{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:47:28Z","timestamp":1790812048975,"version":"4.1.0"},"reference-count":58,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T00:00:00Z","timestamp":1669766400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["21-15-00111"],"award-info":[{"award-number":["21-15-00111"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Uterine leiomyoma is the most common benign tumor of the reproductive system. Current therapeutic options do not simultaneously meet the requirements of long-term efficiency and fertility preservation. Suicide gene delivery can be proposed as a novel approach to uterine leiomyoma therapy. Non-viral vehicles are an attractive approach to DNA delivery for gene therapy of both malignant and benign tumors. Peptide-based vectors are among the most promising candidates for the development of artificial viruses, being able to efficiently cross barriers of DNA transport to cells. Here we described nanoparticles composed of cysteine-crosslinked polymer and histidine-arginine-rich peptide modified with iRGD moiety and characterized them as vehicles for plasmid DNA delivery to pancreatic cancer PANC-1 cells and the uterine leiomyoma cell model. Several variants of nanoparticles were formulated with different targeting ligand content. The physicochemical properties that were studied included DNA binding and protection, interaction with polyanions and reducing agents, size, structure and zeta-potential of the peptide-based nanoparticles. Cytotoxicity, cell uptake and gene transfection efficiency were assessed in PANC-1 cells with GFP and LacZ-encoding plasmids. The specificity of gene transfection via \u03b1v\u03b23 integrin binding was proved in competitive transfection. The therapeutic potential was evaluated in a uterine leiomyoma cell model using the suicide gene therapy approach. The optimal formulation was found to be at the polyplex with the highest iRGD moiety content being able to transfect cells more efficiently than control PEI. Suicide gene therapy using the best formulation resulted in a significant decrease of uterine leiomyoma cells after ganciclovir treatment. It can be concluded that the application of iRGD-modified peptide-based nanoparticles has a high potential for cellular delivery of DNA therapeutics in favor of uterine leiomyoma gene therapy.<\/jats:p>","DOI":"10.3390\/molecules27238363","type":"journal-article","created":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T08:46:41Z","timestamp":1669798001000},"page":"8363","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Peptide-Based Nanoparticles for \u03b1v\u03b23 Integrin-Targeted DNA Delivery to Cancer and Uterine Leiomyoma Cells"],"prefix":"10.3390","volume":"27","author":[{"given":"Anna","family":"Egorova","sequence":"first","affiliation":[{"name":"Department of Genomic Medicine, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Mendeleevskaya Line 3, 199034 Saint-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Selutin","sequence":"additional","affiliation":[{"name":"Department of Immunology and Intercellular Interactions, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Mendeleevskaya Line 3, 199034 Saint-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Maretina","sequence":"additional","affiliation":[{"name":"Department of Genomic Medicine, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Mendeleevskaya Line 3, 199034 Saint-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergei","family":"Selkov","sequence":"additional","affiliation":[{"name":"Department of Immunology and Intercellular Interactions, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Mendeleevskaya Line 3, 199034 Saint-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2487-2423","authenticated-orcid":false,"given":"Anton","family":"Kiselev","sequence":"additional","affiliation":[{"name":"Department of Genomic Medicine, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Mendeleevskaya Line 3, 199034 Saint-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.ijpharm.2013.11.041","article-title":"Gene therapy and DNA delivery systems","volume":"459","author":"Ibraheem","year":"2014","journal-title":"Int. J. Pharm."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1128\/CMR.11.1.42","article-title":"Gene Therapy for Infectious Diseases","volume":"11","author":"Bunnell","year":"1998","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_3","first-page":"138","article-title":"Gene therapy for cardiovascular disease","volume":"2003","author":"Dishart","year":"2003","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1002\/ppul.25055","article-title":"Overview of gene therapy in spinal muscular atrophy and Duchenne muscular dystrophy","volume":"56","author":"Abreu","year":"2021","journal-title":"Pediatr. Pulmonol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Maule, G., Arosio, D., and Cereseto, A. (2020). Gene Therapy for Cystic Fibrosis: Progress and Challenges of Genome Editing. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21113903"},{"key":"ref_6","first-page":"13","article-title":"Progress towards gene therapy for HIV-infection","volume":"1","author":"Yu","year":"1994","journal-title":"Gene Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e3015","DOI":"10.1002\/jgm.3015","article-title":"Gene therapy clinical trials worldwide to 2017: An update","volume":"20","author":"Ginn","year":"2018","journal-title":"J. Gene Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1093\/jnci\/82.4.297","article-title":"Curability of Tumors Bearing Herpes Thymidine Kinase Genes Transfered by Retroviral Vectors","volume":"82","author":"Moolten","year":"1990","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1177\/1933719116630413","article-title":"Targeted Adenoviral Vector Demonstrates Enhanced Efficacy for In Vivo Gene Therapy of Uterine Leiomyoma","volume":"23","author":"Abdelaziz","year":"2016","journal-title":"Reprod. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"169","DOI":"10.2174\/18722156113079990021","article-title":"Recent Advances in Gene Therapy of Endometriosis","volume":"7","author":"Shubina","year":"2014","journal-title":"Recent Pat. DNA Gene Seq."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1038\/nbt1216","article-title":"Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integration","volume":"24","author":"Montini","year":"2006","journal-title":"Nat. Biotechnol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1134\/S0006297916070063","article-title":"Viral vectors for gene therapy: Current state and clinical perspectives","volume":"81","author":"Lukashev","year":"2016","journal-title":"Biochem. Biokhimiia"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/j.hoc.2017.06.007","article-title":"Nonintegrating Gene Therapy Vectors","volume":"31","author":"Athanasopoulos","year":"2017","journal-title":"Hematol. Oncol. Clin. North Am."},{"key":"ref_14","first-page":"3","article-title":"Non-viral and viral vectors for gene therapy","volume":"51","author":"Boulaiz","year":"2005","journal-title":"Cell. Mol. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/35038533","article-title":"Gene therapy: Trials and tribulations","volume":"1","author":"Somia","year":"2000","journal-title":"Nat. Rev. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/S0015-0282(01)03233-2","article-title":"Gene therapy and reproductive medicine","volume":"77","author":"Stribley","year":"2002","journal-title":"Fertil. Steril."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"110173","DOI":"10.1016\/j.micromeso.2020.110173","article-title":"Gene delivery using cell penetrating peptides-zeolitic imidazolate frameworks","volume":"300","author":"Abdelhamid","year":"2020","journal-title":"Microporous Mesoporous Mater."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"330","DOI":"10.2174\/1568026615666150812120755","article-title":"Peptide modules for overcoming barriers of nucleic acids transport to cells","volume":"16","author":"Egorova","year":"2016","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"9506","DOI":"10.1021\/ja0482536","article-title":"Role of Membrane Potential and Hydrogen Bonding in the Mechanism of Translocation of Guanidinium-Rich Peptides into Cells","volume":"126","author":"Rothbard","year":"2004","journal-title":"J. Am. Chem. Soc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.jconrel.2013.11.020","article-title":"Recent progress of cell-penetrating peptides as new carriers for intracellular cargo delivery","volume":"174","author":"Wang","year":"2014","journal-title":"J. Control. Release"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1002\/cbic.200400256","article-title":"Direct Observation of Anion-Mediated Translocation of Fluorescent Oligoarginine Carriers into and across Bulk Liquid and Anionic Bilayer Membranes","volume":"6","author":"Sakai","year":"2005","journal-title":"ChemBioChem"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1101\/gad.5.2.201","article-title":"Analysis of arginine-rich peptides from the HIV Tat protein reveals unusual features of RNA-protein recognition","volume":"5","author":"Calnan","year":"1991","journal-title":"Genes Dev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.jconrel.2006.12.004","article-title":"Optimising histidine rich peptides for efficient DNA delivery in the presence of serum","volume":"118","author":"Mason","year":"2007","journal-title":"J. Control. Release"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e86","DOI":"10.1093\/nar\/gni085","article-title":"A versatile reducible polycation-based system for efficient delivery of a broad range of nucleic acids","volume":"33","author":"Read","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.jconrel.2004.09.018","article-title":"Influence of TAT-peptide polymerization on properties and transfection activity of TAT\/DNA polyplexes","volume":"102","author":"Bisht","year":"2005","journal-title":"J. Control. Release"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1016\/j.ijpharm.2012.10.020","article-title":"Characterization of reducible peptide oligomers as carriers for gene delivery","volume":"441","author":"Kiselev","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Egorova, A., Selutin, A., Maretina, M., Selkov, S., Baranov, V., and Kiselev, A. (2020). Characterization of iRGD-Ligand Modified Arginine-Histidine-Rich Peptides for Nucleic Acid Therapeutics Delivery to \u03b1v\u03b23 Integrin-Expressing Cancer Cells. Pharmaceuticals, 13.","DOI":"10.3390\/ph13100300"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1126\/science.1183057","article-title":"Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs","volume":"328","author":"Sugahara","year":"2010","journal-title":"Science"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1016\/S1359-6446(02)02501-1","article-title":"Drug targeting to specific vascular sites","volume":"7","author":"Ruoslahti","year":"2002","journal-title":"Drug Discov. Today"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"16157","DOI":"10.1073\/pnas.0908201106","article-title":"C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetration","volume":"106","author":"Teesalu","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9367845","DOI":"10.1155\/2019\/9367845","article-title":"iRGD: A Promising Peptide for Cancer Imaging and a Potential Therapeutic Agent for Various Cancers","volume":"2019","author":"Zuo","year":"2019","journal-title":"J. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4028","DOI":"10.1021\/acsnano.8b08177","article-title":"Radiation-Induced Targeted Nanoparticle-Based Gene Delivery for Brain Tumor Therapy","volume":"13","author":"Carvalho","year":"2019","journal-title":"ACS Nano"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Egorova, A., Shtykalova, S., Selutin, A., Shved, N., Maretina, M., Selkov, S., Baranov, V., and Kiselev, A. (2021). Development of iRGD-Modified Peptide Carriers for Suicide Gene Therapy of Uterine Leiomyoma. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13020202"},{"key":"ref_34","first-page":"281","article-title":"Size-dependent internalization of particles via the pathways of clathrin- and caveolae-mediated endocytosis","volume":"377","author":"Raemdonck","year":"2004","journal-title":"Biochem. J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.jconrel.2004.05.004","article-title":"Cytosolic soluble proteins induce DNA release from DNA\u2014Gene carrier complexes","volume":"98","author":"Okuda","year":"2004","journal-title":"J. Control. Release"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.1016\/j.bbagen.2006.09.011","article-title":"An insight into the gene delivery mechanism of the arginine peptide system: Role of the peptide\/DNA complex size","volume":"1760","author":"Choi","year":"2006","journal-title":"Biochim. Biophys. Acta-Gen. Subj."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"15307","DOI":"10.1074\/jbc.272.24.15307","article-title":"Binding of Cationic \u03b1-Helical Peptides to Plasmid DNA and Their Gene Transfer Abilities into Cells","volume":"272","author":"Niidome","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1016\/S0891-5849(01)00480-4","article-title":"Redox environment of the cell as viewed through the redox state of the glutathione disulfide\/glutathione couple","volume":"30","author":"Schafer","year":"2001","journal-title":"Free Radic. Biol. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1002\/path.1437","article-title":"Functional structure and composition of the extracellular matrix","volume":"200","author":"Bosman","year":"2003","journal-title":"J. Pathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"12349","DOI":"10.1073\/pnas.93.22.12349","article-title":"Evidence for the role of proteoglycans in cation-mediated gene transfer","volume":"93","author":"Mislick","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/S0005-2736(98)00199-0","article-title":"Interactions of polymeric and liposomal gene delivery systems with extracellular glycosaminoglycans: Physicochemical and transfection studies","volume":"1415","author":"Ruponen","year":"1999","journal-title":"Biochim. Biophys. Acta-Biomembr."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/S0142-9612(00)00203-9","article-title":"Poly(ethylenimine)-mediated gene delivery affects endothelial cell function and viability","volume":"22","author":"Godbey","year":"2001","journal-title":"Biomaterials"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1021\/bc0700133","article-title":"Cyclic RGD Peptide-Conjugated Polyplex Micelles as a Targetable Gene Delivery System Directed to Cells Possessing \u03b1 v \u03b2 3 and \u03b1 v \u03b2 5 Integrins","volume":"18","author":"Oba","year":"2007","journal-title":"Bioconjugate Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1002\/jgm.331","article-title":"Vectors based on reducible polycations facilitate intracellular release of nucleic acids","volume":"5","author":"Read","year":"2003","journal-title":"J. Gene Med."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Haberland, A., Cartier, R., Heuer, D., Zaitsev, S., Paulke, B.-R., Sch\u00e4fer-Korting, M., and B\u00f6ttger, M. (2005). Structural aspects of histone H1\u2013DNA complexes and their relation to transfection efficiency. Biotechnol. Appl. Biochem., 42.","DOI":"10.1042\/BA20040155"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.jconrel.2010.02.002","article-title":"Antiangiogenic gene therapy of experimental pancreatic tumor by sFlt-1 plasmid DNA carried by RGD-modified crosslinked polyplex micelles","volume":"149","author":"Vachutinsky","year":"2011","journal-title":"J. Control. Release"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/S0140-6736(00)03622-9","article-title":"Uterine fibroids","volume":"357","author":"Stewart","year":"2001","journal-title":"Lancet"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1126\/science.1112063","article-title":"Uterine Fibroids: The Elephant in the Room","volume":"308","author":"Walker","year":"2005","journal-title":"Science"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.jmig.2017.07.007","article-title":"Minimally Invasive Approaches to Myoma Management","volume":"25","author":"Gingold","year":"2018","journal-title":"J. Minim. Invasive Gynecol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.jogoh.2018.10.004","article-title":"The current place of mini-invasive surgery in uterine leiomyoma management","volume":"48","author":"Dubuisson","year":"2019","journal-title":"J. Gynecol. Obstet. Hum. Reprod."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/sj.cgt.7700307","article-title":"Preclinical and therapeutic utility of HVJ liposomes as a gene transfer vector for hepatocellular carcinoma using herpes simplex virus thymidine kinase","volume":"8","author":"Hasegawa","year":"2001","journal-title":"Cancer Gene Ther."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Shved, N., Egorova, A., Osinovskaya, N., and Kiselev, A. (2022). Development of primary monolayer cell model and organotypic model of uterine leiomyoma. Methods Protoc., 5.","DOI":"10.3390\/mps5010016"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Egorova, A., Shtykalova, S., Maretina, M., Selutin, A., Shved, N., Deviatkin, D., Selkov, S., Baranov, V., and Kiselev, A. (2022). Polycondensed Peptide Carriers Modified with Cyclic RGD Ligand for Targeted Suicide Gene Delivery to Uterine Fibroid Cells. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031164"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Shtykalova, S., Egorova, A., Maretina, M., Baranov, V., and Kiselev, A. (2022). Magnetic Nanoparticles as a Component of Peptide-Based DNA Delivery System for Suicide Gene Therapy of Uterine Leiomyoma. Bioengineering, 9.","DOI":"10.3390\/bioengineering9030112"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1097\/00007890-200003270-00006","article-title":"Tissue-binding properties of a synthetic peptide DNA vector targeted to cell membrane integrins: A possible universal nonviral vector for organ and tissue transplantation","volume":"69","author":"Collins","year":"2000","journal-title":"Transplantation"},{"key":"ref_56","unstructured":"Sambrook, J., Fritsch, E.F., and Maniatis, T. (1989). Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press. [2nd ed.]."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1134\/S1022795407060014","article-title":"Lysine dendrimers as vectors for delivery of genetic constructs to eukaryotic cells","volume":"43","author":"Kiselev","year":"2007","journal-title":"Russ. J. Genet."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1002\/jgm.2811","article-title":"Development of a receptor-targeted gene delivery system using CXCR4 ligand-conjugated cross-linking peptides","volume":"16","author":"Egorova","year":"2014","journal-title":"J. Gene Med."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/23\/8363\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:30:34Z","timestamp":1760146234000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/23\/8363"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,30]]},"references-count":58,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["molecules27238363"],"URL":"https:\/\/doi.org\/10.3390\/molecules27238363","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,30]]}}}