LAUSR

Simple Summary Breast cancer is one of the dominant cancers that threaten human beings worldwide. Moreover, the treatment of HER2+ breast cancer is challenging due to heterogeneity. The L-lysine α-oxidase (LO) enzyme is a well-known antitumor enzyme, but its clinical utility has been limited due to side effects, decreased stability, and inability to target tumor cells. To overcome the clinical challenges in delivery of LO enzymes and improve HER2+ breast cancer therapeutics, the present study developed the dual stimuli responsive nanocarrier system (CS-LO-PEG-HER NPs) for pH sensitive and HER2/neu targeted breast cancer therapy. Abstract Herein, we designed a nanocarrier to deliver the LO specifically to HER2+ breast cancer (BC) cells, where functionalization of mAb (anti-HER2+) with PEGylated chitosan enabled it to target the HER2+ BC cells. Taking advantage of overexpression of HER2+ in cancer cells, our nanocarrier (CS-LO-PEG-HER NPs) exhibited promising potency and selectivity against HER2+ BC cells (BT474). The CS-LO-PEG-HER NPs demonstrated the cytotoxicity in BT474 cells by promoting reactive oxygen species, mitochondrial membrane potential loss, and nucleus damage. The biocompatibility of CS-LO-PEG-HER NPs was evidenced by the hemolysis assay and H & E staining of major organs. The CS-LO-PEG-HER NPs showed anticancer potency against the BT474-xenograft tumor-bearing mice, as evident by the reduction of tumor size and cell density. These results indicate that CS-LO-PEG-HER NPs are biocompatible with mice while inhibiting tumor growth through alter the oxidative stress. Overall, this work provides a promising approach for the delivery of LO for good therapeutic effect in combination with mAb.