基于矿化双膦酸微纳米颗粒的新型佐剂免疫作用机制研究

近年越来越多的研究表明，体内代谢与免疫息息相关。双膦酸盐是用于骨疾病、钙代谢性疾病治疗的一类药物，也可作为免疫增强剂刺激机体产生高效的体液和细胞免疫应答。双膦酸类化合物与多价金属离子（如锌、锰）具有高亲和力，可通过成盐或螯合，而矿化成稳定的有机无机杂合微纳米颗粒，该非可溶性颗粒可通过肌肉注射等局部给药，因其具有缓释作用延长抗原递呈时间，增强佐剂活性，同时降低与可溶性钙螯合而引发的低钙血症等系统性毒性。因此，矿化双膦酸微纳米颗粒的药学性能、活性组份的释放及其与抗原间的相互作用将提高其成药性。本研究拟通过CyTOF、Cytometry、Luminex等技术对免疫细胞及细胞因子进行全景式分析，系统性探究免疫活性增强的分子基础，尤其是对Th1/Th2免疫通路的系统及定量分析，提供优于铝佐剂的高效新型佐剂，全面提升机体的适应性免疫应答，尤其在新冠疫情肆虐的当下及老年免疫学上将有效助力疫苗研发。

Recent studies have shown that many compounds used for treating metabolic disorders have significant immune-stimulatory activity, likely due to the close inter-relatedness between metabolism and immune response. Bisphosphonates (BPs) are a class of drugs that have been used for the treatment of skeletal diseases and bone metabolic diseases. In the meantime, clinical studies have shown that the adjuvant treatment using these compounds for multiple myeloma, breast cancer, kidney cancer and other malignant tumors can significantly improve the clinical outcomes due to their immune-stimulatory activity. BPs were shown to induce efficient humoral and cellular immune responses, making them likely candidates as immunopotentiators in the treatment of cancers or emerging infectious diseases. BPs have a high affinity with di- or tri-valent metal ions. Thus, soluble BPs can be mineralized into form insoluble and stable micro-nanoparticles, like the widely used inorganic Alum adjuvants. These organic-inorganic hybrid adjuvants can be administered locally by intramuscular injection. Mineralized BP particulate adjuvants have a depot effect and sustained release of active components and the adsorbed antigens on the surface. The localized delivery would ensure good adjuvant activity in recruiting antigen presenting cells, reducing systemic toxicity such as hypocalcaemia. Therefore, the pharmacological properties of mineralized BP micro-nanoparticles and their interaction with antigens will enhance the druggability of novel adjuvants. In this proposal, Time of Flight Mass Cytometry (CyTOF), Flow Cytometry and Luminex will be used for panoramic analysis of relevant immune cell populations and cytokines, towards the goal of systemic exploration of molecular basis of immunopotentiation for these particulate adjuvants. These in-depth studies on immunomodulation would pave the way for BP-based micro-nanoparticles progressing into a novel and effective adjuvant. Such an adjuvant would offer additional advantages over the widely used aluminum adjuvant platform for stimulating a balanced Th1/Th2 adaptive immune response. With increased knowledge on the immunomodulation and newly developed novel adjuvant platform, tougher problems such as low response to vaccination due to immunosenescence in aged populations and needs for rapid vaccine development against emerging pathogens in an epidemic and/or pandemic setting could be addressed.