Alendronate/folic acid-decorated polymeric nanoparticles for hierarchically targetable chemotherapy against bone metastatic breast cancer

Abstract

Through hierarchically targeting bone matrix and tumor cells, PTX-carrying ALN/FA-nanoparticles substantially accumulate in bone metastases and improve mice survival rate.

Abstract

To considerably enhance treatment efficacy for bone metastatic breast cancer via dual bone/tumor-targeted chemotherapy, a nanoparticle-based delivery system comprising poly(lactic- co-glycolic acid) (PLGA) as the hydrophobic core coated with alendronate-modified d-α-tocopheryl polyethylene glycol succinate (ALN-TPGS) and folic acid-conjugated TPGS (FA-TPGS) was developed as a vehicle for paclitaxel (PTX) in this work. The ALN/FA-decorated nanoparticles not only showed superior ALN-mediated binding affinity for hydroxyapatite abundant in bone tissue but also promoted uptake of payloads by folate receptor-overexpressing cancer cells to significantly augment PTX cytotoxicity. Notably, through dual-targetable delivery to the bone matrix and folate receptor-overexpressing 4T1 tumors, the PTX-loaded nanoparticles substantially accumulated in bone metastases in vivo and inhibited 4T1 tumor growth and lung metastasis, leading to significant improvement of the survival rate of treated mice. Upon treatment with the ALN/FA-decorated PTX-loaded nanoparticles, the bone destruction and bone loss of the tumor-bearing mice were appreciably retarded, and the adverse effects on normal tissues were alleviated. These results demonstrate that the ALN/FA-decorated PTX-loaded delivery system developed in this study shows great promise for the effective treatment of bone metastatic breast cancer.