Synthesis Of Calcium-Based Nanocomposites For Antitumor Immunotherapy

Calcium ions(Ca²⁺),as sencond messengers,paly a crucail role in intracellular physiological processes.Inducing Ca²⁺overload by disturbing Ca²⁺homeostasis in tumor cells is a new way to kill tumor.However,it is difficult to achieve effective inhibition of tumor metastasis and recurrence with Ca²⁺overload therapy alone.Immunotherapy,which kills tumor cells by activating the body’s immune system,is considered as an important means of inhibiting tumor metastasis and recurrence.However,whether Ca²⁺overload can effectively activate the immune system,and how to synergistically enhance the antitumor immune effect of Ca²⁺overload are still urgent problems to be solved.The unique immunosuppressive microenvironment of tumor tissue is a key factor restricting immunotherapy.As an immunogenic programmed cell death method,pyroptosis has been proven to activate antitumor immunity through reversing the immunosuppressive microenvironment.The disordered metabolic state in tumor tissue,especially the elevated lactate level,is conducive to the establishment of an immunosuppressive microenvironment.Based on this,this dissertation proposes two strategies to relieve the immunosuppressive microenvironment,those are Ca²⁺overload combined with pyroptosis,and Ca²⁺overload combined with lactic acid inhibition for antitumor immunotherapy.In this dissertation,two calcium-based nanocomposites（CaO₂@ZIF-8/CUR-HA and CaO₂@ZIF-8@CHC-HA）were constructed by using CaO₂ nanoparticles as the Ca²⁺source and zeolite imidazolate framework（ZIF-8）as the carrier to load curcumin（CUR）andα-cyano-4-hydroxycinnamic acid（CHC）to realize immunotherapy,respectively.The main research contents are listed as follows:1.We successfully synthesized CaO₂@ZIF-8/CUR-HA nanomaterials by encapsulating CaO₂ and CUR in ZIF-8 through a one-step method.This intelligent responsive nanomaterial,which release Ca²⁺release and H₂O₂ in tumor micoenvironment（TME）,can effectively induce Ca²⁺overload and pyroptosis.Moreover,they have shown excellent tumor growth inhibiton and immune activation ability in the CT26 mouse subcutaneous tumor model.The transcriptomic analysis further verified that the nanomaterial can effectively activate immune-related signaling pathways.2.We successfully prepared CaO₂@ZIF-8@CHC-HA nanomaterials by loading the drug CHC in CaO₂@ZIF-8.The nanomaterial,degrading and releasing Ca²⁺and CHC in TME,can induce Ca²⁺overload and inhibit lactic-acid-induced macrophage M2 polarization,effectively reverse the immunosuppressive microenvironment,and demonstrate effective antitumor immunotherapy ability in the mouse 4T1 subcutaneous tumor model.In summary,two calcium-based nanocomposites were designed for antitumor immunotherapy by relieving of immunosuppressive microenvironment through the combination of Ca²⁺overload with pyroptosis,as well as the combination of Ca²⁺overload with inhibition of lactic acid efflux.This research provides an important idea for calcium-based nanocomposites in the field of antitumor immunotherapy.