{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T05:21:38Z","timestamp":1788067298278,"version":"build-2784847793"},"reference-count":84,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T00:00:00Z","timestamp":1660089600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Hepatocellular carcinoma (HCC) is one of the world\u2019s most risky diseases due to the lack of clear and cost-effective therapeutic targets. Currently, the toxicity of conventional chemotherapeutic medications and the development of multidrug resistance is driving research into targeted therapies. The nano-biomedical field\u2019s potential for developing an effective therapeutic nano-sized drug delivery system is viewed as a significant pharmaceutical trend for the encapsulation and release of numerous anticancer therapies. In this regard, current research is centered on the creation of biodegradable chitosan nanoparticles (CSNPs) for the selective and sustained release of bee venom into liver cancer cells. Furthermore, surface modification with polyethylene glycol (PEG) and GE11 peptide-conjugated bee venom-CSNPs allows for the targeting of EGFR-overexpressed liver cancer cells. A series of <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> cellular analyses were used to investigate the antitumor effects and mechanisms of targeted bee venom-CSNPs. Targeted bee venom-CSNPs, in particular, were found to have higher cytotoxicity against HepG2 cells than SMMC-7721 cells, as well as stronger cellular uptake and a substantial reduction in cell migration, leading to improved cancer suppression. It also promotes cancer cell death in EGFR overexpressed HepG2 cells by boosting reactive oxygen species, activating mitochondria-dependent pathways, inhibiting EGFR-stimulated MEK\/ERK pathway, and elevating p38-MAPK in comparison to native bee venom. In hepatocellular carcinoma (HCC)-induced mice, it has anti-cancer properties against tumor tissue. It also improved liver function and architecture without causing any noticeable toxic side effects, as well as inhibiting tumor growth by activating the apoptotic pathway. The design of this cancer-targeted nanoparticle establishes GE11-bee venom-CSNPs as a potential chemotherapeutic treatment for EGFR over-expressed malignancies. Finally, our work elucidates the molecular mechanism underlying the anticancer selectivity of targeted bee venom-CSNPs and outlines therapeutic strategies to target liver cancer.<\/jats:p>","DOI":"10.1371\/journal.pone.0272776","type":"journal-article","created":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T17:37:42Z","timestamp":1660153062000},"page":"e0272776","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":21,"title":["Bee venom-loaded EGFR-targeting peptide-coupled chitosan nanoparticles for effective therapy of hepatocellular carcinoma by inhibiting EGFR-mediated MEK\/ERK pathway"],"prefix":"10.1371","volume":"17","author":[{"given":"Shaymaa","family":"Abdulmalek","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nouf","family":"Mostafa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwa","family":"Gomaa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"El\u2011Kersh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayman I.","family":"Elkady","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0876-6604","authenticated-orcid":true,"given":"Mahmoud","family":"Balbaa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,8,10]]},"reference":[{"key":"pone.0272776.ref001","doi-asserted-by":"crossref","first-page":"16018","DOI":"10.1038\/nrdp.2016.18","article-title":"Hepatocellular carcinoma","volume":"2","author":"JM Llovet","year":"2016","journal-title":"Nat Rev Dis Primers"},{"key":"pone.0272776.ref002","doi-asserted-by":"crossref","first-page":"713","DOI":"10.3181\/0901-MR-12","article-title":"The epidermal growth factor receptor: a link between inflammation and liver cancer","volume":"234","author":"C Berasain","year":"2009","journal-title":"Exp Biol Med"},{"key":"pone.0272776.ref003","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.molcel.2011.03.004","article-title":"Catalytic control in the EGF receptor and its connection to general kinase regulatory mechanisms","volume":"42","author":"N Jura","year":"2001","journal-title":"Mol cell"},{"key":"pone.0272776.ref004","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1002\/hep.22506","article-title":"Molecular targeted therapies in hepatocellular carcinoma","volume":"48","author":"JM Llovet","year":"2008","journal-title":"Hepatology"},{"key":"pone.0272776.ref005","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.3390\/molecules26041076","article-title":"Molecular Targeting of Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR)","volume":"26","author":"NE Kaufman","year":"2021","journal-title":"Molecules"},{"key":"pone.0272776.ref006","first-page":"903","article-title":"Expression of heparin binding epidermal growth factor-like growth factor in hepatocellular carcinoma: an immunohistochemical study","volume":"8","author":"Y Ito","year":"2001","journal-title":"Oncol Rep"},{"key":"pone.0272776.ref007","doi-asserted-by":"crossref","first-page":"2908","DOI":"10.3390\/cells10112908","article-title":"Novel Peptide Therapeutic Approaches for Cancer Treatment","volume":"10","author":"CM Li","year":"2021","journal-title":"Cells"},{"key":"pone.0272776.ref008","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.canlet.2009.11.013","article-title":"Bee venom inhibits tumor angiogenesis and metastasis by inhibiting tyrosine phosphorylation of VEGFR-2 in LLC-tumor-bearing mice","volume":"292","author":"JE Huh","year":"2010","journal-title":"Cancer Lett"},{"key":"pone.0272776.ref009","doi-asserted-by":"crossref","first-page":"4941","DOI":"10.3390\/molecules26164941","article-title":"Bee Venom: From Venom to Drug","volume":"26","author":"A Khalil","year":"2021","journal-title":"Molecules"},{"key":"pone.0272776.ref010","doi-asserted-by":"crossref","first-page":"2264","DOI":"10.3390\/molecules26082264","article-title":"The Cytotoxic Effect of Apis mellifera Venom with a Synergistic Potential of Its Two Main Components-Melittin and PLA2-On Colon Cancer HCT116 Cell Lines","volume":"26","author":"C Yaacoub","year":"2021","journal-title":"Molecule"},{"key":"pone.0272776.ref011","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s10555-011-9339-3","article-title":"Bee venom in cancer therapy","volume":"31","author":"N. 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