Construction And Propertics Of Nano-drug Delivery System Based On Diosgenin

Diosgenin(DGN)is a steroidal saponin active ingredient extracted from Chuandilong or turmeric.It is a new type of natural anticancer drug.Diosgenin can inhibit tumor growth and metastasis in a variety of ways:(1)inhibit tumor cell division and proliferation(2)induce tumor cell differentiation(3)enhance inhibition of oncogene expression(4)regulate cell cycle,etc.The anti-tumor effect of diosgenin has a broad spectrum and has good pharmacological effects on various tumors by inducing apoptosis.Its mechanism of action has the characteristics of multiple targets,multiple effects,and multiple links.However,diosgenin has poor water solubility,short cycle time in vivo,low biocompatibility,and undesired pharmacokinetic properties limit the clinical application of diosgenin.In this paper,the diosgenin was developed in response to the above problems.Chemical modification and its study of nano drug carriers to prolong their half-life and increase their bioavailability.The main work of this paper is as follows:1.The mPEG-DGN water-soluble prodrug was prepared by long-chain polymer PEG coupled with diosgenin(DGN),and the drug-loaded nanoparticles were prepared by self-assembly of 10-hydroxycamptothecin.And in vitro and in vivo drug efficacy testing.Based on the model drug of DGN,we prepared mPEG-DGN amphiphilic prodrug with DGN hydrophobic fragment and PEG hydrophilic fragment.The author also took advantage of the characteristic of the hydrophobic inner core to encapsulate another hydrophobic anticancer drug10-hydroxycamptothecin(HCPT)during the self-assembly process.This step greatly increased the drug loading efficacy,improved the water solubility and in vivo circulating half-life of DGN.The nanoparticle has good stability under physiological conditions,with suitable particle size(?190 nm)and high drug loading(HCPT:13.2%).2.In order to improve the drug-loading efficiency of diosgenin and obtain smaller particle size,8armPEG-DGN conjugate was synthesized from eight-arm polyethylene glycol with more reactive groups,and self-assembled with HCPT to prepare eight-arm polyethylene glycol-diosgenin-10-hydroxycamptothecin nanoparticles(8armPEG-DGN/HCPT NPs).Significantly increased reaction sites with DGN,with higher drug loading capacity(19.85%wt%for DGN and 14.72 wt%for HCPT)and approving particle size(?107 nm).In vivo hemolysis rate experiments showed that 8armPEG-DGN/HCPT NPs had lower hemoglobin release(<5%)and similar levels of IgE and WBC with the control group,and the toxic side effects of nanoparticles were lower than those of natural DGN and HCPT Furthermore,the in vitro and in vivo antitumor activities of nanomedicines have revealed that 8armPEG-DGN/HCPT NPs have excellent tumor growth inhibition effects.3.The nano-drug delivery system with active tumor targeting function was prepared by selecting the iRGD of the peptide as the target molecule and contacting the surface of the nanoparticle.The iRGD-PEG-DGN prodrug with active targeting function was successfully synthesized,the prodrug self-assembled with HCPT to prepared a highly efficient dule drug delivery system iRGD-PEG-DGN/HCPT NPs.The drug loading capacity of HCPT was 17.34 wt%.The fluorescence of the drug in the targeted nanoparticle cells was significantly higher than that of the natural drug group in the in vitro cell uptake experiment,which increased the accumulation of drugs in the tumor site and reduced the side effects on normal tissues.It is a worth learning idea in the construction of nano drug carriers4.The macromolecular prodrug lentinan-polyethylene glycol-diamond saponin(LPD)was successfully prepared by coupling lentinan(LNT)with the natural anticancer drug diosgenin(DGN).LPDH NPs were prepared by self-assembed method.The nanoparticles have good water solubility,stable particle size and controlled and sustainable release behavior.The results showed that LPDH NPs had smaller particle size(?143.2 nm)and higher drug loading capacity(HCPT:15.4 wt%)In the in vivo pharmacokinetic experiments,lentinan-based nano drug-loaded particles(LPDH NPs)prolonged the blood circulation half-life of diosgenin from 1.2 h to 9 h.The cytotoxicity of the nanoparticles was 199.1 times than that of natural drug DGN and 4.9 times of HCPT,respectively(B16)B16 tumor-bearing mice treated with LPDH NPs showed considerable survival advantage(83%survival on day 30).5.An intelligent nano drug carrier LFLPDH NPs based on lentinan redox response with multiple reducible disulfide bonds was prepared by selecting lipoic acid as a redox-responsive molecule.The physicochemical and pharmaceutical properties of the nanoparticles were evaluated.Lentinan and polyethylene glycol were used as co-carriers.First,the polyethylene glycol was coupled with the anticancer drug DGN,then the conjugate,the molecularly-targeted folic acid and the redox-responsive reagent lipoic acid were attached to the chain of the lentinan to prepare the prodrug LFLPD.The LLFPDH NPs prepared by self-assembled with HCPT have higher drug loading capacity(DGN:4.9 wt%),HCPT(20.4 wt%)and stable,uniform nanoparticle size(?186.2 nm).The release rate of the drugs in vitro growing faster as the concentration of glycopeptide(GSH)increased.At 0 and 10 Mm of GSH,the DGN release amount were 18%and 84%and HCPT release amount was 26%and 82%,respectively.The intracellular concentration of glutathione(GSH)and other reducing substances in the tumor site is 100-1000 times than that of the extracellular.Therefore,the prepared nano drug delivery system can remain stable in a non-reducing environment and can rapidly release the drug,promote the disintegration of the nanoparticles,and accelerate the release of the drug in the reducing environment at the tumor site.Anti-tumor experiments in mice showed that LFLPDH NPs have a good inhibitory effect on tumor growth and still have a high survival rate(83%)after 28 days of treatment with very low side effects.