一氧化氮的靶向投递与光控释放

Nitric oxide (NO), an endogenously produced biological signaling molecule, plays key roles in various physiological and pathological processes, including vasodilation, immune response, neurotransmission, respiration and apoptosis. The biological functions of this molecule greatly depend on the location, timing, and dosage at which it is released. It is highly imperative to develop a NO-delivery platform that is capable of holding NO stably during storage and subsequently release optimal amounts of NO spatiotemporally at the desired location and time. In this research proposal, novel multifunctional photo-controlled NO delivery nanoplatforms will be prepared and intensively studied. Firstly, a series of novel ruthenium nitrosyl donors will be designed and prepared. The properties of photo-induced NO release from those ruthenium nitrosyl will be tuned by varying the nature of the coordinated ligands. Secondly, various kinds of NO delivery nanoplatforms will further be assembled, which consist of a covalent attached ruthenium nitrosyl, a target directing group (e.g. folic acids, and galactose) and a nano carrier such as carbon dots, (C/F/B-doped) titanium dioxide, nano graphene oxide, iron oxide and ultrasmall Au nanoclusters. Finally, the feasibility of target directing and photo-triggered intracellular NO release will be investigated by various methods and the photo cytotoxic effects of the nanoplatforms will be evaluated in vitro and in vivo, respectively. The objective of this proposal is to tune the nanoplatform for photo-triggered NO delivery from UV to NIR light through both of ligand design and carrier modification; to prepare a stable, multifunctional NO delivery nanoplatform with functions such as target directing, fluorescence tracking, and NIR photo-controlled multi-targets attacking. The results obtained will offer great potential for precise delivery of NO in targeted cells or sub-cellular sites on demand by NIR light manipulation. It could have significant implications for NO mediated therapy as well as multimodal phototherapy.

一氧化氮是生物体内作用广泛的信号分子，对许多生理过程起着非常重要的调控作用并参与机体疾病的发生和发展过程。实现外源性的一氧化氮小分子在生物体内的靶向定点、定时、定量的可控释放将对一氧化氮介导的治疗具有非常重要的科学理论意义和实用性。本课题从配体分子结构出发设计合成系列新型金属钌亚硝酰供体，通过研究钌亚硝酰供体的光物理学及光致一氧化氮释放动力学性质，建立一氧化氮供体分子结构与光致一氧化氮释放的性能之间的关系；结合纳米和表面涂层技术，构建具有选择性投递到特定细胞或亚细胞器的新型近红外光光控一氧化氮纳米投递体系，研究光控释放一氧化氮对细胞生理功能的影响规律；结合光动力学、光热等多模式疗法，构建稳定性高，生物相容性好，集荧光示踪诊断和多模式治疗于一体的多功能一氧化氮纳米药物体系并研究其抗肿瘤活性及作用机制。通过该项目的研究将进一步丰富和发展一氧化氮介导的治疗方法并奠定一定的理论基础。

一氧化氮是一种内源性的生物信号分子，参与机体多种生理和病理过程。开发出生物相容性好，能在特定位点可控释放一氧化氮的递送体系对于其介导的疾病治疗具有非常重要的意义。本课题针对生理环境中不稳定的一氧化氮的精准可控递送科学问题从配体分子结构和纳米载体的表面功能化出发设计合成了系列新型金属钌亚硝酰供体共价负载的一氧化氮纳米递送体系，通过改变钌亚硝酰供体的结构和纳米载体的种类与表面功能修调控纳米递送体系的光致一氧化氮释放性能、体系的光热、光动力学性能、体系的示踪，靶向性能及联合给药性能。成功构建了具有选择性靶向投递到特定癌细胞（如肝癌细胞，人宫颈癌细胞）及定位于线粒体，溶酶体亚细胞器的新型近红外光光控一氧化氮纳米投递体系；结合光动力学、光热、化疗等多模式疗法，构建了稳定性高，生物相容性好，集荧光示踪诊断和多模式治疗于一体的多功能一氧化氮纳米药物体系，并研究了其抗菌、抗肿瘤活性及作用机制。研究结果对于发展一氧化氮介导的多模式肿瘤治疗和伤口细菌感染治疗具有非常重要的理论意义和潜在应用价值。