"Attractive/adhesion force" dual-regulatory nanogels capable of CXCR4 antagonism and autophagy inhibition for the treatment of metastatic breast cancer.

Metastasis is refractory systemic disease resulting in low survival rate of breast cancer patients, especially in the late stage. The processes of metastasis are mainly initiated by strong "attractive force" from distant organs and deteriorated by weak "adhesion force" in primary tumor. Here, we reported "attractive/adhesion force" dual-regulatory nanogels (CQ-HF/PTX) for the precise treatment of both primary and metastasis of metastatic breast cancer. Hydroxychloroquine (HCQ) and hydrophobic Fmoc were grafted on hydrophilic hydroxyethyl starch (HES) to obtain amphiphilic CQ-HF polymer, which was assembly with chemotherapy drug paclitaxel (PTX) to form the nanogels for anti-primary tumor. Meanwhile, CQ-HF/PTX nanogels play two roles in anti-metastasis: i) For reducing the "attractive force", it could block the CXCR4/SDF-1 pathway, preventing tumor cells metastasis to the lung; ii) For reinforcing "adhesion force", it could inhibit the excessive autophagy for hindering the degradation of paxillin and enhancing the cell adhesion. As a result, dual-regulatory CQ-HF/PTX nanogels dramatically inhibited tumor and the lung metastasis of mouse breast cancer. Therefore, the fabricating of synergetic dual-regulatory nanogels uncovered the explicit mechanism and provided an efficient strategy for combating malignant metastatic tumors. [Display omitted] • Nanogels cut off "attractive force" via CXCR4 antagonism and reinforce "adhesion force" via inhibiting autophagy. [ABSTRACT FROM AUTHOR]