EPR效应增强型空心介孔有机硅纳米诊疗剂在乏氧肿瘤氧增强型增敏放疗中的应用研究

Sensitized radiotherapy based on nanotheranostics has drawn increasing interest for tumor high efficient treatment. How to enhance the enrichment of nanotheranostics in tumor and how to elevate the sensitivity of radiotherapy by effectively overcoming tumor hypoxia are the two key scientific problems to be solved. In this project, we design nanotheranostics based on small-sized hollow mesoporous organosilica nanoparticles (HMON). The cavity of HMON is filled with heat-sensitive NO donor BNN, and the surface is combined with Mo(VI)-based polyoxometalate (POM) and 64Cu. O2 can be adsorbed with fluorocarbon (FC) chain contained in the organosilica shell. POM clusters drives the self-assembly of HMON in the mild acidic tumor microenvironment (TME) to achieve enhanced tumor retention and accumulation. At the same time, the reduced POM by glutathione (GSH) in TME endows the nanotheranostics with photothermal conversion and photoacoustic (PA) imaging ability. The heat produced by near-infrared (NIR) laser irradiation of POM could induce the FC chain releasing O2 and BNN decomposed to release NO. NO inhibits the consumption of O2 by tumor cells, thereby effectively overcoming tumor hypoxia and enhancing radiotherapy sensitivity. POM and 64Cu achieve PA/PET dual-modality imaging, real-time monitoring intratumoral oxygenation and distribution of nanotheranostics in vivo. Moreover, the nanotheranostics are biodegradable by GSH in TME. This project is expected to provide a new strategy for oxygen-elevated sensitized radiotherapy of hypoxic tumors under real-time imaging monitoring.

基于纳米诊疗剂的增敏放疗是当今肿瘤高效诊治的研究热点。如何增强纳米诊疗剂在肿瘤内的富集以及如何通过高效克服肿瘤乏氧来增强放疗敏感性是所要解决的两大关键科学问题。本项目设计了基于小尺寸空心介孔有机硅的纳米诊疗剂，空腔中装载热敏型NO供体BNN，表面鳌合钼基多金属氧酸盐（POM）及64Cu，含氟碳链的骨架吸附O2。POM在肿瘤弱酸性微环境中自组装成大颗粒，延长其在肿瘤内滞留时间，增强了肿瘤区富集量；同时，POM被肿瘤内谷胱甘肽还原后具备了光热转化和光声成像能力，在近红外激光照射下产热使氟碳链释放O2，同时分解BNN释放NO。NO抑制肿瘤细胞消耗O2，从而高效克服肿瘤乏氧、增强放疗敏感性。POM及64Cu可实现光声/PET双模态成像，实时监测肿瘤内乏氧环境的改善及纳米诊疗剂体内分布代谢。同时，该纳米诊疗剂在谷胱甘肽作用下可生物降解。本项目有望为实时影像监控下的乏氧肿瘤氧增强型增敏放疗提供新策略。

基于纳米诊疗剂的增敏治疗是当今肿瘤高效诊治的研究热点。为了解决增强纳米诊疗剂在肿瘤内的富集以及高效克服肿瘤乏氧来增强治疗敏感性这两大关键科学问题，本项目构建了基于可变形空心介孔有机硅纳米颗粒（DMONs）及仿生二氧化钛纳米颗粒（RBC-mTNP@AQ4N）的新型诊疗剂，并探索了其在乏氧肿瘤增敏治疗中的应用。DMONs的合成具备高度可控性，可以通过控制其形态、粒径及空腔大小来实现肿瘤区域的高富集量及化疗药物的高效担载能力，实验结果表明DMONs具有良好的生物相容性及生物安全性，其变形能力促进了肿瘤细胞的摄取，并且担载化疗药物后具有良好的肿瘤增敏治疗效果。RBC-mTNP@AQ4N一方面拥有免疫逃逸能力，可有效降低免疫清除率，增强了纳米诊疗剂的肿瘤富集量，另一方面，超声（US）激活后，mTNP作为声敏剂可产生活性氧物质，不仅能诱导细胞凋亡和坏死，进行声动力治疗（SDT），而且还能破坏红细胞膜实现US介导的AQ4N按需释放。释放后的AQ4N被乏氧环境激活，转化为有毒产物AQ4，有效地补充了SDT在乏氧组织中治疗的低效性。重要的是，SDT加重了肿瘤乏氧环境，从而进一步加强了AQ4N的乏氧特异性化疗，高效克服了肿瘤乏氧、增强了协同治疗的敏感性。该项目构建的纳米诊疗剂表现了出色的治疗效果，为乏氧肿瘤增敏治疗提供了新策略。