Increasing The Solubility Of Hydrophobic Drug 7-ethyl-10-hydroxy Camptothecin Based On Pi-Pi Interaction

Cancer generally refers to all malignant tumors.It is a major public problem endangering human health and the second leading cause of death in the world.Because cancer is often found in the advanced stage,the cancer cells will spread through the blood or lymph,radiotherapy and surgery are localized,the treatment of advanced cancer has little effect.Chemotherapy is a common treatment for advanced cancer,in which patients take or inject chemicals to kill cancer cells in order to cure the cancer.Most anticancer drugs have poor water solubility,and because human cells are in an aqueous environment,increasing the water solubility of anticancer drugs will make an important contribution to the treatment of cancer.7-ethyl-10-hydroxy-camptocampin(SN38)is an active metabolite of the first-line anticancer chemotherapy drug Irinotecan hydrochloride(CPT-11).Its anticancer effect in vitro is 100-1000 times higher than that of CPT-11,and it is a potential anticancer drug.However,due to the very low solubility and poor stability of SN38 and other shortcomings,the practical clinical application is largely limited.Aiming at the problem of extremely low solubility of SN38,the exploration of solubility enhancement has important research value and significance.In this study,7-ethyl-10-hydroxy camptothecin and containing hydrophilic groups of small molecular aromatic compound dopamine(DA)according to π-πstacking principle combined together to form 7-ethyl-10-hydroxy camptothecin-dopamine(DA-SN38)complex,using the added hydrophilic groups to enhance the solubility of hydrophobic drugs.The solubilization degree,particle size,potential,toxicity of cancer cells and binding mechanism of SN38 were systematically studied by ultraviolet absorption spectrum,fluorescence spectrum,dynamic light scattering,cytotoxicity test,molecular docking,Density functional methods and molecular dynamics simulation.The experimental results showed that the solubility of Da-SN38 after the combination of SN38 and DA was 33.5 times higher than that of SN38,and the cancer cell toxicity of the binding compound was significantly stronger than that of SN38.MD simulation results show that the RMSD value of the system reaches equilibrium and fluctuates around the mean value after 76 ps simulation time,indicating the formation of stable DA-SN38 complex.In summary,this study increased the solubility of the insoluble anticancer drug7-ethyl-10-hydroxycamptothecin.Based on this,the cancer cell toxicity experiment proved that the drug effect was enhanced,and the use of Gaussian and Discovery studio 2019 And other software for dynamics and molecular simulation.We believe that DA-SN38 with a particle size as small as 40 nm will have an EPR effect;cancer cells are in a water environment in the human body,and drugs with high solubility are easy to enter cancer cells;DA-SN38 has a potential of-20 m V,and the surface of cancer cells is positively charged;All of the above characteristics are conducive to the entry of drugs into cancer cells.This article has made an important supplement for the combination of small molecules and poorly soluble drugs,and hopes to provide ideas for the combination of other different types of small molecules and poorly soluble drugs,and contribute to the treatment of cancer or other diseases.