Anti-angiogenic treatment of endometriosis via anti-VEGFA siRNA delivery by means of peptide-based carrier in a rat subcutaneous model

Egorova, Anna; Petrosyan, M. A.; Maretina, Marianna; Balashova, N. N.; Polyanskih, Lyudmila; Baranov, V. S.; Kiselev, Anton

doi:10.1038/s41434-018-0042-7

Cited by 25 publications

(32 citation statements)

References 36 publications

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“…RNAi-mediated down-regulation of VEGFA gene expression was achieved in the EA.Hy926 cell line (hybridoma of primary HUVEC and A549 cells) which reproduces the main morphological, phenotypical and functional features of the endothelium [ 43 ]. VEGFA is a key regulator of angiogenesis and silencing of its expression is a promising approach to anti-angiogenic therapy of cancer and some other diseases related to pathological angiogenesis e.g., choroidal neovascularization and endometriosis [ 4 , 44 , 45 ]. The most efficient RGD1/siRNA polyplexes formed at 8/1 and 16/1 charge ratios were tested for their ability to down-regulate gene expression.…”

Section: Resultsmentioning

confidence: 99%

“…According to the results in Figure 10 b, VEGFA gene expression was decreased by RGD1-mediated anti-VEGFA siRNA delivery by 28.74% and 41.9%, respectively. Previously, we have shown that similar silencing of VEGFA gene expression resulted in significant anti-angiogenic effects in endothelial cell modeland in rat model of endometriosis [ 44 , 46 ]. Thus, RGD1-polyplexes can be suggested as siRNA-carriers in anti-angiogenic therapeutic RNAi.…”

Section: Resultsmentioning

confidence: 99%

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Characterization of iRGD-Ligand Modified Arginine-Histidine-Rich Peptides for Nucleic Acid Therapeutics Delivery to αvβ3 Integrin-Expressing Cancer Cells

et al. 2020

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Efficient and specific delivery of nucleic acid (NA) therapeutics to tumor cells is extremely important for cancer gene therapy. Various therapeutic strategies include delivery of DNA-therapeutics such as immunostimulatory or suicide genes and delivery of siRNA-therapeutics able to silence expression of cancer-related genes. Peptides are a promising class of non-viral vehicles which are biodegradable and can efficiently condense, protect and specifically deliver NA to the cells. Here we designed arginine-histidine-rich peptide carriers consisting of an iRGD ligand to target αvβ3 integrins and studied them as vehicles for DNA and siRNA delivery to cancer cells. Combination of iRGD-modified and unmodified arginine–histidine-rich peptides during NA complexation resulted in carriers with different ligand contents. The NA-binding and protecting properties in vitro transfection efficiency and cytotoxicity of the DNA- and siRNA-polyplexes were studied and the most efficient carrier RGD1 was determined. The ability of the peptides to mediate specific intracellular uptake was confirmed inhuman cervical carcinoma (HeLa), human kidney (293T) and human pancreatic (PANC-1) cell lines with different αvβ3 integrins surface expression. By means of RGD1 carrier, efficient delivery of the herpes simplex virus (HSV-1) thymidine kinase gene to PANC-1 cells was demonstrated. Subsequent ganciclovir treatment led to a reduction of PANC-1 cells’ viability by up to 54%. Efficient RNAi-mediated down-regulation of GFP and VEGFA gene expression was achieved in MDA-MB-231-GFP+ breast cancer and EA.hy926 endothelial cells, respectively, by means of RGD1/siRNA polyplexes. Here we demonstrated that the peptide carrier RGD1 can be considered as promising candidate for development of NA therapeutics delivery systems useful in cancer gene therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Characterization of iRGD-Ligand Modified Arginine-Histidine-Rich Peptides for Nucleic Acid Therapeutics Delivery to αvβ3 Integrin-Expressing Cancer Cells

et al. 2020

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“…Total RNA extraction and quantitative real-time PCR analysis was performed as previously described [36,38]. The following primers were used: VEGFR1 forward primer 5′-GAGCTAAAA ATCTTGACCCACATTG-3′, reverse primer 5′-CAGTATTCAACAATCACCATCAGAG-3′; endoglin forward primer 5′-TGGTACATCTACTCGCACACGC-3′, reverse primer 5′-GGCTATGCCATGCTG CTGGTGG-3′; and endogenous reference gene β-actin was detected using forward 5′-TGCCGACAGGATGCAGAAG-3′, reverse primer 5′-GCCGATCCACACGGAGTACT-3′.…”

Section: Methodsmentioning

confidence: 99%

“…Moreover, SDF1 plays an important role during neoangiogenesis by being a main recruiter of endothelial progenitor cells [34]. The targeted delivery via CXCR4 was achieved in our previous studies by using modular peptide carriers modified with ligand derived from the N-terminus of SDF1 [31,35,36,37,38,39]. The developed carriers were based on cationic cysteine-flanked cross-linking peptides that can effectively bind and protect DNA and RNA fromnuclease degradation [35,36,37].…”

Section: Introductionmentioning

confidence: 99%

“…Achieved VEGFA gene silencing by means of RNAi resulted in a significant decrease of VEGFA protein production and the rate of endothelial cell migration. Polyplexes were formed by anti-VEGFA siRNA and the most efficient peptide carrier L1 was tested using an in vivo treatment of endometriosis in a rat subcutaneous model [38]. Significantinhibition of endometriotic implants growth (55–60%) and a two-fold decrease in VEGFA gene expression were demonstrated.…”

Section: Introductionmentioning

confidence: 99%

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Synergistic Anti-Angiogenic Effects Using Peptide-Based Combinatorial Delivery of siRNAs Targeting VEGFA, VEGFR1, and Endoglin Genes

et al. 2019

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Angiogenesis is a process of new blood vessel formation, which plays a significant role in carcinogenesis and the development of diseases associated with pathological neovascularization. An important role in the regulation of angiogenesis belongs to several key pathways such as VEGF-pathways, TGF-β-pathways, and some others. Introduction of small interfering RNA (siRNA) against genes of pro-angogenic factors is a promising strategy for the therapeutic suppression of angiogenesis. These siRNA molecules need to be specifically delivered into endothelial cells, and non-viral carriers modified with cellular receptor ligands can be proposed as perspective delivery systems for anti-angiogenic therapy purposes. Here we used modular peptide carrier L1, containing a ligand for the CXCR4 receptor, for the delivery of siRNAs targeting expression of VEGFA, VEGFR1 and endoglin genes. Transfection properties of siRNA/L1 polyplexes were studied in CXCR4-positive breast cancer cells MDA-MB-231 and endothelial cells EA.Hy926. We have demonstrated the efficient down-regulation of endothelial cells migration and proliferation by anti-VEGFA, anti-VEGFR1, and anti-endoglin siRNA-induced silencing. It was found that the efficiency of anti-angiogenic treatment can be synergistically improved via the combinatorial delivery of anti-VEGFA and anti-VEGFR1 siRNAs. Thus, this approach can be useful for the development of therapeutic angiogenesis inhibition.

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Endometriosis, the Silent Disease: Molecular Targets, Active Principles, and Drug Delivery Systems

Teworte

Luciani

2022

Helvetica Chimica Acta

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In this perspective, we provide a broad overview of pathophysiological processes involved in endometriosis, including the role of inflammation, fibrosis, angiogenesis, hormonal regulation, and genetic factors. For each of the functional changes involved with the etiology of the disease, we showcase a selection of active principles in various stages of preclinical and clinical development. Finally, we highlight the role of drug delivery for endometriosis, particularly oral vs. vaginal administration. In doing so, we wish to draw the community's attention to this debilitating disease and highlight the need for interdisciplinary approaches to endometriosis treatment development.

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Anti-angiogenic treatment of endometriosis via anti-VEGFA siRNA delivery by means of peptide-based carrier in a rat subcutaneous model

Cited by 25 publications

References 36 publications

Characterization of iRGD-Ligand Modified Arginine-Histidine-Rich Peptides for Nucleic Acid Therapeutics Delivery to αvβ3 Integrin-Expressing Cancer Cells

Characterization of iRGD-Ligand Modified Arginine-Histidine-Rich Peptides for Nucleic Acid Therapeutics Delivery to αvβ3 Integrin-Expressing Cancer Cells

Synergistic Anti-Angiogenic Effects Using Peptide-Based Combinatorial Delivery of siRNAs Targeting VEGFA, VEGFR1, and Endoglin Genes

Endometriosis, the Silent Disease: Molecular Targets, Active Principles, and Drug Delivery Systems

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