Overcoming Multidrug Resistance by Codelivery of MDR1-Targeting siRNA and Doxorubicin Using EphA10-Mediated pH-Sensitive Lipoplexes: In Vitro and In Vivo Evaluation

Zhang, Jiulong; Du, Zhouqi; Pan, Shengli; Shi, Menghao; Li, Jie; Yang, Chunrong; Hu, Haiyang; Qiao, Mingxi; Chen, Dawei

doi:10.1021/acsami.8b01806

Cited by 51 publications

(38 citation statements)

References 41 publications

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“…We further uncovered that US could increase ROS activity, but could not significantly decrease P-gp expression in these cells. Our results are similar to previous studies showing targeting P-gp was less effective in treating MCF-7 cells than that in treating MCF-7/ADR cells [ 55 , 56 ]. These probably result from the rather low baseline level of P-gp expression in drug-sensitive cells, which decreases the silence efficiency [ 56 ].…”

Section: Discussionsupporting

confidence: 92%

The effects of ultrasound exposure on P-glycoprotein-mediated multidrug resistance in vitro and in vivo

Huang

Huang²,

et al. 2018

J Exp Clin Cancer Res

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BackgroundMultidrug resistance (MDR) is often responsible for the failure of chemotherapy treatment, and current strategies for cancer MDR are not adequately satisfying as to their efficacy and safety. In this study, we sought to determine the anti-MDR effects of ultrasound (US) irradiation and its underlying mechanisms against drug-resistance.MethodsMDR variant MCF-7/ADR cell lines and endothelial cell lines were used to determine the appropriate ultrasound intensity for in vitro experiments. MCF-7/ADR cell and HEPG2/ADM cells were used to assess the anti-MDR effect of US irradiation. Intracellular adriamycin (ADM) accumulation, Cell viability, cell proliferation and cell apoptosis were evaluated after ADM + US treatment or ADM treatment alone. MCF-7/ADR xenograft mice were used to investigate the appropriate ultrasound intensity for in vivo experiments and its effect on the long-term prognosis. Underlining mechanisms by which ultrasound exposure reversing MDR phenotype were investigated both in vitro and in vivo.ResultsCombination of ADM and 0.74 W/cm2 US irradiation enhanced ADM intracellular concentration and nuclear accumulation in MCF-7/ADR and HEPG2/ADM cells, compared to those treated with ADM alone. Enhanced cellular ADM uptake and nuclei localization was associated with increased cytotoxicity of ADM to ADM-resistant cells, lower ADM-resistant cell viability and proliferative cell ratio, and higher apoptotic cell ratio. More importantly, US exposure increased the effectiveness of ADM to inhibit tumor growth in MCF-7/ADR xenograft mice. Mechanistically, US exposure promoted ADM accumulation in MDR cells mainly through down-regulation of P-glycoprotein (P-gp), which is dependent on US-induced intracellular reactive oxygen species (ROS) production. US-induced oxidative stress promoted miR-200c-3p and miR-34a-3p expression by forming miR-200c/34a/ZEB1 double-negative feedback loop. Finally, US-induced miR-200c/34a overexpression decreased P-gp expression and reversed MDR phenotype.ConclusionUS irradiation could reverse MDR phenotype by activating ROS-ZEB1-miR200c/34a-P-gp signal pathway. Our findings offer a new and promising strategy for sensitizing cells to combat MDR and to improve the therapeutic index of chemotherapy.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0900-6) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 92%

The effects of ultrasound exposure on P-glycoprotein-mediated multidrug resistance in vitro and in vivo

Huang

Huang²,

et al. 2018

J Exp Clin Cancer Res

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“…Therefore, a 50% reduction of p-glycoprotein levels by TD3/MDR1gap-ON is sufficient to restore the sensitivity of cells to vinblastine and to decrease the cell viability in the presence of vinblastine by 40–45% ( Figure 3 , Figure 4 , and Figure 12 ). In vivo suppression of MDR1 gene expression has been examined in a number of works [ 70 , 71 , 72 , 73 , 74 ] where xenograft models showed a decrease in tumor growth during chemotherapy combined with MDR1 silencing. However, in these studies, the silencing of MDR1 expression was achieved by using siRNA and the delivery was performed by liposomes, which may have side effects, including immunostimulation.…”

Section: Discussionmentioning

confidence: 99%

Transport Oligonucleotides—A Novel System for Intracellular Delivery of Antisense Therapeutics

et al. 2020

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Biological activity of antisense oligonucleotides (asON), especially those with a neutral backbone, is often attenuated by poor cellular accumulation. In the present proof-of-concept study, we propose a novel delivery system for asONs which implies the delivery of modified antisense oligonucleotides by so-called transport oligonucleotides (tON), which are oligodeoxyribonucleotides complementary to asON conjugated with hydrophobic dodecyl moieties. Two types of tONs, bearing at the 5′-end up to three dodecyl residues attached through non-nucleotide inserts (TD series) or anchored directly to internucleotidic phosphate (TP series), were synthesized. tONs with three dodecyl residues efficiently delivered asON to cells without any signs of cytotoxicity and provided a transfection efficacy comparable to that achieved using Lipofectamine 2000. We found that, in the case of tON with three dodecyl residues, some tON/asON duplexes were excreted from the cells within extracellular vesicles at late stages of transfection. We confirmed the high efficacy of the novel and demonstrated that MDR1 mRNA targeted asON delivered by tON with three dodecyl residues significantly reduced the level of P-glycoprotein and increased the sensitivity of KB-8-5 human carcinoma cells to vinblastine. The obtained results demonstrate the efficacy of lipophilic oligonucleotide carriers and shows they are potentially capable of intracellular delivery of any kind of antisense oligonucleotides.

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“…9−12 To improve delivery to specific cell types, functionalization of the nanoparticle surface with ligands that target cell-specific receptors is successfully used in vitro as well as in vivo. 13−16…”

Section: Cellular Uptake Of Gene Delivery Vectorsmentioning

confidence: 99%

Carriers Break Barriers in Drug Delivery: Endocytosis and Endosomal Escape of Gene Delivery Vectors

et al. 2019

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ConspectusOver the past decades, major efforts were undertaken to develop devices on a nanoscale level for the efficient and nontoxic delivery of molecules to tissues and cells, for the purpose of either diagnosis or treatment of disease. The application of such devices in drug delivery has proven to be beneficial for matters as diverse as drug solubility, drug targeting, controlled drug release, and transport of drugs across cellular barriers. Multiple nanotherapeutics have been approved for clinical treatment, and more products are being evaluated in preclinical and clinical trials. However, many biological barriers hinder the medical application of nanocarriers. There are two main classes of barriers that need to be overcome by drug nanocarriers: extracellular and intracellular barriers, both of which may capture and/or destroy therapeutics before they reach their target site. This Account discusses major biological barriers that are confronted by nanotherapeutics, following their systemic administration, focusing on cellular entry and endosomal escape of gene delivery vectors. The use of pH-responsive materials to overcome the endosomal barrier is addressed.Historically, cell biologists have studied the interaction between cells and pathogens in order to unveil the mechanisms of endocytosis and cell signaling. Meanwhile, it is becoming clear that cells may respond in similar ways to artificial drug delivery systems and, consequently, that knowledge on the cellular response against both pathogens and nanoparticulate systems will aid in the design of improved nanomedicine. A close collaboration between bioengineers and cell biologists will promote this development. At the same time, we have come to realize that tools that we use to study fundamental cellular processes, including metabolic inhibitors of endocytosis and overexpression/downregulation of proteins, may cause changes in cellular physiology. This calls for the implementation of refined methods to study nanocarrier–cell interactions, as is discussed in this Account.Finally, recent papers on the dynamics of cargo release from endosomes by means of live cell imaging have significantly advanced our understanding of the transfection process. They have initiated discussion (among others) on the limited number of endosomal escape events in transfection, and on the endosomal stage at which genetic cargo is most efficiently released. Advancements in imaging techniques, including super-resolution microscopy, in concert with techniques to label endogenous proteins and/or label proteins with synthetic fluorophores, will contribute to a more detailed understanding of nanocarrier-cell dynamics, which is imperative for the development of safe and efficient nanomedicine.

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Overcoming Multidrug Resistance by Codelivery of MDR1-Targeting siRNA and Doxorubicin Using EphA10-Mediated pH-Sensitive Lipoplexes: In Vitro and In Vivo Evaluation

Cited by 51 publications

References 41 publications

The effects of ultrasound exposure on P-glycoprotein-mediated multidrug resistance in vitro and in vivo

The effects of ultrasound exposure on P-glycoprotein-mediated multidrug resistance in vitro and in vivo

Transport Oligonucleotides—A Novel System for Intracellular Delivery of Antisense Therapeutics

Carriers Break Barriers in Drug Delivery: Endocytosis and Endosomal Escape of Gene Delivery Vectors

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