Construct A PH-sensitive Silicon Nano-drug Carrier System For Vitamin C Anti-tumor Process Research

In vivo redox balance plays crucial role in maintaininghuman's life away from inevitable cell damage and apoptosis.For decades,research interestsfocuses on the oxidative stress's damage to human bodies,from which a number of studies on oxidative stress-induced apoptosis of tumor cells have been carried out.However,besides the oxidative stress's kill effect on tumor cells,it will also cause vital damage to normal cells,which becomes a bottleneck that is difficult to overcome in current cancer treatment.In fact,reductive stress,the other imbalance form of redox balance,also is able to induce tumor cell death.As tumor cells stay in a weak reducing environment?the concentration of glutathione is higher than that in the normal cells?,the reductive drugs can further enhance the degree of reducing stress in the tumor cells to induce apoptosis,but providing little damage to normal tissues,which offers a new way for the development of new drugs for cancer treatment.Ascorbic acid?AA?is an essential nutrient for human growth and plays an important role in human health.As a reducing agent,AA can eliminate reactive oxygen species?ROS?in the body to avoid oxidative damage,and has the functions of improving human immunity,preventing cancers and curing cancers.Due to the low transmembrane efficiency of AA,the application of AA on cancer treatment is still very limited.Therefore,developing nanocarriers to deliver AA into the tumor environment and investigating its anti-tumor mechanism will be ofgreat theoretical and practical research significance.In order to improve the deliveryefficiency of AA into tumor cells,we synthesized two pH-regulated nano drug carriers,which can control the release of AA under tumors'hypoxic microenvironment to break the redox balance and further induce tumor cell apoptosis.This thesis mainly carries out the following two aspects of research work:1.In this chapter,a novel drug delivery system?CTMP-AA?was designed to controllable release AA in tumor cells by pH difference.A core-shell nanostructure of CdTe quantum dots with mesoporous silica coating was synthesized,and further functionalized by poly?2-vinylpyridine?-polyethylene glycol-folic acid?PPF?for both targeting and AA's reversibly pH controlled release in cancer cells.Under hypoxia,AA was found to enhance the reductive species,break the redox balance in HepG2cells to induce the apoptotic signaling pathway.The in vivo study further verified CTMP-AA's anti-cancer therapeutic effect for inhibiting tumor growth.Herein,we proposed the concept for applying reductive stress into cancer treatment,which brings great advantage of high efficiency,less toxicity and fewer side effects.This technique has taken an important step in the development of tumors'targeting treatment system,providesnovel perspectives for the drug design via reductive stress,and offers new insights into future clinical mild-therapies.2.In this chapter,the difference in the antitumor process of reduced/oxidized ascorbic acid?AA/DHA?was investigated.Silicon nanoparticles?SiNPs?,a fluorescent nano drug carrier,were synthesized and modified with polymer PPF to achieve cancer cells'targeting delivery and reversibly pH controlled release of AA/DHA.The changes of intracellular concentration of H₂O₂ and NAD?P?H were monitored,which demonstrated that AA could consume H₂O₂ and promote the accumulation of NAD?P?H under hypoxia,while DHA could increase the concentration of H₂O₂ and NAD?P?H slightly.After respectively incubating HepG2cells with the same dose of SiNP@PPF-AA and SiNP@PPF-DHA,the Caspase-3probe verifies that both reduced and oxidized AA induce tumor cells'apoptosis.