Saporin-loaded CD44 and EGFR dual-targeted nanogels for potent inhibition of metastatic breast cancer in vivo

Abstract

Metastasis poses a long-standing treatment challenge for many cancers including breast cancer. Once spreading out, cell-selective delivery of drug appears especially critical. Here, we report on epidermal growth factor receptor and CD44 dual-targeted hyaluronic acid nanogels (EGFR/CD44-NGs) that afford enhanced targetability and protein therapy for metastatic 4T1 breast cancer in vivo. Flow cytometry in CD44 and EGFR-positive 4T1 metastatic breast cancer cells showed over 6-fold higher cellular uptake of EGFR/CD44-NGs than mono-targeting CD44-NGs. MTT and scratch assays displayed that saporin-loaded EGFR/CD44-NGs (Sap-EGFR/CD44-NGs) was highly potent in inhibiting growth as well as migration of 4T1 cells in vitro, with an IC₅₀ of 5.36 nM, which was 1.7-fold lower than that for Sap-CD44-NGs. In 4T1-luc metastatic breast cancer model in mice, Sap-EGFR/CD44-NGs exhibited significant inhibition of tumor metastasis to lung at a small dose of 3.33 nmol Sap equiv./kg. Increasing the dosage to 13.3 nmol Sap equiv./kg resulted in further reduced lung metastasis without causing notable adverse effects. These dual-targeted nanogels with improved cancer cell selectivity provide a novel platform for combating breast cancer metastasis.

Keywords: CD44; Epidermal growth factor receptor; Nanogels; Targeted delivery; Therapeutic proteins; Tumor metastasis.