Anti-solid Tumor Effects Of Arsenic Trioxide Synergism Nanodiamonds

Autophagy is an evolutionarily ancient and highly conserved catabolic process that involves the formation of double-membraned vesicles known as autophagosomes that engulf cellular proteins and organelles for delivery to the lysosome for digestive recycling to maintain the cellular metabolism.It is a stress response of the cells against starvation or stress.In the process of tumor growth,in order to meet the need of metabolism,one way is to secrete angiogenic factors for stimulating the development of new blood vessels,autophagy is also a way.Therefore,the strategy for clinical treatment of tumors is to perform surgical resection firstly,then implement radiotherapy and chemotherapy,making the remaining tumor cells under growth pressure,and use a combination of autophagy inhibitors and chemotherapy drugs to kill tumor cells finally.Chloroquine or hydrochloroquine is often used as an autophagy inhibitor in clinical trials,but as a chemical agent,it has a certain degree of toxicity,and may cause side effects during the treatment or prognosis.In view of the fact that it is a lysosomal alkalizer,the acidic environment of the tumor itself will affect its ability to block autophagy.Therefore,it is urgent to develop safe and effective autophagy inhibitor to guide the conduct of clinical trials.With the development of nanomedicine,the role of naonparticles has become increasingly prominent,and the regulation of autophagy by naonparticles in cells has received more and more attention.With a five-year disease-free survival rate above 90%,arsenic trioxide(ATO)is effective in the acute promyelocytic leukemia treatment,making it became the first cured cancer.However,the effect of treating solid tumors is not ideal.The reason may be ATO-induced autophagy behavior,which increases the resistance of tumor cells to drugs.Therefore,an effective means to improve the sensitivity of ATO to solid tumor cells is autophagy inhibitor intervention.Therefore,we will apply nanoparticles with the regulation of autophagy in combination with ATO to improve the treatment of solid tumors.The main research results are summarized as follows:(1)The morphology and physical parameters of a variety of commercially available nanomaterials were characterized firstly,then the nanoparticles with autophagy block were screened by autophagy marker proteins under a uniform safe concentration.Furthermore,the cell survival rate of human solid tumor cell HepG2 was studied through the combination of ATO to screen out the most effective nanoparticles NDs.(2)In acute promyelocytic leukemia cells,we found that ATO had no effect on its autophagy,and thus when combined with NDs had no significant effect.At low concentrations of ATO,autophagy can be significantly induced in solid tumor cells,and this behavior will increase the resistance of cells to chemotherapy,making them insensitive to chemotherapeutic drugs.We have demonstrated through a variety of means that the effective combination ATO and NDs in vitro is autophagy dependent.Furthermore,according to the intracellular arsenic concentration and distribution,the significant effect of combination therapy was not based on the NDs as excellent drug delivery vectors,and intracellular uptake of arsenic was not increased in the presence of NDs.(3)In view of the significant effect of killing solid tumor cells in vitro.This strategy of combination treatment was applied to the treatment of hepatic in situ mice.The combination of medium dose ATO and NDs can effectively inhibit tumor growth and increase the tumor inhibition rate to 90%.Comparing to treatment with ATO alone,which increased the tumor inhibition rate by 50%.The survival time of the nude mice is greatly prolonged,the effect of the tumor growth on the liver and renal function is relieved,and advanced-cancer complications is reduced.The body weight as normal nude mice reflect the prognosis health condition.A large number of apoptosis and immunoblot results in tumors highlight the significant effect of NDs as an autophagy inhibitor.As the results in vitro,the presence of NDs did not allow tumor cells to take up more arsenic.In conclusion,we have screened a naonparticles which is safe,effective,and has autophagy block properties,replacing the clinically used autophagy inhibitor chloroquine or hydrochloroquine,and providing new ideas for the development of new clinical autophagy inhibitor.Based on the significant killing effect of solid tumors in vivo and in vitro,the application of ATO to solid tumors is expected to have the similar therapeutic effect of acute promyelocytic leukemia,which expands the scope of treatment of this ancient prescription and has broad clinical application prospects.