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These focal lesions are well suited for local intraductal treatment. Intraductal administration supported target site drug retention, improved efficacy, and reduced systemic exposure. Here, we used a poly(N-isopropyl acrylamide, pNIPAM) nanoparticle delivery system loaded with cytotoxic piplartine and an MAPKAP Kinase 2 inhibitor (YARA) for this purpose. For tumor environment targeting, a collagen-binding peptide SILY (RRANAALKAGELYKSILYGSG-hydrazide) was attached to pNIPAM nanoparticles, and the nanoparticle diameter, zeta potential, drug loading, and release were assessed. The system was evaluated for cytotoxicity in a 2D cell culture and 3D spheroids. In vivo efficacy was evaluated using a chemical carcinogenesis model in female Sprague\u2013Dawley rats. Nanoparticle delivery significantly reduced the IC50 of piplartine (4.9 times) compared to the drug in solution. The combination of piplartine and YARA in nanoparticles further reduced the piplartine IC50 (~15 times). Treatment with these nanoparticles decreased the in vivo tumor incidence (5.2 times). Notably, the concentration of piplartine in mammary glands treated with nanoparticles (35.3 \u00b1 22.4 \u03bcg\/mL) was substantially higher than in plasma (0.7 \u00b1 0.05 \u03bcg\/mL), demonstrating targeted drug retention. These results indicate that our nanocarrier system effectively reduced tumor development with low systemic exposure.<\/jats:p>","DOI":"10.3390\/pharmaceutics16020231","type":"journal-article","created":{"date-parts":[[2024,2,5]],"date-time":"2024-02-05T08:41:43Z","timestamp":1707122503000},"page":"231","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Thermosensitive Polymeric Nanoparticles for Drug Co-Encapsulation and Breast Cancer Treatment"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4967-3121","authenticated-orcid":false,"given":"Vanessa Franco Carvalho","family":"Dartora","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Institute of Biomedical Sciences, University of S\u00e3o Paulo (USP), S\u00e3o Paulo 05508-900, Brazil"},{"name":"Department of Biomedical Engineering, College of Engineering, University of California Davis, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7494-810X","authenticated-orcid":false,"given":"Julia S.","family":"Passos","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Institute of Biomedical Sciences, University of S\u00e3o Paulo (USP), S\u00e3o Paulo 05508-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1861-5153","authenticated-orcid":false,"given":"Leticia V.","family":"Costa-Lotufo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Institute of Biomedical Sciences, University of S\u00e3o Paulo (USP), S\u00e3o Paulo 05508-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana B.","family":"Lopes","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Institute of Biomedical Sciences, University of S\u00e3o Paulo (USP), S\u00e3o Paulo 05508-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0360-1480","authenticated-orcid":false,"given":"Alyssa","family":"Panitch","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, College of Engineering, University of California Davis, Davis, CA 95616, USA"},{"name":"Wallace H. Coulter Department of Biomedical Engineering, College of Engineering, Georgia Institute of Technology, School of Medicine, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,5]]},"reference":[{"key":"ref_1","first-page":"231","article-title":"An atlas of subgross pathology of the human breast with special reference to possible precancerous lesions","volume":"55","author":"Wellings","year":"1975","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"ref_2","first-page":"579","article-title":"The safety parameters of the study on intraductal cytotoxic agent delivery to the breast before mastectomy","volume":"26","author":"Zhang","year":"2014","journal-title":"Chin. J. 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