Development and Evaluation of Folate-conjugated flacestrant-Loaded PLGA Nanoparticles for Targeted therapy of Estrogen receptor positive Breast Cancer

Abstract

Breast cancer remains one of the leading causes of cancer-related mortality among women worldwide, with estrogen receptor-positive (ER+) breast cancer accounting for nearly 70% of all diagnosed cases. Elacestrant, a recently approved oral selective estrogen receptor degrader (SERD), has shown promising therapeutic efficacy in ER-positive breast cancer; however, its clinical performance may be limited by poor aqueous solubility and non-specific systemic distribution. The present study aimed to develop folate-conjugated polymeric nanoparticles of Elacestrant for targeted delivery to ER-positive breast cancer cells. Elacestrant-loaded PLGA nanoparticles were prepared using the emulsion solvent evaporation method and subsequently functionalized with folic acid via EDC/NHS-mediated conjugation. The optimized nanoparticles exhibited a particle size of 168.2 ± 5.3 nm, polydispersity index of 0.205 ± 0.03, zeta potential of −18.9 ± 1.5 mV, entrapment efficiency of 82.8 ± 2.4%, and folate conjugation efficiency of 71.6 ± 3.2%. The formulation demonstrated sustained drug release over 48 h and followed Korsmeyer-Peppas release kinetics. Cellular studies revealed significantly enhanced uptake of folate-conjugated nanoparticles in MCF-7 cells compared with free drug and non-targeted nanoparticles. The targeted formulation exhibited superior cytotoxicity, increased intracellular reactive oxygen species generation, and markedly enhanced apoptosis induction. Furthermore, the nanoparticles demonstrated improved selectivity toward cancer cells while maintaining acceptable stability during storage. Collectively, these findings suggest that folate-conjugated Elacestrant-loaded PLGA nanoparticles may serve as a promising targeted nanotherapeutic strategy for the treatment of estrogen receptor-positive breast cancer.