Estrone-modified pH-sensitive glycol chitosan nanoparticles for drug delivery in breast cancer

Abstract Estrone-modified glycol chitosan nanoparticles (GCNP-ES) based on the mechanisms of ES-mediated endocytosis and intracellular pH-responsive drug release were developed for the treatment of breast cancer. GCNP-ES were prepared by grafting copolymerization of glycol chitosan with 2-(diisopropylamino)ethyl methacrylate to generate GCNP prior to ES conjugation. The particle size, zeta potential, and paclitaxel (PTX) encapsulation efficiency of GCNP-ES were characterized. In particular, GCNP-ES exhibited pH-responsive dissociation properties while maintaining stability under long-term storage and lyophilization. The drug release of PTX-loaded GCNP-ES (PTX/GNCP-ES) was modestly prolonged with considerable pH sensitivity. GCNP-ES promoted internalization in breast cancer MCF-7 cells by approximately 5-fold as compared to GCNP, and the internalized GCNP-ES was mainly localized in the endosomes of MCF-7 cells. PTX/GNCP-ES exhibited higher cytotoxicity and cell apoptosis ratio than GCNP. In mice with MCF-7 breast cancer xenograft, PTX/GCNP-ES showed higher accumulation at the tumor site, which resulted in a higher tumor inhibition ratio (81.4%) than that achieved by PTX/GCNP (69.4%) and PTX solution (48.8%). Furthermore, no histological and hematological toxicity was detected in in vivo studies of PTX/GCNP-ES. Overall, these results suggested the potential applicability of GCNP-ES as a drug delivery system for breast cancer therapy. Statement of Significance Most breast cancers are hormone dependent. Herein, we developed a estrone-modified glycol chitosan nanoparticles (GCNP-ES) as a drug delivery system to overcome the drawbacks of chemotherpeutic drugs, including poor water solubility and lack of specifity. GCNP-ES could provide efficient drug delivery in breast cancer cells. The study demonstrated that GCNP-ES could dissociate under mildly acidic conditions, leading to the timely payload release of the drug in target tumor cells following internalization. The conjugated estrone of the nanoparticles could significantly increase drug accumulation in the tumor site and result in enhanced therapeutic effect. Thus, the potential applicability of GCNP-ES was suggested.