超声/荧光双模态靶向纳米诊疗剂对胰腺癌HIFU治疗及化疗增效机制的基础研究

HIFU treatment for pancreatic cancer has been a new research hotspot due to its invasive treatment character. The currently investigating HIFU enhancements agents failed in allowing multiple enhanced HIFU ablations under only once drug injection and monitoring ablation process. In previous work, we utilized inorganic silica as platform to construct a nanotheranostic agent that can achieve multiple enhanced HIFU ablations for VX2 tumors implanted in livers of rabbits under once drug injection in our previous work. However, the poor degradability and long-term toxicity of inorganic silica composition restrict the clinical translation, and simultaneously no targeting and no synergistic therapy constituting by loaded antitumor drug and HIFU ablation was implemented. Given this, in this project, solid L-menthol as inner core medium instead of conventional gas or liquid perfluorocarbon compounds was loaded in biocompatible polymers to overcome the drawbacks of gas or liquid compounds, e.g., facile fluidity and leakage resulted in structure collapse or deformation and high hydrophobic property made them immiscible with anti-tumor drugs, which is beneficial for improving the structure stability. Afterwards, marriage of structure and function designs will be integrated to construct a novel triphase transition-based targeted nanotheranostic agent, and concurrently performances and accordingly underlying principles of targeting, ultrasound/fluorescence bimodal imaging, triphase transition-controlled HIFU ablation and HIFU/chemotherapy synergistic treatment will be investigated, expectedly providing a new treatment avenue to clinical pancreatic cancer HIFU ablation.

HIFU因其无创治疗方式已成为胰腺癌治疗中一个新的研究热点，但目前HIFU增效剂均不具备一次给药多次增强HIFU消融以及监控消融过程的能力。前期工作中虽然我们利用无机氧化硅为载体构建出纳米诊疗剂实现了一次给药反复增强HIFU消融VX2兔肝肿瘤的治疗，但氧化硅载体存在降解性差、潜在的长期毒性等问题，同时工作未涉及靶向性以及与药物协同治疗研究。鉴于此，本课题以具有三相转变功能的固态薄荷醇取代传统的液态和气态氟碳化合物担载于生物相容性较好的聚合物中，克服传统的液态或气态化合物易于流动、泄露造成的结构坍塌以及与抗癌药物分子难混溶的缺陷，提高有机载体结构稳定性，然后通过结构化和功能化设计构建新型三相转变基靶向纳米诊疗剂，评价其在胰腺癌靶向、荧光/超声双模态诊断、三相转变介导HIFU消融增效以及与化疗协同治疗效果并研究其相应机制，为临床胰腺癌HIFU治疗提供新的治疗思路。

肿瘤的精确诊断和高效治疗一直是肿瘤诊治中的一个难题。随着纳米技术的发展，纳米诊疗这一概念已经得到越来越广泛的关注。该课题以恶性肿瘤为研究对象，围绕肿瘤的精准诊治开展了一系列研究工作，首先构建了粘度介导迁移位垒增加策略用于抑制纳米包封技术中有机荧光分子聚集、萃灭，提高荧光成像性能；其次构建了连续空化的理论增强HIFU、射频消融体积，同时内部担载化疗药，表面敖合RGD配体，实现RGD靶向的射频/化疗协同治疗；进一步，构建磁性复合诊疗剂实现磁热转变、连续空化协同增强射频消融以及纵向弛豫调节策略监控射频消融过程。此外，我们还构建了配位响应的纵向弛豫调节策略针对特定肿瘤标志物设计对应探针，实现肿瘤标志物的探测；利用氟碳链与O2结合的特性构建了自给氧声动力治疗系统，其在超声激励下释放O2，产生的空化可增强肿瘤渗透性，促进更多治疗系统富集于肿瘤，同时O2改善乏氧微环境，逆转乏氧肿瘤耐药性，提高声动力治疗效果；构建“接力靶向”策略，提高NO释放系统在肿瘤处富集量，实现超声响应的NO释放，抑制肿瘤生长；基于组分、结构设计角度制备了超薄、超弹性壳的中空有机硅纳米颗粒，提高肿瘤超声成像效果，通过各种表征、测试手段评价他们在肿瘤中的精准诊治效果和机制，为肿瘤诊治提供了一个新的发展方向，同时也为癌症的综合诊治提供新的思路。