pH和NIR双重响应型靶向纳米气体诊疗剂的合成及其协同诊疗性能研究

The nanotheranostic agent based on therapeutic gases (e.g. CO) is an emerging strategy for tumor theranostics, and is expected to achieve significant therapeutic potential with high efficiency and low toxicity. An appropriate concentration of CO has selective cytotoxic effects on cancer cell and cytoprotective effects on normal tissue. However, the safety and feasibility of the use of inhaled CO or CO-releasing molecules (CORMs) remains uncertain owing to the lack of expeditious controllability. Targeted delivery and real-time monitoring for spatiotemporal concentrations administration of CO is therefore vitally important but challenging. Hence, we will design and synthesize a new type of pH and NIR dual-responsive gas nanotheranostic agent based on acid-responsive polymer carrier, black phosphorus nanosheet (BPN) and CORMs through novel ligand coordination. With the aggregation and growth of amphiphilic polymer stimulated by tumor acidic microenvironment, the retention and cellular uptake of nanotheranostic agent in tumors can be enhanced. Due to the photothermal effect of BPN and NIR-triggered CO release of CORMs-BPN, the highly efficient photoacoustic-imaging-guided synchronous gas therapy/phototherapy can be achieved, which will significantly improve the therapeutic effects on tumors. We will reveal the mechanism of acid responsive accumulation and retention of nanomedicine and NIR-triggered release of CO, and explore the influence of the molecular composition and structure on tumor theranostics. This project will provide an intriguing approach for the design and synthesis of intelligent nanomedicines to realize high-efficacy gas therapy.

基于治疗性气体的纳米诊疗剂是一种新兴的诊疗策略，有望实现高效低毒的肿瘤诊疗。合适浓度的CO气体具有选择性杀死癌细胞、并保护正常细胞的抗癌特性；然而CO的不可控释放和蓄积将导致潜在的中毒风险。因此，如何实现CO气体的靶向运输、可控释放和医学成像监控，是当前亟待解决的关键科学问题。本项目提出基于酸响应性聚合物载体、光活性黑磷纳米片（BPN）和金属羰基类CO释放分子，通过新颖的配位络合途径，构建具有pH和NIR双重响应性的新型纳米气体诊疗剂。利用聚合物载体的靶向肿瘤酸性微环境聚集长大特性，实现高效的靶向药物传输；利用包覆BPN的稳定光热效应和CORMs-BPN前药的NIR光响应性CO释放性能，同时实现气体治疗与热疗的联合协同治疗、以及基于光声成像的联合同步诊断。揭示酸响应靶向滞留机制和NIR光响应可控气体释放机制，研究分子组成和结构对诊疗性能的影响，为开发智能高效的靶向纳米药物体系提供新的思路。

与常规化疗药物相比，CO气体具有选择性杀死癌细胞、并保护正常细胞的抗癌特性，具备“低毒”和“高效”的显著优势，因而CO气体治疗成为一种新兴的、具有应用前景的抗肿瘤策略。然而，CO气体的不可控释放将导致潜在的中毒风险，因此实现CO气体的可控释放和释放监控是目前气体治疗研究的重点和难点。本项目提出一种新型治疗思路，即借助光热纳米载体实现肿瘤微环境的光控气体释放用于协同的光热增强的气体治疗。利用近红外光敏感的黑磷纳米片（BPN）与金属羰基化合物（MnCO）的化学配位作用设计了纳米药物BPN-MnCO@LM。一方面，这种直接配位既能够实现近红外光化学裂解MnCO释放CO，另一方面又可以稳定BPN，实现长效的光热效应。在不同动物模型中，纳米药物均展现了良好的抑制甚至消除肿瘤的效应，进一步机制研究发现光热效应可以抑制机体自我修复CO引起的DNA损伤，并激化ATM–GADD45–P53–CyclinB细胞凋亡通路。本研究对于新型气体诊疗剂的设计和开发具有启发性意义，也为开发新型高效低毒的肿瘤诊疗剂奠定了理论和实验基础。