Cancer chemotherapy is often accompanied by severe off-target effects that both damage quality of life and can decrease therapeutic compliance. This could be minimized through selective delivery of cytotoxic agents directly to the cancer cells. This would decrease the drug dose, consequently minimizing side effects and cost. With this goal in mind, a dual-gated folate-functionalized nanodiamond drug delivery system (NPFSSD) for doxorubicin with activatable fluorescence and cytotoxicity has been prepared. Both the cytotoxic activity and the fluorescence of doxorubicin (DOX) are quenched when it is covalently immobilized on the nanodiamond. The NPFSSD is preferentially uptaken by cancer cells overexpressing the folate receptor. Then, once inside a cell, the drug is preferentially released within tumor cells due to their high levels of endogenous of glutathione, required for releasing DOX through cleavage of a disulfide linker. Interestingly, once free DOX is loaded onto the nanodiamond, it can also evade resistance mechanisms that use protein pumps to remove drugs from the cytoplasm. This nanodrug, used in an in vivo model with local injection of drugs, effectively inhibits tumor growth with fewer side effects than direct injection of free DOX, providing a potentially powerful platform to improve therapeutic outcomes.
Keywords: Chemotherapy; Controlled drug release; Doxorubicin; Drug-resistance; Nanoparticle; Targeted delivery.
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