ArticleScientific reports2026
Multifunctional and dual-targeting polymeric prodrug nanomicelles against tamoxifen-resistant breast cancer.
Article in Scientific reports, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Tamoxifen (TAM) resistance remains a significant challenge in treating estrogen receptor (ER)-positive breast cancer. Overexpression of epidermal growth factor receptor (EGFR), variations in TAM metabolism, and increased expression of drug-resistant proteins (P-glycoprotein, P-gp) all contribute to the development of TAM-resistant breast cancer. The lack of specific drug distribution to tumors further complicates the treatment of TAM-resistant breast cancer. Simultaneously addressing these four factors—EGFR overexpression, TAM metabolic variations, P-gp-mediated drug efflux, and poor tumor-specific delivery—can significantly enhance the treatment of TAM-resistant breast cancer. This study aimed to design a multifunctional and dual-targeting polymeric prodrug nanomicelle platform. The platform was self-assembled using the amphipathic precursor drug material [hyaluronic acid (HA)-4-hydroxytamoxifen (4-OH-TAM) ester (esterified by HA and 4-OH-TAM)] and D-α-tocopheryl polyethylene glycol succinate (TPGS), loaded with dasatinib (DAS). The nanosystem could target breast cancer mediated by HA and 4-OH-TAM, releasing DAS, 4-OH-TAM, and TPGS in tumor microenvironment. 4-OH-TAM, an active metabolite of TAM, substantially impacted TAM-resistant breast cancer by avoiding the metabolic differences in TAM. TPGS inhibited P-gp-mediated drug efflux, thereby increasing intracellular accumulation of DAS and enhancing its inhibitory effect on TAM-resistant breast cancer cells. The results showed that the nanomicelles released drugs in a pH-sensitive manner. The cumulative release rates of 4-OH-TAM and DAS were (72.73 ± 3.99)% and (78.39 ± 3.09)%, respectively, within 48 h in a pH 5.0 solution, significantly higher than those in pH 6.0 and 7.4 solutions. The findings regarding cellular uptake and biodistribution indicated that the nanomicelles exhibited effective targeting capabilities toward TAM-resistant breast cancer. Both in vitro and in vivo studies demonstrated a marked effect of nanomicelles against TAM-resistant breast cancer through the targeting characteristic of nanoparticles and the actions of drugs (4-OH-TAM, DAS, and TPGS). The study provides fresh perspectives and suggestions for the clinical treatment of TAM-resistant breast cancer.
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