Studies Of PH-sensitive MOF Nanoparticles Encapsulating Drugs For Autophagy And Antitumor Therapy

The synthesis of special-responsive materials for drug delivery can decrease the toxicity of drug in therapy and increase the target for cancerous cells.ZIF-8,one kind of MOFs was been synthesed to encapsulate autophagy inhibitor(3-methyladenine),major component of green tea(epigallocatechin-3-gallate)and epigallocatechin-3-gallate derivative(EGCG palmitate)through one-pot in this paper.The study of morphology,pH-responsivity,effects on autophagy and antitumor can provide a series of experimental and theoretical supports in the utilization of biomedical and materials fields.The main contents and results are summarized as follows.Cisplatin,as a significant chemotherapeutic drug for the treatment of cancers,has been combined with rapamycin(RAPA),an autophagy inducer,or 3-methyladenine(3-MA),an autophagy inhibitor.Cisplatin combination drugs have been explored stronger effects on the autophagy and the cytotoxicity than solo drugs.The thermodynamic function of interaction between cisplatin combination drugs and human serum albumin(HSA)is investigated under fluorescence,synchronous fluorescence and circular dichroism analysis.Isothermal titration calorimetry(ITC)was used to record the heat flow power-time curves of HeLa cells in the presence of cisplation combination drugs with various concentrations,which indicate that when the autophagy is induced,the heat speed is increased which is consistent with the TEM images showing increasing number of autphagosomes.Due to the pH-sensitivitiy,zeolitic imidazolate framework(ZIF-8)crystal,an advanced functional material for small-molecule delivery,were designed to load 3-methyladenine(3-MA)for antitumor.In the acidic microenvironment of tumor,3-MA@ZIF-8 nanoparticles degrade and release 3-MA.The experiments in vitro demonstrate that ZIF-8 nanoparticles have low toxicity.It can increase the uptake efficiency and effective concentration of 3-MA.Therefore,3-MA@ZIF-8 have stronger effects on autophagy than 3-MA.The in vivo experiment shows that ZIF-8 can delivery 3-MA to tumor site,downregrate the autophagy related protein and inhibit the growth of tumor without effecting vital organs.Moreover,the pharmacokinetics in vivo reveal the 3-MA@ZIF-8 nanoparticles can be excreted through urine and feces while having no toxicity on liver and renal function.Zeolitic imidazolate(ZIF-8)framework are optimized to encapsulate EGCG with target toward tumor and increased stability in air,which can increase antitumor effects of EGCG.EGCG@ZIF-8 nanoparticles with EGCG loading rate of 50%(which exceeds the loading percentage of other drugs in ZIF-8 nanoparticles)maintain stable and good compability in neutral environment,while dissociating and releasing EGCG in an acidic environment.The in vitro experiments reveal that EGCG@ZIF-8 nanoparticles can decrease the ROS levels,as compared to free EGCG which indicates a higher antioxidative bioactivity.The improved therapeutic efficiencies of EGCG@ZIF-8 NPs are demonstrated by targeting towards tumor sites,up-regulating apoptosis and autophagy proteins in tumor tissues,and effectively inhibiting tumor growth.A kind of EGCG derivative,EGCG palmitate(PEGCG),was synthesized and encapsulated in ZIF-8 nanoparticles with functionalization of folic acid(FA),which is commonly used as pH-responsive drug carrier.The chemical characterization reveal that ZIF-8 nanoparticles encaplucate PEGCG inside and their outside is successifully modified by FA molecule.The end of FA is contected by PEG,which ensures the flexibility of FA.With the target recognition between folic acid(FA)on the surface of nanoparticles and overexpressed FA receptor(FR)on cancerous cells,the nanoparticles can be efficiently internalized into cells,release PEGCG in acic environment,regulate oxidative stress,consistent with upregulation of LC3 and downregulation of p62.It results in the decrease of ROS levels,induction of autophagy and inhibition of tumor growth.