| 7-Ethyl-10-hydroxycamptothecin(SN38)was a semi-synthetic anticancer drug of HCPTs,which could combine with topoisomerase I,inhibit the synthesis of DNA and lead to cell apoptosis.SN38 had good anticancer activity on gastric cancer,pancreatic cancer,lung cancer and so on.SN38 was almost insoluble in water,and in most organic solvents,which restricted its application in clinical.In order to improve the solubility of SN38 in water,irinotecan(CPT-11)had been developmented.CPT-11 had been widely used in colon cancer,lung cancer,gastric cancer and other malignant tumors.CPT-11 could be hydrolysised to SN3 8 in vivo by carboxylesterase.Furthermore,the transformation of CPT-11 was only 2?8%in vivo with huge individual differences,delayed diarrhea and other serious side effects.Recently,the polymer micelles were prepared to improve the solubility,reduce side effects and target drug delivery.However,the polymer micelles was often companied with low drug loading,drug burst effect and other issues.In recent years,the macromolecular prodrug micelles were widely investigated.These macromolecular prodrug micelles not only can improve the solubility of poorly soluble drugs,but also have good biocompatibility,good in vivo pharmacokinetics and tissue distribution characteristics.The macromolecular prodrug micelles can effectively improve the problems of low drug loadings,drug burst release and so on.Our research used biocompatible water-soluble chitosan as carrier,succinic acid as connecting arm,with EDCI as esterification coupling agent,successfully synthesised the CS-(10s)SN38 and CS-(20s)SN38.We used the 1H-NMR,FT-IR,DSC and XRD to confirm the successfully synthesis of the two macromolecular prodrugsThese macromolecular prodrugs can self-assemble into nanomicelles,the particle size of CS-(10s)SN38 and CS-(20s)SN38 were 128.0 ± 1.8 nm and 122.4 ± 1.1 nm,respectively.PDI were 0.301 ± 0.025 and 0.248±0.013.Zeta potential were 21.1±0.5 mV ? 22.3±0.4 mV.The in vitro release of SN38 were studied by dialysis in different release medium for 48 hours.Both CS-(10s)SN38 and CS-(20s)SN38 could slowly release the active product of SN38 in the release medium.Cytotoxicity experiments showed that IC50 of CS-(10s)SN38 and CS-(20s)SN38 on CT26·WT cell line were(3.5 ± 0.2)× 103 nmol/L and(1.8±0.4)× 103 nmol/L,which were significantly lower than CPT-11.The endocytosis inhibition mechanism of the two macromolecular prodrug micelles were investigated.The uptake process of the two chitosan-SN38 macromolecular prodrugs has obvious energy dependence,the clathrin mediated endocytosis process is an important part of micellar uptake,endocytosis and caveolin mediated invagination were also existed.The pharmacokinetics of the two macromolecular prodrug micelles were investigated,the results showed that plasma AUC0-24 of SN38 of CS-(10s)SN38 and CS-(20s)SN38 were 20.8 and 16.3 times higher than that of CPT-11,respectively.The plasma half-life of SN38 of the macromolecular prodrugs were much longer than that of CPT-11(P<0.05).The tissue distribution was carried out with H22 tumor bearing mice,and the results showed that the drug in both of the macromolecuar prodrug micelles had aggregation in liver,spleen and lung tumor.Pharmacodynamic experiments showed that two macromolecular prodrug micelles had better tumor inhibitory effect than CPT-11 at the same dosage on CT26·WT bearing BABL/c mice.In the dosage of 2.5 mg/kg,the tumor inhibition rate of CS-(10s)SN38 and CS-(20s)SN38 were 47.8%and 64.7%,respectively,which were significantly higher than that of CPT-11(P<0.05)In summary,the chitosan-SN38 macromolecular prodrug micelles were sucessfully synthesized.Both of the macromolecular prodrug micelles can significantly improve solubility,the pharmacokinetics and tissue distribution characteristics and the antitumor activity. |
PDF Full Text Request