Liver Targeting Of Glycyrrhetinic Acid Modified Calcium Carbonate Hollow Nanospheres

Objectives To prepare a composite cavity nanospheres with sustained release,pH sensitivity,targeting and synergistic function in combinational drug delivery,using it as a drug carrier for liver cancer,and study its preparation conditions and in vitro and in vivo performance.Methods 1.The hollow spherical CaCO₃ nanospheres were prepared using soluble starch as a template.Glycyrrhetinic acid and sodium alginate were connected by ethylenediamine to generate polymer GA-ALG.The polymer GA-ALG was aggregated on the surface of the hollow CaCO₃ nanospheres to form the shell-core composite nanospheres GA-ALG-CaCO₃.2.The composite nanospheres loaded with DOX?DOX/GA-ALG-CaCO₃?was prepared by one-step method.The drug loading,encapsulation efficiency and in vitro release of drug loaded nanospheres were measured by fluorescence spectrophotometer.3.The human liver cancer cell HepG2 was selected to determine the cytotoxicity of CaCO₃,ALG-CaCO₃,GA-ALG-CaCO₃ in the blank group and DOX,DOX/ALG-CaCO₃,DOX/GA-ALG-CaCO₃ in the drug loading group by the MTT method.The uptake of DOX/ALG-CaCO₃ and DOX/GA-ALG-CaCO₃ nanospheres by HepG2 was investigated using the BCA method.4.The targeting evaluation of doxorubicin hydrochloride and drug-loaded nanospheres DOX/GA-ALG-CaCO₃ in mice were investigated respectively,using normal KunMing mice as a model.Results 1.The GA-ALG-CaCO₃ nanospheres were spherical with an average particle size of about 400 nm;Zeta potential was-17.0 mV.2.The DOX/GA-ALG-CaCO₃ nanospheres are spherical,with an average particle size of about 430 nm;Zeta potential was-13.6 mV.The drug loading was 13.06%,and the encapsulation rate was 75.11%.The results of in vitro release showed that the cumulative release rate of GA-ALG-CaCO₃ carrier on the condition of pH=7.4,pH=6.8,pH=5.5 were about 19.77%,38.73%,59.73% respectively in 24 h.3.The results of the cytotoxic experiments showed that the blank group of CaCO₃,ALG-CaCO₃ and GA-ALG-CaCO₃ had little effect on the survival rate of HepG2 cells.The IC₅₀values of DOX,ALG-CaCO₃,DOX/GA-ALG-CaCO₃ in the drug loading group were 0.551 ?g·mL^-1,0.241 ?g·mL^-1,0.095 ?g·mL^-1respectively.The results of cell uptake experiments showed that the uptake of DOX/GA-ALG-CaCO₃ nanosphere cells was much higher than that of DOX/ALG-CaCO₃,which indicated that GA modified nanospheres were more easily taken up by HepG2 cells.4.The results of animal experiments showed that GA-ALG-CaCO₃ nanospheres can improve the distribution of DOX in vivo and make DOX accumulated more in the liver.The results of liver targeting research showed that the targeting efficiency of DOX/GA-ALG-CaCO₃ drug-loaded nanospheres was 68.2%,which was much higher than that of the DOX control group 24.2%.Conclusions As a new type of drug carrier,the GA-ALG-CaCO₃ composite nanospheres have good pH-responsivity,higher drug loading,an obvious sustained-release property,and good liver targeting ability with the prospect of using in liver cancer targeting therapy.Figure 13;Table 23;Reference 88...