Folic Acid-Functionalized Carbon Dot-Enabled Starvation Therapy in Synergism with Paclitaxel against Breast Cancer.

Glucose oxidase (GOx)-induced cancer starvation has recently emerged for halting the abnormal proliferation of triple-negative breast cancer (TNBC). However, monotherapy with GOx or a conventional chemotherapeutic displays suboptimal efficacy in eliminating tumors and poses impending risks to healthy tissues. To augment therapeutic efficacy and tumor selectivity, folic acid (FA)-functionalized carbon dots (CDs) embedded with GOx and paclitaxel (PTX) [FA-CD-(PTX-GOx)] was developed that showed the efficient killing of TNBC, MDA-MB-468 cells over noncancerous HEK 293 cells through synergistic effects of cancer starvation-induced oxidative stress and chemotherapy. The cargo-laden FA-CD complex resulted in a 4-8 fold increase in cancer cell death at 60 μg/mL when compared to standalone therapy with the native compounds and individually loaded cargo on FA-CD. This improved cancer cell killing efficacy of the FA-CD-(PTX-GOx) complex could be endorsed by folate receptor (FR)-mediated target-specific cellular internalization of the FA-CD complex. The antitumorigenic efficacy of the FA-CD-(PTX-GOx) complex was further validated in a three-dimensional (3D) breast tumor spheroid model. A significant 4.5-fold reduction in spheroid dimension along with antiproliferation was observed with time up to 72 h following exposure to the FA-CD-(PTX-GOx) complex. This antitumorigenic potential of FA-CD-(PTX-GOx) could be attributed to the enhanced intratumoral reactive oxygen species generation following glucose depletion by GOx that has been facilitated by the chemotherapeutic efficacy of PTX resulting in the efficient killing of cancer cells. The present study provides a novel strategy of FR-mediated fluorescent CD-enabled combined formulation of GOx and PTX for the target-specific superior killing of TNBC cells in the synergism of glucose starvation with chemotherapy.