Zinc-organic Hybrid Materials Loaded With Natural Active Small Molecule Drug And Its Biological Activity

With the development of cancer research,more and more natural active small molecules have become candidate drugs for clinical treatment of cancer.However,most of these natural drugs are difficult to dissolve in water,easily decomposed by light and heat,and difficult to be absorbed and utilized by organisms,which makes them suffer the great limitations in clinical application.Drug delivery systems(DDS)can improve the dispersibility of drugs in the aqueous phase,protect the drug by encapsulation,and promote the cellular uptake of the drug.Zeolitic Imidazolate Framework-8(ZIF-8),constituted of Zn2+and dimethylimidazole(2-MIM)by in-situ self-assembly,has low toxicity and good biocompatibility.In particular,ZIF-8 is easy to disintegrate under acidic conditions,which could be used as a carrier material for the pH-stimulated DDS.Furthermore,adenine,the bio-based ligand,was used to replace the organic ligand 2-MIM to prepare DDS with better biocompatible.The natural drugs curcumin and glabridin were loaded respectively to explore their biological activities,and make the certain contribution to the clinical treatment of cancer.1.The curcumin-loaded ZIF-8(CCM-ZIF-8)was prepared by an anti-solvent co-precipitation method.Firstly,the microcrystalline particles of the hydrophobic drug curcumin were prepared in the aqueous solution,and then used as the growth core of ZIF-8.Subsequently,Zn2+and 2-MIM are self-assembled in situ to form ZIF-8,and aggregate on the surface of the microcrystalline particles to simultaneously encapsulate the curcumin.CCM-ZIF-8 has the drug encapsulation efficiency of 98.21%,about 4 μm in size,and a regular fusiform or cruciate flower-like structure.The encapsulation of curcumin by ZIF-8 was characterized by UV,FS,TEM,SEM,Zeta potential,FTIR,XRD and TGA.In addition,the drug release behavior of CCM-ZIF-8 exhibits pH-sensitive properties.,and the cumulative release rate of curcumin was as high as 81.22%for 72 h in the simulated tumor slightly acidic environment.Compared with free curcumin,CCM-ZIF-8 exhibited mild DPPH free radical scavenging ability and significantly enhanced tyrosinase-inhibiting activity.Further,the anticancer activity of CCM-ZIF-8 against A549 cells was obviously improved,and the cellular antioxidant activity of CCM-ZIF-8 on MGC80-3 cells as an oxidative cell model was significantly enhanced,which is due to the good biocompatibility of ZIF-8 and improved cellular uptake capacity.2.The glabridin-loaded ZIF-8(Gla-ZIF-8)was prepared according to the idea of crystal seeded growth.Glabridin was chosen as the model drug to further verify the universality of the new ZIF-8 drug loading process for hydrophobic drugs.The prepared Gla-ZIF-8 has the drug encapsulation efficiency of 98.67%and a regular fusiform or cruciate flower-like structure with 3 μm in size.In addition,the characterization results of UV,TEM,SEM,Zeta potential,FTIR,XRD and TGA indicated that glabridin was loaded into ZIF-8.Further,Gla-ZIF-8 exhibits the pH-regulable drug release behavior,and the ability of Gla-ZIF-8 to inhibit melanogenesis was significantly enhanced.At the same time,Gla-ZIF-8 showed the pacific in vitro antioxidant capacity and the enhanced cellular antioxidant activity.In conclusion,the universality of the ZIF-8 drug-loading pathway based on crystal seeded growth for hydrophobic drugs was verified by two drug models(curcumin and licorice).3.CCM-Zn/Adenine was prepared by the coordination of adenine and Zn2+ to loading curcumin.The drug encapsulation efficiency of CCM-Zn/Adenine reaches up to 98.99%and the drug loading encapsulation efficiency of CCM-Zn/Adenine was 18.53%.Further,it was confirmed by UV,TEM,SEM,Zeta potential,FTIR,XRD and TGA that curcumin was loaded by Zn/Adenine.In addition,CCM-Zn/Adenine exhibited pH-responsive drug release character,the moderate DPPH free radical scavenging ability,and the enhanced inhibition of tyrosinase activity.In particular,Zn/Adenine showed excellent biocompatibility,and CCM-Zn/Adenine also exhibited low toxicity on normal cells(3T3 cells).Moreover,the anticancer activity of CCM-Zn/Adenine against A549 cells was markedly increased,and the intracellular antioxidant activity on MGC80-3 cells was signally enhanced.Therefore,Zn/Adenine is a safe and effective drug carrier,showing great potential for clinical treatment of cancer.