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Currently, methotrexate (MTX) is the first\u2010line treatment for CC; however, due to the aggressive and metastatic nature of CC, multiple doses are often required, leading to severe side effects from the lack of tumor specificity. The first targeted MTX\u2010loaded polymersomes (Ps) designed for efficient drug delivery to CC tumors are introduced. The modification of these Ps nanoplatforms with guanosine (Gn), which targets the ENT\u20101 transporter overexpressed in CC cells, significantly enhances tumor uptake. Upon internalization by CC cells, the disulfide bonds in the Ps are reduced by high intracellular glutathione levels, causing Ps disintegration and efficient drug release. Biodistribution studies also reveal significant accumulation in subcutaneous CC tumors with minimal distribution in major organs. The ENT\u20101\u2010targetedpolymersomes show twice the tumor accumulation compared to the nontargeted ones based on in\u2010vivo fluorescence imaging. ENT\u20101\u2010targeted MTX\u2010loaded polymersomes (Gn\u2010MTX@SS\u2010Ps) achieve significantly greater tumor shrinkage in mice, reducing tumors by 30% more than nontargeted MTX@SS\u2010Ps and 75% more than free MTX at the same dosage regimen. Consequently, developed CC\u2010targeted MTX\u2010loaded polymer\u2010based delivery system holds the potential to significantly enhance the treatment of CC.<\/jats:p>","DOI":"10.1002\/smsc.202400361","type":"journal-article","created":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T01:58:45Z","timestamp":1738115925000},"source":"Crossref","is-referenced-by-count":4,"title":["ENT\u20101\u2010Targeted Polymersomes to Enhance the Efficacy of Methotrexate in Choriocarcinoma Treatment"],"prefix":"10.1002","volume":"5","author":[{"given":"Babak","family":"Mamnoon","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences College of Pharmacy Oregon State University  2730 S Moody Avenue Portland OR 97201 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Paula","family":"Mesquita Souza","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences College of Pharmacy Oregon State University  2730 S Moody Avenue Portland OR 97201 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetiana","family":"Korzun","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences College of Pharmacy Oregon State University  2730 S Moody Avenue Portland OR 97201 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maureen K.","family":"Baldwin","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology School of Medicine Oregon Health &amp; Science University  3181 SW Sam Jackson Park Road Portland OR 97239 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. 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