PSMA靶向Hybrid-SiO2基纳米诊疗剂用于前列腺癌HIFU治疗及增效机制研究

High intensity focused ultrasound (HIFU) is a type of clinical therapy that has been used for the ablation of localized prostate tumor, however, it generally leads to unsatisfactory ablation effect for the deep tumor as result of low energy deposition. In the previous research, a poly (lactic-co-glycolic acid) (PLGA) microsphere-based HIFU synergistic agent was fabricated by our group to significantly enhance the HIFU therapeutic efficacy. However, this organic agent still suffers from several problems including over-large particle size, rapid structural collapse and complex synthetic process, which limit its clinical translation. To solve the above problems, we propose to design a novel organic-inorganic silica (Hybrid-SiO2) nanosystem in this project, which possesses both HIFU synergistic liquid in the hollow cavity and plenty of superparamagnetic nanodots on the particle surface. Furthermore, the J591 antibody is chemically linked to the Hybrid-SiO2 nanosystem for the biological recognition of PSMA antigen in order to realize the positive targeting therapy for the prostate cancer. Thus, the designed nanosystem is a single multifunctional platform with HIFU ablation enhancement, magnetic resonance (MR) imaging and prostate cancer targeting capabilities, which is ideally feasible to be applied in MRI-guided HIFU therapy of prostate cancer. The effectiveness of the PSMA-targeting Hybrid-SiO2 nanosystem on theranostic application and tumor-specific recognition will be systemically evaluated in vitro, ex vivo and in vivo. Overall, this research will provide sufficient theoretic and experimental basis for the future study of HIFU synergistic therapy.

HIFU对于前列腺癌疗效确切，但仍存在病灶消融不完全和周边正常组织易损伤等问题。项目组前期制备了PLGA微球诊疗剂，具备一定的HIFU增效性能，但该类有机增效剂存在粒径大、结构不稳定和制备过程复杂等缺点，限制了其成像及增效效果。为了解决上述问题，本研究提出了采用简单可控的乳化聚合方法，制备粒径小和结构稳定的有机无机杂化（Hybrid-）纳米诊疗剂的思路。该诊疗剂表面镶嵌超顺磁纳米颗粒，内核负载乙酸异戊酯，将实现MRI示踪和HIFU治疗增效双重性能。进一步对诊疗剂表面链接特异性识别PSMA的J591单抗，将有效提高前列腺癌的靶向疗效。本项目将开展PSMA靶向Hybrid-SiO2基纳米诊疗剂的可控合成和结构表征，通过动物模型系统地评价诊疗剂的体内分布、安全性、示踪成像和HIFU增效等性能，并对其主动靶向和增效机制进行研究。本项目的开展将对HIFU增效剂的研究提供更加完善的理论基础和实验证据。

高强度聚焦超声（HIFU）作为一种微创治疗手段，在实体瘤消融方面展现了巨大的应用潜力，然而仍存在着肿瘤消融不彻底、易残留的问题。针对以上问题，本项目设计并合成了一系列具有超小粒径和稳定结构的有机/无机杂化纳米诊疗剂，包括Cu2-xS/PFOB@PLGA纳米颗粒，PEA@OSNC纳米颗粒和CoPP@MSN纳米颗粒等。针对不同纳米诊疗剂的功能和特点对其形貌和结构进行了完整和系统的表征；开展了包括光声成像、核磁共振成像等体内外多模态成像性能评价；通过细胞实验和动物实验证明了不同新型纳米诊疗剂体内外的生物安全性；通过体内外HIFU增效实验证实了上述有机无机杂化新型纳米诊疗剂可显著提高HIFU治疗的效果，并获得了治疗的最佳的治疗参数。此外，基于所得成果，还创新地提出干细胞标记与多功能声学诊疗剂相结合的治疗策略，进一步拓展了超声诊疗剂的研究领域，促进了医学影像与生物材料学科之间的交叉融合。本项目共发表标注本项目基金号的SCI论文5篇，其中以第一作者发表SCI论文3篇，并申请国家发明专利1项，已经完成了预期目标。本项目的开展显著提高了HIFU对于实体瘤的消融效率，并在多模态显像模式引导下HIFU对于实体瘤的消融治疗提供了详实的实验数据和可靠的理论依据，具有积极而重要的科学意义。