Targeted Delivery Of SNX-2112 By Novel Graphene Nanocarriers For Treatment Of Lung Cancer

Background:Lung cancer is the malignant tumor with the highest morbidity and mortality in the world,with a poor prognosis and a 5-year survival rate of less than 20%.Previous studies have shown that patients with malignant tumors have elevated levels of heat shock protein 90(Hsp90).High levels of Hsp90 can inhibit tumor cell apoptosis,induce tumor angiogenesis,and promote tumor invasion and metastasis.The level of Hsp90 in peripheral blood and tissues of patients with lung cancer is significantly increased.High level of Hsp90 indicates poor prognosis.Down-regulation of Hsp90 can inhibit tumor growth.SNX-2112 is an Hsp90 inhibitor,which is a promising anti-tumor drug by competitively binding to the ATP site on Hsp90,causing degradation of the receptor protein and inducing apoptosis of various tumor cells.There are few studies on whether down-regulation of Hsp90 can inhibit lung cancer growth.However,SNX-2112 has little research in lung cancer,and the anti-tumor mechanism is still unclear,and the poor water solubility limits its wide application.In order to better carry out the therapeutic effect and molecular mechanism of SNX-2112 on lung cancer,we introduce the nano drug carrier graphene oxide-Chitosan-hyaluronic acid(GO-CHI-HA)to enhance its water solubility,so as to achieve specific recognition of lung cancer cells and improve the anti-tumor efficacy of SNX-2112.Methods and results:1.Effects of SNX-2112 on proliferation,apoptosis,invasion and migration of lung cancer cells:As the concentration of SNX-2112 increased and the time prolonged,the inhibition and killing effect on lung cancer cells increased by CCK-8 and flow cytometry.With the increase of SNX-2112 concentration,the invasion and migration ability of lung cancer cells decreased by wound healing test and transwell assay.2.Molecular mechanism of anti-tumor effect of SNX-2112:Western blot test results showed that after treatment with SNX-2112,the levels of E-cadherin,GSK3?,and p-?-catenin increased,while those of ?-catenin,p-GSK3?,N-cadherin,and Vimentin decreased in lung cancer cells,and SNX-2112 might exert its effects by inhibiting epithelial-mesenchymal transition(EMT)and Wnt/?-catenin pathway.3.SNX-2112 inhibited proliferation and induced apoptosis of lung cancer cells in vivo:The results of tumor formation test in nude mice showed that the tumor volume was significantly reduced,tumor necrosis and apoptosis significantly increased,and proliferative index Ki-67 decreased in the SNX-2112 group compared with the control group.4.Synthesis and characterization of nanocomposite:Nanocomposite carriers GO-CHI-HA and GO-CHI were prepared.The characterization of the nanocarriers suggested that GO-CHI and GO-CHI-HA were successfully prepared and exhibited great drug loading efficiencies Drug release experiments in vitro showed that the release behaviour of SNX-2112 from GO nanocomposites was time-dependent and pH-triggered.Confocal microscopy images indicated that GO-based nanocomposites could be efficiently and rapidly internalised into A549 cells,and the nanocomposites were observed to localise both in the cytoplasm and nucleus.The cellular uptake of GO-CHI-HA-FITC was greater than GO-CHI-FITC.5.In vitro and in vivo studies on the safety of nanocarriers before and after loading SNX-2112:GO-CHI-HA and GO-CHI-HA/SNX-2112 have lower cytotoxicity to HBE.GO-CHI-HA within 0.2mg/mL was safe to RBCs.GO-CHI-HA at a concentration of under 0.05 mg/mL in the whole blood was more suitable for intravenous injection applications.Compared with the control group,the changes of blood and biochemical indicators before and after administration of the other groups were not significant,indicating that systemic side effects of GO-CHI-HA and GO-CHI-HA/SNX2112 can be tolerated.6.Nanocarriers enhanced anti-tumor effect of SNX-2112:Compared with the SNX-2112 group,GO-CHI-HA/SNX-2112 is more effective in inhibiting and killing lung cancer cells,which confirming its enhanced antitumor effect in vitro by CCK-8 and flow cytometry.CONCLUSIONS:SNX-2112 may inhibit the proliferation,invasion and migration of lung cancer cells by inhibiting the Wnt/?-catenin pathway in vitro and in vivo.The GO nanocomposite has a promising biomedical application,due to its small side effects on normal cells and tissues and improved the anti-tumor effect of SNX-2112.