具有仿生催化活性介孔纳米体系的构建及其靶向诱导一氧化氮释放研究

Deficiencies in NO biosynthesis have been linked to disfunctions or disorders of a number of living organs. Thus, strategies for delivering exogenous NO with a targeting, controlled and long-term style hold great promise for a number of disease therapies.The current project aims to develop a novel drug delivery system based on mesoporous silica nanoparticles (MSNs), which could trigger the nitric oxide (NO) generation in situ from the endogenous S-nitrosothiols (RSNOs) within the special pathological milieus, such as cardiovascular disease or cancers with a targeting profile. Mesoporous nanocarriers with tunable large pore sizes will be synthesized. The optimized NO generation would be achieved by finely matching the sizes of the different mimic catalytic molecules and the pore channels of the employed nanocarriers.Various mimic catalytic active centers will be designed, which could be effectively grafted onto the internal surface of the synthesized nanocarriers and serve as catalysts for the long-term NO generation from RSNOs. The amount and speed of the generated NO would be correlated with the grafted amount of the active centers. Large quantities of bonding sites would be available for the mimic catalytic active centers on the internal surface of the nanocarrier with specific surface areas up to a thousand square meters per gram; meanwhile, the PEG and targeted group modification on the external surface would benefit to the delivery of the nanocarrier to the special tissue populations.This project would pave a new way for the drug deliveries and the therapies of some serious diseases through current researches on some pivotal physiological and pathophysiological processes, such as anti-platelet aggregation or the inhibition of the cancer cell proliferation, where NO would play a key role in the regulation of their development.

人体内NO缺失会引起多种器官功能失调，因此，靶向、可控并长效地提供外源性NO对诸多疾病的治疗具有重要意义。本项研究拟针对各种疾病（如心血管、癌症）的特殊环境中存在的亚硝基硫醇(RSNOs)，开发出新型介孔纳米可靶向原位诱导NO从RSNOs分子中释放的药物系统。合成孔径可调的大孔道介孔纳米载体，依据不同仿生催化活性组分的大小，选择不同孔大小的载体与之匹配，达到最佳催化NO释放的效果。设计出多种仿生催化活性中心，能够有效催化RSNOs持续产生NO且能嫁接到所合成的纳米载体的内表面，所产生的NO的速度和量可依赖活性中心的量进行调节。纳米级的，比表面积高达上千平方米每克的内表面为仿生活性催化中心的负载提供了大量位点，而外表面PEG和靶向基团的修饰可使纳米载体充分导向到病变组织。通过选择对NO药物具有明显响应的生物学特性，如抗血小板凝集和抑制癌细胞生长等的研究，可望为重大疾病的治疗提供新的给药途径。

一氧化氮(NO)是生物体内重要的信使和效应分子,可控提供NO对诸多疾病的治疗具有重要意义。利用载体负载并释放NO为它的可控供给提供了有效途径。本项目中，我们合成了系列纳米载体，应用于NO的输送，并对所合成的体系进行了生物学效应研究。. 首先，合成了粒径小于150纳米的介孔载体，控制了形貌和孔大小，为药物释放应用提供良好平台。载体能够被癌细胞吞噬，表明材料可做为生物大分子胞内输送载体。成功合成具有羧基功能化、尺寸可调的介孔载体。该载体分散性好、具有高的比面积、大的孔容。同时在纳米载体中成功引入具有磁性功能的核，使得该体系具有磁靶向功能。该载体能有效负载药物，并将其输送到胞内环境，为其生物医用应用奠定良好基础。. 其次，成功开发NO释放体系，该体系能够长时间释放NO，释放总量可达0.148μmol/mg，为NO的可控释放奠定基础。开发出可催化亚硝基硫醇（RSNO）原位释放NO的催化体系，利用Cu2+，抗坏血酸，光照促发GSNO分解释放NO，为靶向传递NO提供了充分依据。制备出稳定性好的含有金纳米粒子的水凝胶体系，能够催化GSNO释放NO，为原位NO的产生提供了载体。. 最后，合成了数种颗粒尺寸小于100nm的金属有机骨架（MOFs）载体。该载体能有效被癌细胞吞噬，具有出色的稳定性以及好的生物相容性。获得了一种新型的能够释放NO的RSNO化MOFs，实现了抑制癌细胞生长的目的，并可持续缓慢释放NO。基于UiO-66-SNO优异的抑癌功效，可望成为新一代NO载体。合成了数种颗粒表面具有连续磷脂层（PBLs）的MOFs纳米晶体，可显著提高材料的耐磷酸盐和其他化学稳定性，这种策略为实现生理环境下众多生物医药应用提供基础。