{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T18:28:17Z","timestamp":1784140097632,"version":"3.55.0"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T00:00:00Z","timestamp":1764633600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T00:00:00Z","timestamp":1767830400000},"content-version":"vor","delay-in-days":37,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    A pH-responsive PEGylated chitosan nanocarrier was developed for the targeted delivery of 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG) to HER2\n                    <jats:sup>+<\/jats:sup>\n                    breast cancer cells. The nanoparticle formulation was prepared using ionic gelation with sodium tripolyphosphate (TPP), followed by post-loading of 17-AAG. The resulting nanoparticles exhibited a spherical morphology, an average size of ~\u2009152\u00a0nm, and a positive zeta potential (+\u200928.60 mV). Drug encapsulation efficiency reached 80%, with sustained release under acidic conditions (pH 5.50), mimicking the tumor microenvironment. In vitro cytotoxicity assays demonstrated a significant enhancement in potency, with an IC\n                    <jats:sub>50<\/jats:sub>\n                    of 2.30 \u00b5M after 72\u00a0h, representing a threefold increase compared to free 17-AAG. The nanoformulation induced G2\/M cell cycle arrest and apoptosis in T47D cells. qRT-PCR analysis revealed a 72.10% downregulation of\n                    <jats:italic>HSP90<\/jats:italic>\n                    mRNA, indicating effective intracellular delivery and target engagement. Furthermore, combination with trastuzumab showed synergistic effects, suggesting disruption of the HER2 signaling pathway. These findings highlight the potential of this nanoplatform as a strategy with therapeutic potential for improving the therapeutic efficacy of 17-AAG in HER2\n                    <jats:sup>+<\/jats:sup>\n                    breast cancer.\n                  <\/jats:p>","DOI":"10.1038\/s41598-025-30507-2","type":"journal-article","created":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T07:16:35Z","timestamp":1764659795000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Development of a pH-responsive pegylated chitosan nanocarrier for targeted delivery of 17-AAG and synergistic therapy in HER2+ breast cancer"],"prefix":"10.1038","volume":"16","author":[{"given":"Samira","family":"Alipour","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud Reza","family":"Aghamaali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atiyeh","family":"Mahdavi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,2]]},"reference":[{"key":"30507_CR1","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","volume":"71","author":"H Sung","year":"2021","unstructured":"Sung, H. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71, 209\u2013249. https:\/\/doi.org\/10.3322\/caac.21660 (2021).","journal-title":"CA Cancer J. Clin."},{"key":"30507_CR2","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1038\/nrc1719","volume":"5","author":"L Whitesell","year":"2005","unstructured":"Whitesell, L. & Lindquist, S. L. HSP90 and the chaperoning of cancer. Nat. Rev. Cancer 5, 761\u2013772. https:\/\/doi.org\/10.1038\/nrc1719 (2005).","journal-title":"Nat. Rev. Cancer"},{"key":"30507_CR3","doi-asserted-by":"publisher","first-page":"R187","DOI":"10.1530\/ERC-13-0142","volume":"20","author":"G Krishnamoorthy","year":"2013","unstructured":"Krishnamoorthy, G. et al. Targeting steroidogenesis in hormone-dependent cancers. Endocr. Relat. Cancer 20, R187\u2013R201. https:\/\/doi.org\/10.1530\/ERC-13-0142 (2013).","journal-title":"Endocr. Relat. Cancer"},{"key":"30507_CR4","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1038\/nbt.3258","volume":"33","author":"E Blanco","year":"2015","unstructured":"Blanco, E., Shen, H. & Ferrari, M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat. Biotechnol. 33, 941\u2013951. https:\/\/doi.org\/10.1038\/nbt.3258 (2015).","journal-title":"Nat. Biotechnol."},{"key":"30507_CR5","doi-asserted-by":"publisher","first-page":"336","DOI":"10.3390\/polym10030336","volume":"10","author":"I Aranaz","year":"2018","unstructured":"Aranaz, I. et al. Basic and applied research on chitosan: a review. Polymers (Basel) 10, 336. https:\/\/doi.org\/10.3390\/polym10030336 (2018).","journal-title":"Polymers (Basel)"},{"key":"30507_CR6","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/S0144-8617(01)00135-8","volume":"46","author":"KM V\u00e5rum","year":"2001","unstructured":"V\u00e5rum, K. M. et al. Inhibition of DNA synthesis in HeLa cells by chitosans of different molecular weights. Carbohydr. Polym. 46, 155\u2013158. https:\/\/doi.org\/10.1016\/S0144-8617(01)00135-8 (2001).","journal-title":"Carbohydr. Polym."},{"key":"30507_CR7","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/S0031-6997(24)01494-7","volume":"53","author":"SM Moghimi","year":"2001","unstructured":"Moghimi, S. M., Hunter, A. C. & Murray, J. C. Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol. Rev. 53, 283\u2013318 (2001).","journal-title":"Pharmacol. Rev."},{"key":"30507_CR8","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/S0065-2571(00)00018-3","volume":"41","author":"H Maeda","year":"2001","unstructured":"Maeda, H. The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Adv. Enzyme Regul. 41, 189\u2013207. https:\/\/doi.org\/10.1016\/S0065-2571(00)00018-3 (2001).","journal-title":"Adv. Enzyme Regul."},{"key":"30507_CR9","doi-asserted-by":"publisher","first-page":"12098","DOI":"10.1039\/D1CS00333A","volume":"50","author":"J Yin","year":"2021","unstructured":"Yin, J. et al. Chem. Soc. Rev. 50, 12098 https:\/\/doi.org\/10.1039\/D1CS00333A (2021).","journal-title":"Chem. Soc. Rev."},{"key":"30507_CR10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.carbpol.2019.01.064","volume":"210","author":"Y Li","year":"2019","unstructured":"Li, Y., Zhang, Q. & Chen, X. pH-responsive chitosan nanoparticles for controlled release of doxorubicin: synthesis, characterization, and in vitro evaluation. Carbohydr. Polym. 210, 1\u20139. https:\/\/doi.org\/10.1016\/j.carbpol.2019.01.064 (2019).","journal-title":"Carbohydr. Polym."},{"issue":"3","key":"30507_CR11","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1158\/1078-0432.CCR-05-1793","volume":"12","author":"DB Solit","year":"2006","unstructured":"Solit, D. B., Osman, I. & Rosen, N. 17-AAG induces tumor regression and apoptosis in HER2-overexpressing breast cancer xenografts. Clin. Cancer Res. 12 (3), 839\u2013846. https:\/\/doi.org\/10.1158\/1078-0432.CCR-05-1793 (2006).","journal-title":"Clin. Cancer Res."},{"key":"30507_CR12","doi-asserted-by":"publisher","first-page":"4321","DOI":"10.2147\/IJN.S382741","volume":"17","author":"L Zhang","year":"2022","unstructured":"Zhang, L. et al. Development of 17-AAG-loaded PLGA-PEG nanoparticles using a post-loading strategy to preserve drug stability and enhance antitumor efficacy in breast cancer models. Int. J. Nanomed. 17, 4321\u20134335. https:\/\/doi.org\/10.2147\/IJN.S382741 (2022).","journal-title":"Int. J. Nanomed."},{"key":"30507_CR13","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1007\/s10616-023-00608-1","volume":"75","author":"T Szekeres","year":"2023","unstructured":"Szekeres, T. et al. Dimethyl sulfoxide (DMSO) in cell culture: a comprehensive review on its effects and recommended safe concentrations. Cytotechnology 75, 457\u2013470. https:\/\/doi.org\/10.1007\/s10616-023-00608-1 (2023).","journal-title":"Cytotechnology"},{"key":"30507_CR14","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1200\/JCO.20.3.719","volume":"20","author":"CL Vogel","year":"2002","unstructured":"Vogel, C. L. et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J. Clin. Oncol. 20, 719\u2013726. https:\/\/doi.org\/10.1200\/JCO.20.3.719 (2002).","journal-title":"J. Clin. Oncol."},{"key":"30507_CR15","doi-asserted-by":"publisher","first-page":"1421","DOI":"10.1016\/j.addr.2008.04.012","volume":"60","author":"GM Thurber","year":"2008","unstructured":"Thurber, G. M., Schmidt, M. M. & Wittrup, K. D. Antibody tumor penetration: transport opposed by systemic and antigen-mediated clearance. Adv. Drug Deliv. Rev. 60, 1421\u20131434. https:\/\/doi.org\/10.1016\/j.addr.2008.04.012 (2008).","journal-title":"Adv. Drug Deliv. Rev."},{"key":"30507_CR16","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1007\/s40005-025-00731-z","volume":"55","author":"Y Zhang","year":"2025","unstructured":"Zhang, Y. et al. Disulfide bond-driven nanoassembly of lipophilic epirubicin prodrugs for breast cancer therapy. J. Pharm. Investig. 55, 100\u2013112. https:\/\/doi.org\/10.1007\/s40005-025-00731-z (2025).","journal-title":"J. Pharm. Investig."},{"key":"30507_CR17","doi-asserted-by":"publisher","first-page":"103749","DOI":"10.1016\/j.jddst.2021.103749","volume":"75","author":"X Wang","year":"2021","unstructured":"Wang, X. et al. Chitosan-based nanoparticles for Paclitaxel delivery: formulation, characterization, and in vitro evaluation. J. Drug Deliv. Sci. Technol. 75, 103749. https:\/\/doi.org\/10.1016\/j.jddst.2021.103749 (2021).","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"30507_CR18","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1016\/j.jconrel.2023.08.042","volume":"362","author":"Y Zhou","year":"2023","unstructured":"Zhou, Y. et al. pH-Responsive polymeric micelles co-delivering 17-AAG and SiRNA for synergistic therapy of HER2-positive breast cancer. J. Control Release 362, 321\u2013334. https:\/\/doi.org\/10.1016\/j.jconrel.2023.08.042 (2023).","journal-title":"J. Control Release"},{"key":"30507_CR19","doi-asserted-by":"publisher","first-page":"2104","DOI":"10.1007\/s11095-012-0712-5","volume":"29","author":"V Saxena","year":"2012","unstructured":"Saxena, V. & Sahoo, S. K. Enhanced cytotoxicity and cellular uptake of tamoxifen-loaded pegylated PLGA nanoparticles against breast cancer cells. Pharm. Res. 29, 2104\u20132117. https:\/\/doi.org\/10.1007\/s11095-012-0712-5 (2012).","journal-title":"Pharm. Res."},{"key":"30507_CR20","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.ejps.2014.01.006","volume":"56","author":"M Gandomkar Ghalhar","year":"2014","unstructured":"Gandomkar Ghalhar, M. et al. \u03b2-Cyclodextrin complexation improves solubility and anticancer activity of 17-AAG in breast cancer cells. Eur. J. Pharm. Sci. 56, 105\u2013113. https:\/\/doi.org\/10.1016\/j.ejps.2014.01.006 (2014).","journal-title":"Eur. J. Pharm. Sci."},{"key":"30507_CR21","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1586\/14760584.6.4.551","volume":"6","author":"M Amidi","year":"2007","unstructured":"Amidi, M. et al. Chitosan-based systems for the delivery of vaccine antigens. Expert Rev. Vaccines. 6, 551\u2013565. https:\/\/doi.org\/10.1586\/14760584.6.4.551 (2007).","journal-title":"Expert Rev. Vaccines"},{"key":"30507_CR22","doi-asserted-by":"publisher","first-page":"4567","DOI":"10.2147\/IJN.S312345","volume":"16","author":"L Pan","year":"2021","unstructured":"Pan, L. et al. Hyaluronic acid-modified PLGA nanoparticles for targeted delivery of 17-AAG to colon cancer cells. Int. J. Nanomed. 16, 4567\u20134580. https:\/\/doi.org\/10.2147\/IJN.S312345 (2021).","journal-title":"Int. J. Nanomed."},{"key":"30507_CR23","doi-asserted-by":"publisher","unstructured":"Gao, Y. et al. Stimuli-responsive polymeric nanoparticles for tumor microenvironment-triggered drug release. Small 2024 (202411432). https:\/\/doi.org\/10.1002\/smll.202411432 (2024).","DOI":"10.1002\/smll.202411432"},{"key":"30507_CR24","doi-asserted-by":"publisher","first-page":"2100","DOI":"10.1039\/D4TB02345K","volume":"13","author":"J Chen","year":"2025","unstructured":"Chen, J., Li, H. & Zhang, Y. Citric acid\/graphene oxide nanocomposite beads for pH-sensitive release of anticancer drugs. J. Mater. Chem. B. 13, 2100\u20132110. https:\/\/doi.org\/10.1039\/D4TB02345K (2025).","journal-title":"J. Mater. Chem. B"},{"key":"30507_CR25","doi-asserted-by":"publisher","first-page":"148115","DOI":"10.1016\/j.ijbiomac.2025.148115","volume":"292","author":"A Mahoutforoush","year":"2025","unstructured":"Mahoutforoush, A. et al. Dermatan sulfate-recognized UiO-66 metal-organic frameworks: an active and passive targeting nanomedicine for methotrexate delivery. Int. J. Biol. Macromol. 292, 148115. https:\/\/doi.org\/10.1016\/j.ijbiomac.2025.148115 (2025).","journal-title":"Int. J. Biol. Macromol."},{"key":"30507_CR26","doi-asserted-by":"publisher","first-page":"1625","DOI":"10.1158\/1078-0432.CCR-06-1990","volume":"13","author":"W Xu","year":"2007","unstructured":"Xu, W. & Neckers, L. Targeting the molecular chaperone heat shock protein 90 provides a multifaceted effect on diverse cell signaling pathways of cancer cells. Clin. Cancer Res. 13, 1625\u20131629. https:\/\/doi.org\/10.1158\/1078-0432.CCR-06-1990 (2007).","journal-title":"Clin. Cancer Res."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-30507-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-30507-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-30507-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T13:55:07Z","timestamp":1767880507000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-30507-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,2]]},"references-count":26,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["30507"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-30507-2","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,2]]},"assertion":[{"value":"17 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 November 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 December 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"909"}}