| Background and ObjectiveIt is well know that malignant tumor is one of the life-threatening diseases and remained as a major health burden throughout the word.At present,chemotherapy is still one of the most important therapeutic options for cancer therapy.Doxorubicin is an excellent anthracycline-based and cell non-specific antitumor drug which can inhibit the synthesis of DNA and RNA,mainly used for the treatment of acute lymphoblastic and breast cancer.However,a large number of research data show that this kind of drugs have lots of side effects,including does-dependent irreversible myocardial lesions,bone marrow suppression,vomiting,hair loss and the mortality rate caused by congestive heart failure could reach to 20-40%,have limited the application in cancer therapies.In recent years,the emergence of nanotechnology have provide a new idea for design the anticancer drugs.Nanodrug delivery systems are expected to could release drugs slowly,prolong the action time and change the tissues distribution of drugs since could enhance the therapeutic efficiency and reduce the toxic side effects which could realize its application in tumor therapy.Metal-Organic Frameworks(MOFs)are new kind of porous organic-inorganic hybrid functional materials.Compared with other classic inorganic microporous materials,MOFs have better structure to be cut,easy functionalization and the characteristic of high specific surface area,which show important prospect in optics,catalysis,biological imaging,biological sensing,gas recognition and storage.Interestingly,recent studies suggest that MOFs also show many characteristics of the drug carrier,such as MOFs have high surface area and large pore size which are suitable for coating drugs.In addition,there are relatively unstable coordination bond between metal and ligand so that MOFs get biodegradability.Besides,MOFs also can carry multiple functional groups by modifying.In recent years,foreign scholars also have studied the MOFs as a drug delivery system and the results show that the MOFs can achieve high drug loading rate as well as controlled release.Therefore,our research group has synthesized a new MOFs called MOFs NP-101 and try to use DOX as a model drug to obtain MOFs NP-101/DOX inclusion compound and then the pharmacokinetics were evaluated in vivo.We expect MOFs NP-101/DOX could realease the DOX slowly,reduce its side effects,which could provide basic data for the development of new preparations of DOX.Methods: The study try to investigate the structure and toxicity of MOFs NP-101 and then build the drug-loading MOFs NP-101/DOX system.To detecte the pharmacokinetic characteristics and cardiac toxicity of MOFs NP-101/DOX.1.SEM assay was used to confirmed the structure of MOFs NP-101 2.The particle size and Zeta potential of MOFs NP-101 were analysised through the nanometer particle size assay.3.MTT and Zebrafish experiment were used to evaluate the toxicity of MOFs NP-101 on non-tumor cell lines HEK293,NIH3T3 and zebrafish embryos,respectively.4.Freeze-drying method was used to construct MOFs NP-101/DOX delivery system.5.The preparation technics were optimized by the single factor experiment and the central composite design with response surface methodology.6.In vitro drug release experiment was conducted to investigated the release characteristics of MOFs NP-101/DOX.7.Pharmacokinetic model was constructed to test the pharmacokinetic characteristics of MOFs NP-101/DOX.8.Myocardial enzymology check and HE staining assay were used to detect the cardiotoxicity of MOFs NP-101/DOX.Results:1.SEM results showed that MOFs NP-101 had oblong shape,smooth surface and possessed high crystallinity and purity.2.Average particle size of MOFs NP-101 was about 130 nm and Zeta potential was about-12.5 mv.3.MOFs NP-101 was low toxicity on both non-tumor cells and zebralish embryos.Treatment with the highest concentrations of MOFs NP-101 between 0 and 500 ?M for 48 h didn't inhibit the proliferation of non-tumor cells(HEK293 and NIH3T3)and the growth of zebralish embryos.4.The optimum prepatation method of MOFs NP-101/DOX was determined by the single factor experiment and the central composite design experiment: the ration of the drug to carrier was 1.5,the p H of the aqueous phase was 7.17 and the ultrasonic time was 25 min.Under this condition,the best entrapment efficiency of MOFs NP-101/DOX was 95.6%.5.The releasing test results in vitro showed that MOFs NP-101/DOX released DOX faster within 10 h and the cumulative release of DOX was 60%.Then MOFs NP-101/DOX could release DOX more stablely,the cumulative release of DOX within 72 h was 85.1%,indicating that MOFs NP-101/DOX possessed the sustained-release effect in vitro.6.The plasma concentration results showed that the half-life time and MRT were about 3.6 and 1.73 times than that of DOX group,respectively.Suggesting that MOFs NP-101 possessed the ability of slow-release drugs as a carrier and MOFs NP-101/DOX could decreased the clearance rate of DOX.7.The results of tissue distribution in heart showed that the half-life time and MRT in MOFs NP-101/DOX group were 2.922 and 3.055,which was singnificantly lower than that of 33.148 and 11.409 in DOX group,respectively.Additionally,the AUC of the DOX group was 57.738,while the AUC of the MOFs NP-101/DOX group was 5.874,which was about 1/10 of the DOX group.These results suggested that MOFs NP-101/DOX could significantly accelerated the metabolic of DOX in the heart and reduce the cardiotoxicity of DOX to a certain extent.Furthermore,in the liver tissue,the half-life time,AUC and MRT of DOX in MOFs NP-101/DOX were 19.62,182.094,12.032,which was significantly larger than that of 9.509,45.566 and 10.758 in DOX group,respectively.Indicating that MOFs NP-101/DOX could increase DOX accumulation and decrease its metabolism in the liver,which possessed a certain passive targeting property to liver.8.The results of myocardial enzyme test showed that the amount of LDH,AST,CK and CK-MB were significantly increased in DOX group compared with control group,while MOFs NP-101/DOX group had no obvious difference compared with control group.9.H&E staining results showed that compared with control group,the myocardic fibers in DOX group came to disorder,and part of them became fracture,lighter sarcoplasmic staining and eosinophilic lesions which showed larger cardiotoxicity,while MOFs NP-101/DOX group had no significant difference compared with control group.Conclusions:1.MOFs NP-101 possessed excellent characteristics as a drug carrier.2.MOFs NP-101/DOX delivery system possessed the sustained-release effect of DOX in vitro and in vivo.3.MOFs NP-101/DOX delivery system possessed certain liver passive targeting property and could reduce cardiotoxicity of DOX to a certain extent. |
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