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Nanoparticle delivery of a pH-sensitive prodrug of doxorubicin and a mitochondrial targeting VES-H₈R₈ synergistically kill multi-drug resistant breast cancer cells.

ABSTRACT: Multi-drug resistance (MDR) remains a major obstacle in cancer treatment while being heavily dependent on mitochondrial activity and drug efflux. We previously demonstrated that cationic lipids, such as the vitamin E succinate modified octahistidine-octaarginine (VES-H₈R₈) conjugate, target mitochondria, resulting in depolarized mitochondria and inhibited drug efflux in MDR breast cancer cells. We hypothesized that the effective cell uptake, efflux inhibition, and mitochondrial depolarization properties of VES-H₈R₈ would synergistically enhance the toxicity of a pH-sensitive prodrug of doxorubicin (pDox) when co-encapsulated in nanoparticles (NPs). pDox was successfully synthesized and validated for pH-sensitive release from NPs under lysosome-mimicking, acidic conditions. The synergistic effect of VES-H₈R₈ and pDox was confirmed against MDR breast cancer cells in vitro. Importantly, synergism was only observed when VES-H₈R₈ and pDox were co-encapsulated in a single nanoparticulate system. The synergistic mechanism was investigated, confirming superior pDox uptake and retention, Pgp efflux inhibition, mitochondrial depolarization, and enhanced induction of ROS, and apoptosis. This work demonstrates the translational potential of doubly-loaded NPs co-encapsulating pDox with VES-H₈R₈ to synergistically kill MDR breast cancer cells.

SUBMITTER: Czupiel P

PROVIDER: S-EPMC7251113 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Nanoparticle delivery of a pH-sensitive prodrug of doxorubicin and a mitochondrial targeting VES-H8R8 synergistically kill multi-drug resistant breast cancer cells.

Czupiel Petro P Delplace Vianney V Shoichet Molly M

Scientific reports 20200526 1

Multi-drug resistance (MDR) remains a major obstacle in cancer treatment while being heavily dependent on mitochondrial activity and drug efflux. We previously demonstrated that cationic lipids, such as the vitamin E succinate modified octahistidine-octaarginine (VES-H8R8) conjugate, target mitochondria, resulting in depolarized mitochondria and inhibited drug efflux in MDR breast cancer cells. We hypothesized that the effective cell uptake, efflux inhibition, and mitochond ...[more]

PMID: 32457422

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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

Nanoparticle delivery of a pH-sensitive prodrug of doxorubicin and a mitochondrial targeting VES-H₈R₈ synergistically kill multi-drug resistant breast cancer cells.

Publications

Nanoparticle delivery of a pH-sensitive prodrug of doxorubicin and a mitochondrial targeting VES-H<sub>8</sub>R<sub>8</sub> synergistically kill multi-drug resistant breast cancer cells.

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