate its specific binding to tumor cells mediated via recognition of folate receptor (FR) after US exposure. In vitro experiments showed higher tumor specificity and killing ability of DPMC with US than free DOX and DP for breast cancer MCF-7 cells. Furthermore, significant accumulation and specificity for tumor tissues of DPMC with US were detected using in vivo fluorescence and ultrasound molecular imaging, indicating its potential to integrate tumor imaging and therapy. In particular, through inducing apoptosis, inhibiting cell proliferation and antagonizing angiogenesis, DPMC with US produced higher tumor inhibition rates than DOX or DPMC without US in MCF-7 xenograft tumor-bearing mice while inducing no obvious body weight loss. Our strategy provides an effective platform for the delivery of large-sized or aggregated particles to tumor sites, thereby extending their therapeutic applications in vivo.

Dataset Information

Mitochondria-targeted delivery of doxorubicin to enhance antitumor activity with HER-2 peptide-mediated multifunctional pH-sensitive DQAsomes.

Publications

Mitochondria-targeted delivery of doxorubicin to enhance antitumor activity with HER-2 peptide-mediated multifunctional pH-sensitive DQAsomes.

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