| Renal cell carcinoma is one of the main malignant tumors in the urinary system,with the characteristics of strong concealment and high malignancy.In recent years,the incidence and mortality of renal cell carcinoma(RCC)in China have been increasing year by year.In addition,advanced RCC is often accompanied by metastasis,resulting in poor prognosis of patients.Sunitinib,a Tyrosine kinase inhibitor(TKI)with dual effects of targeting vascular endothelial growth factor and inhibiting tumor growth,is widely used in the first-line treatment of advanced renal cell carcinoma in clinic.It has greatly improved the clinical treatment effect of renal cell carcinoma and improved the clinical benefit of patients.However,drug resistance reactions will occur rapidly during clinical application,which will gradually reduce the clinical efficacy and shorten the survival time of patients.Therefore,how to overcome the problem of drug resistance has become the key to efficient tumor treatment.The tumor microenvironment(TME)provides the necessary physiological basis for the malignant proliferation of tumors.Different from normal tissue metabolism and secretion,abnormal metabolism in the tumor microenvironment includes glutathione,the accumulation of reactive oxygen species,the release of inflammatory factors,and the abnormal metabolism of glucose and lipids,all of which have received extensive attention in the study of tumor treatment and drug resistance.Numerous studies have also shown that tumor cells reduce the p H in the tumor microenvironment by interfering with normal glycolytic pathways and causing changes in the corresponding pathways,thereby reducing drug sensitivity.However,compared with carbohydrate metabolism,abnormal lipid metabolism has received less attention,but recently more and more researchers have realized that highlevel lipid anabolism is another important feature of abnormal tumor metabolism and further verified the relationship between fatty acid oxidation and chemotherapy resistance,for example.This provides a basis for exploring the relationship between lipid metabolism and tumor drug resistance.Improving drug resistance by regulating lipid metabolism has gradually become a new therapeutic idea to be developed.As a kind of transmembrane mucin,Mucin1(MUC1)is highly expressed in a variety of tumors,including breast cancer,lung cancer,and colorectal cancer,and is involved in multiple processes of tumor development,such as tumor cell growth and proliferation,apoptosis inhibition,chemotherapy resistance,metastasis and invasion,etc.Recent studies have found that MUC1 is also involved in the lipid metabolism of tumor cells,mainly by promoting cholesterol synthesis in tumor cells through up-regulation of cholesterol synthetase.However,the increase in cholesterol content enables tumor cells to maintain their homeostasis through active ATP-binding cassette transporter(ABC)efflux cholesterol,and the increase in the expression of these family proteins leads to the generation of drug resistance.The presence of peripheral fat in the physiological environment of the kidney acts as a "greenhouse" for the development of kidney cancer drug resistance,and controlling the lipid metabolism of tumor cells offers a novel strategy for enhancing kidney cancer treatment resistance and suppressing tumor.Additionally,giving drug vectors tailored features can greatly enhance therapeutic efficacy.In the treatment of acute kidney damage,targeting selection between sialic acid and E-selectin receptors has been used.The physiological phenomena of increased E-selectin receptor expression in inflammatory environments also offers the potential for use in tumor therapy,however further research is still required to confirm E-selectin expression in kidney cancer.A self-assembled nanogene delivery vehicle made of polythylenimide can target E-selectin receptors to deliver small interfering RNA(siRNA)to silence MUC1 expression and reverse sunitinib resistance in renal cancer therapy.PEI,a common cationic polymer,can electrostatically interact with siRNA.PEI’s "proton sponge effect" also enhances gene medicines’ lysosome escape.We modified PEI using Polyethylene glycol(PEG),Ibuprofen(IBU),and Sialic acid(SA)at one end of PEG.Finally,SA-PEI-PEG-IBU(SPPI),an E-selectin receptor-targeting nanomicellar gene vector,was produced.FT-IR,1H-NMR,and GPC were used to characterize SPPIsupported material synthesis.SPPI micelles had good gene loading capacity and avoided anionic chemicals in vivo and gene drug degradation.DLS and TEM showed spheroid micelles with consistent particle size and zeta potential.SPPI/siMUC1 can function in vivo because SPPI was stable in vitro.SPPI micelles delivered siMUC1 into cells,regulated cholesterol,and regulated drug resistance.Confocal microscopy and flow cytometry examined SPPI vector cell entrance and uptake.Grid protein enabled SPPI vector entry into tumour cells,and sialic acid-mediated receptor targeting boosted tumour cell uptake.Real-time quantitative PCR and Western Blot measured tumour cell m RNA and protein expression following medication treatment.SPPI/siMUC1 in micellar delivery group showed better gene silencing efficiency and ability to regulate protein expression level,and the synthesis of lipid metabolite cholesterol in cells was also significantly reduced.As a result,the expression levels of some membrane pump proteins related to drug resistance,P-GP,ABCG2 and MRP1,were subsequently down-regulated.ELISA detected that the contents of inflammatory factors in PEI material delivery system and micellar delivery group were down-regulated to a certain extent,such as the secretion of interleukin-6(IL-6)and tumor necrosis factor(TNF-α)were reduced.The inflammatory microenvironment around tumor tissue was effectively improved.In addition,the scratch and Transwell experiments showed that siMUC1 had a significant inhibitory effect on tumor metastasis and invasion while regulating drug resistance.In vivo,SPPI/siMUC1 inhibits tumours and metastasis.SPPI targets and enriches tumour locations in in vivo drug distribution experiments.SPPI/siMUC1 nano-gene carrier injection into the tail vein and oral Sunitinib therapy reduced mouse tumour development in the subcutaneous tumour model.In vitro tumour tissue analysis showed that the SPPI/siMUC1 vector showed good histocompatibility,significantly inhibited tumour proliferation,reconstructed Sunitinib’s inhibitory effect on tumour neovascularization without obvious biological toxicity,and effectively inhibited tumour cell metastasis and invasion in lung tissue in vivo.This project’s SPPI gene carrier micelles load siRNA and silencing effectively.After suppressing MUC1,SPPI/siMUC1 altered tumour cell cholesterol metabolism,lowered drug-resistant protein expression,and restored tumour resistance to Sunitinib,restoring its clinical therapeutic efficacy.To treat tumours comprehensively,SPPI/siMUC1 inhibits lung metastasis and has a strong anticancer impact in vivo.This project’s vector delivery of gene drugs regulates lipid metabolism to reverse drug resistance and inhibits tumour progression,expanding kidney cancer treatment options and clarifying the relationship between abnormal lipid metabolism and tumour treatment.This provides a new way to improve drug resistance and inhibit tumor development by regulating the metabolism of the tumor itself. |
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