Construction Of PH-responsive Drug-loaded Calcium Nanomodulator And Its Synergistic Anti-tumor Research

Cancer is a serious public health problem and is currently treated by radiation therapy and chemotherapy.However,the lack of specificity and selectivity for tumor tissues of the conventional therapies is a drawback that can lead to numerous adverse effects on patients.In recent years,scientists have devoted energy to the progress of nano drug delivery systems,which have greater potential for multi-targeted functionalization,in vivo imaging,extended circulation time,systemic controlled release,and drug co-delivery than conventional drug delivery systems.Among them,calcium nanomodulators have been developed as"calcium overload"mediated mitochondrial damage for cancer therapy.Calcium nanomodulators release calcium ions as intracellular second messengers,and the intracellular concentration of calcium ions is critical for apoptosis,as excessive intracellular calcium ions can upregulate oxidative stress,causing mitochondrial damage and inducing apoptosis.However,there are various limitations of current calcium nanomodulators.For example,Ca²⁺concentration in mitochondria may rapidly return to normal levels due to natural excretion through Ca²⁺channels,which cannot affect calcium homeostasis.The lack of clear target sites which may cause damage to normal tissue and the poor therapeutic effect of single"calcium overload"therapy are also the problems need to be solved.To solve the above problems,a p H-responsive drug-loaded calcium nanomodulator（CaO₂@ZIF8:CUR@PAA NPs）was constructed to trigger the release of drug and calcium ions through the p H difference between tumor tissue and normal tissue.The zeolite imidazole backbone（ZIF8）was wrapped around CaO₂NPs by in situ deposition to maintain its stability,and the chemotherapeutic drug curcumin（CUR）was loaded on CaO₂@ZIF8 NPs by electrostatic adsorption,and the p H-responsive release was achieved by polyacrylic acid capping（PAA）.The morphology and structure of the calcium nanomodulators were characterized by TEM,nanoparticle sizer,XPS,XRD,UV-vis,etc.The experimental results demonstrated that the calcium nanomodulators were successfully prepared and showed a distinct core-shell structure with a particle size of about 164 nm.By in vitro Ca²⁺release experiments,in vitro drug release experiments,it was verified that the drug loading rate of CaO₂@ZIF8:CUR@PAA NPs is 21.12%,the encapsulation rate was 88.86%and CaO₂@ZIF8:CUR@PAA NPs had good p H responsiveness and sustained drug release properties.After CaO₂@ZIF8:CUR@PAA NPs encountered an acidic environment,the PAA layer was dissociated from ZIF8 and Ca²⁺was released from CUR,which promoted Ca²⁺release from the endoplasmic reticulum to the cytoplasm and inhibited Ca²⁺efflux,resulting in intra-tumor cell CUR promoted Ca²⁺release from the endoplasmic reticulum to the cytoplasm and inhibited Ca²⁺efflux,causing intracellular"calcium overload"and mitochondrial damage;intracellular mitochondrial damage and Ca²⁺accumulation experiments demonstrated that CUR-mediated chemotherapy synergistically enhances the effect of"calcium overload"therapy.The in vitro cytotoxicity and in vitro antitumor assays demonstrated that CaO₂@ZIF8:CUR@PAA NPs could accumulate in cancer cells with less damage to normal cells,and could significantly enhance the killing effect on cancer cells with the synergistic effect of chemotherapy and"calcium overload"therapy.In summary,we have successfully prepared CaO₂@ZIF8:CUR@PAA NPs combining"calcium overload"and chemotherapy by a simple synthesis method,which is an effective cancer therapeutic agent with synergistic effect,good biocompatibility,p H responsiveness,and this well-designed multifunctional calcium nanomodulators have immense potentiality for clinical applications.