Ascorbic acid induced HepG2 cells' apoptosis via intracellular reductive stress

: Goals: Destruction of the redox balance in tumor cells is of great significance for triggering their apoptosis in clinical applications. We designed a pH sensitive multifunctional drug nanocarrier with controllable release of ascorbic acid under hypoxic environment to induce tumor cells' apoptosis via enhancing reductive stress, thereby dealing minimum damage to normal tissues. Methods: A core-shell nanostructure of CdTe quantum dots with mesoporous silica coating was developed and functionalized with poly(2-vinylpyridine)-polyethylene glycol-folic acid, which achieves cancer cells' targeting delivery and reversibly pH controlled release of ascorbic acid both in vitro and in vivo. Results: The result demonstrated that ascorbic acid can indeed lead liver cancer cells' death with the increase of nicotinamide adenine dinucleotide phosphate, while normal cells not being affected. The molecular mechanism of apoptosis induced by ascorbic acid was firstly elucidated at cellular levels, and further confirmed via in vivo investigations. Conclusion: For the first time we proposed the concept for applying reductive stress into cancer treatments, which brings great advantage of toxicity free and less damage to normal tissues. In general, this technique has taken an important step in the development of a targeted tumor treatment system, providing perspectives for the design of medicines via reductive stress, and offers new insights into future clinical mild-therapies.