Ferroptosis Inducer Combination With Photodynamic Therapy On The Treatment Of Oral Cancer

Photodynamic therapy(PDT)refers to a therapy in which a photosensitizer is introduced into a target tissue,and then excited by a specific wavelength of light to generate reactive oxygen species by photochemical reaction,thereby specifically killing the target tissue.It has been widely used in the treatment of superficial malignant tumors and precancerous lesions in the maxillofacial region.However,PDT requires the participation of oxygen,and the hypoxic environment at the tumor site leads to low efficiency of reactive oxygen species production,which severely limits the efficacy of PDT.Therefore,improving the hypoxic environment inside the tumor become a key problem to be solved in improving the efficacy of PDT.Feroptosis is a novel form of cell death that affects the biosynthesis of glutathione(GSH)by inhibiting the glutamate/cysteine transporter System x_c~-and causes the aggregation of intracellular lipid peroxides and triggers cell death.In this process,the participation of intracellular iron ions is required.The Fenton reaction in which iron ions participate is a necessary step for directly generating peroxide.The peroxide produced by ferroptosis and the molecular oxygen produced during the Fenton reaction are expected to make the combination of ferroptosis and PDT possible.Based on this,this thesis intends to design carrier-free superamolecular system.In detail,the photosensitizer chlorin e6(Ce6)and the ferroptosis inducer erastin were self-assembled into a novel nanodrug via supramolecular force.On the one hand,the excessive accumulation of lipid peroxides during ferroptosis and the reactive oxygen species generated by PDT aggravate the destruction of the redox balance in the cells.On the other hand,the oxygen generated via the Fenton reaction during ferroptosis could supply the consumption of oxygen during PDT to further improve the efficacy of PDT.Thereby,a brand-new synergistic anti-tumor therapy is achieved by inducing ferroptosis and PDT.Firstly,Ce6 and erastin were assembled into a supramolecular nano twindrug Ce6-erastin byπ-πstacking and hydrogen bonding and the characterization and functional properties were determined.The cellular uptake and cytotoxicity were tested.The toxicity and ability of increasing oxygen concentration was identified.The influences on the expression of ferroptosis-related protein were further examined.The in vivo study of its targeting ability was domenstrated.In this theis,the nano twindrug Ce6-erastin was successfully constructed.Ce6-erastin can be taken up quickly and efficiently by tumor cells and have no dark toxicity to cells.More importantly,Ce6-erastin nano twindrug can increase the oxygen concentration in cell culture medium through Fenton reaction to supply the oxygen consumption of PDT.The synergistic therapy of ferroptosis and PDT mediated by can effectively inhibit tumor cell proliferation and increase apoptosis rate and has no obvious toxicity to nude mice model.Ce6-erastin has clinical application prospects due to the ability of inducing ferroptosis in vivo,improving the bioavailability of photosensitizers,enhancing the ability of promoting apoptosis without systemic toxic side effects,therefore improving anti-tumor efficiency.