Extracellular vesicle (ECV)-modified polyethylenimine (PEI) complexes for enhanced siRNA delivery in vitro and in vivo

Zhupanyn, Petro; Ewe, Alexander; Büch, Thomas; Malek, Anastasia; Rademacher, Phil; Müller, Claudia; Reinert, Anja; Jaimes, Yarúa; Aigner, Achim

doi:10.1016/j.jconrel.2019.12.032

Cited by 118 publications

(93 citation statements)

References 73 publications

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“…Complex sizes in the range of ~ 130 nm, an irregular shape of the complexes, as visualized by TEM, and a positive zeta potential of ~ 28 mV, as determined by Phase Analysis Light Scattering (PALS; Fig. 2 c, right), were very similar to previously described PEI/siRNA complexes (see e.g., [ 39 , 40 ]). Concomitantly, efficient uptake of PEI/antimiR complexes containing Cy3-labeled antimiRs was observed.…”

Section: Resultssupporting

confidence: 81%

Nanoparticle-complexed antimiRs for inhibiting tumor growth and metastasis in prostate carcinoma and melanoma

et al. 2020

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Background MiRNAs act as negative regulators of gene expression through target mRNA degradation or inhibition of its translation. In cancer, several miRNAs are upregulated and play crucial roles in tumorigenesis, making the inhibition of these oncomiRs an interesting therapeutic approach. This can be achieved by directly complementary single-stranded anti-miRNA oligonucleotides (antimiRs). A major bottleneck in antimiR therapy, however, is their efficient delivery. The nanoparticle formation with polyethylenimine (PEI) may be particularly promising, based on the PEI’s ability to electrostatically interact with oligonucleotides. This leads to their protection and supports delivery. In the present study, we explore for the first time PEI for antimiR formulation and delivery. We use the branched low molecular weight PEI F25-LMW for the complexation of different antimiRs, and analyse tumor- and metastasis-inhibitory effects of PEI/antimiR complexes in different tumor models. Results In prostate carcinoma, transfection of antimiRs against miR-375 and miR-141 leads to tumor cell inhibition in 2D- and 3D-models. More importantly, an in vivo tumor therapy study in prostate carcinoma xenografts reveals anti-tumor effects of the PEI/antimiR complexes. In advanced melanoma and metastasis, we identify by a microRNA screen miR-150 as a particularly relevant oncomiR candidate, and validate this result in vitro and in vivo. Again, the systemic application of PEI/antimiR complexes inhibiting this miRNA, or the previously described antimiR-638, leads to profound tumor growth inhibition. These effects are associated with the upregulation of direct miRNA target genes. In a melanoma metastasis mouse model, anti-metastatic effects of PEI/antimiR treatment are observed as well. Conclusions We thus describe PEI-based complexes as efficient platform for antimiR therapy, as determined in two different tumor entities using in vivo models of tumor growth or metastasis. Our study also highlights the therapeutic relevance of miR-375, miR-141, miR-150 and miR-638 as target miRNAs for antimiR-mediated inhibition.

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Section: Resultssupporting

confidence: 81%

Nanoparticle-complexed antimiRs for inhibiting tumor growth and metastasis in prostate carcinoma and melanoma

et al. 2020

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“…They demonstrated high knockdown efficacy in mrR-155 and miR-1246 genes of the PEI/siRNA modified with ECV. These results could be associated with the PEIs structure which makes possible the formation of non-covalent complexes with RNA molecules [233]. Table 4 summarizes the most recent application of polymeric nanoparticles in cancer therapy.…”

Section: Polymeric Nanoparticlesmentioning

confidence: 99%

Gene Therapy in Cancer Treatment: Why Go Nano?

et al. 2020

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The proposal of gene therapy to tackle cancer development has been instrumental for the development of novel approaches and strategies to fight this disease, but the efficacy of the proposed strategies has still fallen short of delivering the full potential of gene therapy in the clinic. Despite the plethora of gene modulation approaches, e.g., gene silencing, antisense therapy, RNA interference, gene and genome editing, finding a way to efficiently deliver these effectors to the desired cell and tissue has been a challenge. Nanomedicine has put forward several innovative platforms to overcome this obstacle. Most of these platforms rely on the application of nanoscale structures, with particular focus on nanoparticles. Herein, we review the current trends on the use of nanoparticles designed for cancer gene therapy, including inorganic, organic, or biological (e.g., exosomes) variants, in clinical development and their progress towards clinical applications.

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“…Silencing of Bcl-2 using siRNA induces apoptosis in cancer cells and diminishes their proliferation [ 71 ]. Thus, we are increasingly witnessing the potential of siRNA in cancer therapy and how siRNA treatment can be used as a tool to accelerate our pace in the treatment and eradication of cancer(s) [ 72 ]. A study was conducted on using siRNA tools in the treatment of cancer patients.…”

Section: Sirna Structure and Function: A Brief Overviewmentioning

confidence: 99%

Progress in Delivery of siRNA-Based Therapeutics Employing Nano-Vehicles for Treatment of Prostate Cancer

et al. 2020

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Prostate cancer (PCa) accounts for a high number of deaths in males with no available curative treatments. Patients with PCa are commonly diagnosed in advanced stages due to the lack of symptoms in the early stages. Recently, the research focus was directed toward gene editing in cancer therapy. Small interfering RNA (siRNA) intervention is considered as a powerful tool for gene silencing (knockdown), enabling the suppression of oncogene factors in cancer. This strategy is applied to the treatment of various cancers including PCa. The siRNA can inhibit proliferation and invasion of PCa cells and is able to promote the anti-tumor activity of chemotherapeutic agents. However, the off-target effects of siRNA therapy remarkably reduce its efficacy in PCa therapy. To date, various carriers were designed to improve the delivery of siRNA and, among them, nanoparticles are of importance. Nanoparticles enable the targeted delivery of siRNAs and enhance their potential in the downregulation of target genes of interest. Additionally, nanoparticles can provide a platform for the co-delivery of siRNAs and anti-tumor drugs, resulting in decreased growth and migration of PCa cells. The efficacy, specificity, and delivery of siRNAs are comprehensively discussed in this review to direct further studies toward using siRNAs and their nanoscale-delivery systems in PCa therapy and perhaps other cancer types.

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Extracellular vesicle (ECV)-modified polyethylenimine (PEI) complexes for enhanced siRNA delivery in vitro and in vivo

Cited by 118 publications

References 73 publications

Nanoparticle-complexed antimiRs for inhibiting tumor growth and metastasis in prostate carcinoma and melanoma

Nanoparticle-complexed antimiRs for inhibiting tumor growth and metastasis in prostate carcinoma and melanoma

Gene Therapy in Cancer Treatment: Why Go Nano?

Progress in Delivery of siRNA-Based Therapeutics Employing Nano-Vehicles for Treatment of Prostate Cancer

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