Prolonged Local In Vivo Delivery of Stimuli-Responsive Nanogels That Rapidly Release Doxorubicin in Triple-Negative Breast Cancer Cells

Abstract

Triple negative breast cancer patients remain with chemotherapy as their only viable therapeutic option. However, the toxicity of available anticancer drugs and their inefficient delivery have limited the development of effective chemotherapy administration protocols and combination therapies. Drug delivery devices that can properly target chemotherapy to the right cells with efficient cancer-cell killing may play a vital role in eliminating triple-negative breast cancer. While systemic delivery results in low drug accumulation at the tumor site and for a short period of time, local delivery enables sustained drug release. However, a system that is able to provide rapid, yet prolonged action, would enable efficient tumor elimination. Herein, the development of dual-sensitive nanogels is described that are designed to rapidly dislodge the chemotherapy drug, doxorubicin, inside cancer cells through dual-sensitive action-pH and redox sensitivities-enabling efficient cancer-cell killing while eliminating systemic side effects. Their embedding within a hydrogel injected next to a tumor in a triple-negative breast-cancer mouse model enables prolonged release of the drug with instantaneous action when inside the cells resulting in efficacious tumor elimination compared to sustained local delivery only. This technology can be used for the delivery of combination therapies and for the treatment of other solid tumors.

Keywords: breast cancer; composite hydrogels; dual sensitive nanogels; pH sensitivity; redox sensitivity.