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

Abstract

IntroductionMultidrug resistance (MDR) of breast cancer is the major challenge to successful chemotherapy while mitochondria-targeting therapy was a promising strategy to overcome MDR.Materials and methodsIn 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).ResultsThe 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.ConclusionIn summary, multifunctional HPS-DQAsomes provide a novel and versatile approach for overcoming MDR via mitochondrial pathway in cancer treatment.

Peptide functionalized liposomes for receptor targeted cancer therapy

“… 55,56 Using the antibody as a template, Shi et al synthesized an HER-2 peptide analog, sequence YCDGFYACYMDV, which showed increased tumoral delivery of doxorubicin-loaded and pH-sensitive liposomes toward multidrug-resistant MCF-7 breast cancer cells. 56 In this study, they showed a strong increase in mitochondrial localization compared to other organelles, which is important for increasing mitochondrial-driven apoptosis. Zahmatkeshan and coworkers also studied HER2 targeting with a different peptide and Anti-HER2/neu peptide (AHNP) with sequence FCDGFYACYADV, this time to improve localization of doxorubicin-loaded PEGylated liposomes.…”

Differential Effects of the Mitochondria-Active Tetrapeptide SS-31 (D-Arg-dimethylTyr-Lys-Phe-NH2) and Its Peptidase-Targeted Prodrugs in Experimental Acute Kidney Injury

“…As ROS also play important roles in normal physiology, chronic inhibition of ROS may result in off-target responses and side effects. Previous attempts have been done to increase mitochondria targeting of therapeutic drugs, mostly using conjugation of agents to various compounds (Wolf et al, 1997, Wolf et al, 2000), including nanoparticles (Hidaka et al, 2017; Akhmadishina et al, 2018; Battogtokh et al, 2018; Mattarei et al, 2018; Shi et al, 2018). We have previously shown that high enzymatic activities of the peptidases APA and γ-GT in diseased human and rat kidneys may represent targets to develop prodrug therapeutics (Juillerat-Jeanneret et al, 1992; Juillerat-Jeanneret et al, 2015).…”

<p>RASSF6 Is Downregulated In Human Bladder Cancers And Regulates Doxorubicin Sensitivity And Mitochondrial Membrane Potential Via The Hippo Signaling Pathway</p>

“…Our current findings revealed the role of RASSF6 as a positive regulator of chemosensitivity. It has been reported that mitochondria are involved in apoptosis, and chemotherapeutic drugs induce apoptosis through mitochondria-dependent pathways 8–10. The JC-1 staining assay was first performed to examine Δψm to characterize the role of RASSF6 on mitochondrial function.…”