Rational Design of Tumor Microenvironment‐Activated Micelles for Programed Targeting of Breast Cancer Metastasis

Abstract The poor drug delivery to primary and metastatic tumors of breast cancer remains a great challenge for effective antimetastasis therapy. Herein, a tumor microenvironment‐activated cabazitaxel micelles decorated with legumain‐specific melittin (TCM‐legM) are rationally designed for programed targeting of breast cancer metastasis. TCM‐legM is quiescent in blood circulation, but can be specifically activated by the highly expressed legumain in tumor microenvironments to improve their specific targeting and deep penetrating to primary or metastatic tumors. Thereafter, the activated TCM‐legM can be efficiently internalized by cancer cells and motivate the rapid pH‐responsive drug release for antimetastasis therapy. In metastatic 4T1 breast cancer cells, TCM‐legM presents significant inhibition on the proliferation, migration, and invasion activities. In vivo, TCM‐legM can be effectively delivered to both primary and metastatic tumors of breast cancer with deep tumor penetration and efficient cellular internalization, thereby resulting in a notable reduction of tumor growth and producing a 93.4% suppression of lung metastasis. Taken together, the rationally designed TCM‐legM can provide an intelligent drug delivery strategy to enhance the medical performance on treating breast cancer metastasis.