The Application And Mechanism Of The Stress Nanoload System Based On The "Redox Switch" In Targeted Treatment Of Renal Cell Carcinoma

Objective: Currently,targeted therapy offers a systemic treatment for advanced and metastatic renal cancer.However it is limited in clinical administration due to its serious side effects.In the early stage of the research group,clinical studies on patients with advanced metastatic renal cancer targeted drug use and follow-up found that targeted drugs have large toxic and side effects in the treatment of advanced metastatic renal cell carcinoma,seriously affecting the patient's physical and mental health and treatment.Nanoparticles drug delivery systems(DDS)can sustainedly release anticancer drug at the specific site and reduce the incidence of toxicity on normal tissues.We have developed a novel functional nanoparticle(FNP)containing a disulfide bonded "redox switch" that embeds the everolimus drug RAD001,and then explore its antitumor effects.Methods: 1.based on the "redox switch" nano drug loading system(which was independently developed and synthesized by the team),RAD001 is encapsulated to form multifunctional nanoparticle loaded particles.2.The breakthrough in PEG "redox switch" helps us to explore the accurate and efficient RAD001 release mechanism;3.Clearing the controlled release of RAD001 in the treatment of renal cell carcinoma and its mechanism.Results: 1.The presence of the eight-arm PEG can greatly enhance the stability of drug delivery in vivo,and greatly reduce its toxicity;The drug will be better released with the breakage of PEG under redox stimulus conditions.2.In the dynamic light scattering and transmission electron microscopy confirmed that the PEG containing disulfide bond switch and the 3rd generation dendrimer(PAMAM 3)particle size of about 100 nm are suitable for phagocytosis,It also can be observed under the laser confocal microscope that the nano drug delivery system can be well phagocytosed by the cells.3.FNP released a large amount of drug molecules in the reducing stimulus environment of GSH,the cumulative drug release reached 81.5%,significantly higher than the maximum cumulative release in neutral PBS.4.By nanomaterial embedding,PSPPG3@RAD001 has enhanced inhibition on ACHN and 786-O cells of renal cell carcinoma.5.The phosphorylation of m TOR in ACHN cells under different dosages and RAD001 alone was compared and analyzed,and the PSPPG3@RAD001 was detected by Western blot method,which significantly enhanced the phosphorylation on the m TOR in mammals.6.After injection of normal saline(control group),Free CY5.5 RNA and PSPG3/CY5.5 RNA 6 h into the caudal vein of nude mice,the in vivo fluorescence showed that the nanomaterial system can greatly improved drug's targeting to the tumor.7.Compared with the RAD001@?CD,PSPPG3@RAD001 has a significant anti-tumor effect,and its anti-tumor effect gradually increases with time.Conclusion: 1.The encapsulation of functional nanomaterial drug delivery system FNP can increase water solubility of drugs.2.The nanomaterial structure design has complete independent intellectual property rights,and the results can be applied to many other non-water-soluble targeting drugs,also other types of cancers.The structure contains PEG which was certified by FDA for clinical transformation and pharmaceutical research.3.The current drug controlled release system for medical research was a multidisciplinary field of medicine,chemistry,biology,materials,showing inspiring prospects and advantages.