Hydrophilic and Lipophilic Carbon Dots Impart Thermosensitivity to Doxorubicin Loaded Phospholipid Liposomes

Background/Objectives: Hyperthermia coupled with temperature-triggered drug delivery systems, including drug-loaded thermosensitive liposomes, that exhibit increased membrane permeability at hyperthermia-relevant temperatures is a promising therapeutic strategy for cancer treatment. Our previous study revealed that nitrogen-doped carbon dots (CD) partially interact with the phospholipids of liposomes, increasing the membrane permeability of an encapsulated anticancer drug. In vitro cell experiments indicated that their presence in the culture medium, albeit at relatively high concentrations, also affect cell membrane permeability, enhancing drug internalization in cancer cells. This study aims to introduce either hydrophilic or lipophilic carbon dots into liposomes and evaluate them as thermosensitive drug delivery systems. Methods: Alkylated carbon dots (CD-C16) were synthesized and liposomal systems with either the lipophilic CD-C16 or the parent hydrophilic CD were prepared and efficiently loaded with doxorubicin (DOX). Following physicochemical characterization, their thermosensitivity was studied vs. time and temperature, while their effect on cell survival at 37 and 40 °C was evaluated against HEK293 and PC3 cells. Results: At 40 °C, for CD containing liposomes 50% DOX release is observed, whereas for CD-C16 containing liposomes 95% DOX is released within 5 min. Against PC3 cells at 40 °C, both DOX-loaded CD containing liposomes and CD-C16 containing liposomes are more potent compared to the parent drug-loaded liposomes, whereas CD-C16 containing liposomes are equally potent to free DOX. Against HEK293 cells the thermosensitive formulations at 40 °C prove even more cytotoxic, with CD-C16 containing liposomes being more potent than free DOX, but CD containing liposomes are advantageous for being less toxic than free DOX at 37 °C. Conclusions: Although work is needed to elucidate the mechanism at the molecular level, the results suggest that it is possible to adjust liposomal membrane permeability through the incorporation of carbon dots in order to optimize performance for hyperthermia-based applications.