功能型聚集诱导发光纳米粒的制备及在肿瘤光学免疫治疗中的应用

Tumor associated macrophages (TAMs) play important role in tumor progression and metastasis, chemo-resistance and tumor micro-environment regulation, which becomes new target for cancer therapy. Fluorogens with aggregation-induced emission (AIE) characteristics show weak fluorescence in molecularly diluted state but become highly emissive in aggregation state, which offers new ways for cancer imaging guided therapy. This project focuses on the design and synthesis of bi-functional red/near infrared AIE fluorogens, through functional modification of polymeric polymer PLGA to prepare MMP-2 sensitive and TAMs targeted AIE nanoparticles, which can achieve cancer imaging and photo-immunotherapy. The effect of AIE nanoparticles on TAMs imaging and photodynamic therapy will be evaluated in vitro on TAMs cell models. Further, the TAMs and cancer cells co-culture system is constructed to test the impact of nanopartical-targeted TAMs on cancer cells. More importantly, the tumor model will be constructed and the red/near infrared AIE nanoparticles will be applied in tumor imaging and photodynamic therapy in vivo. The Tumor angiogenesis, cytokine secretion in tumor microencironment and liver metastasis will be investigated to elucidate the mechanism of TAMs based cancer immunotherapy. This AIE fluorogen based multifunctional nanoparticles provides a unique strategy for potential cancer image-guided therapy and personalized therapy.

肿瘤相关巨噬细胞(TAMs)在肿瘤生长转移，化疗药物耐药性以及微环境调控中扮演着重要的角色，是肿瘤治疗的新靶标。聚集诱导发光(AIE) 是一类在聚集状态下由于分子内旋转受限而导致荧光增强的新型荧光分子，为肿瘤的可视化治疗开辟了新途径。本课题设计合成双功能的红/近红外AIE荧光探针，利用功能化修饰的高分子药物载体PLGA携载，制备肿瘤外基质MMP-2酶响应的TAMs靶向的多功能纳米粒，实现肿瘤诊断与光学免疫治疗一体化。建立TAMs细胞模型，考察AIE纳米粒对TAMs的示踪及光学治疗效果，并验证靶向TAMs的光学治疗对共培养的肿瘤细胞的作用。最终在动物肿瘤模型上，检验AIE纳米粒对肿瘤生长及治疗过程的示踪并判定疗效，从肿瘤血管生长，细胞因子分泌以及肿瘤的肝脏转移方面揭示TAMs靶向的肿瘤免疫治疗机理，为开发AIE纳米粒在肿瘤可视化和个性化治疗中的应用提供了新思路。

纳米材料与免疫系统的相互作用是纳米医学领域的关键问题。本课题从免疫视角，探讨提高纳米材料靶向肿瘤的效率，实现肿瘤诊疗一体化，并进一步探讨肿瘤光热治疗对肿瘤微环境的调控。其主要研究成果包括：由于巨噬细胞吞噬作用，作为外源物质的纳米材料在肿瘤部位的富集大大折扣，首先通过具有“自我识别”机制的CD47肽和RGD靶向肽修饰的聚集诱导发光性质的纳米粒，能够显著降低巨噬细胞的吞噬，提高肿瘤靶向效率；合成并制备具有光热和荧光性能的TA1 NPs，实现肿瘤诊疗一体化，同时，TA1 NPs表现出良好的激光照射下肿瘤杀伤作用以及抑制细胞迁移能力，肿瘤模型结果显示，光热治疗能够显著抑制肿瘤肝脏转移；考虑到肿瘤微环境在肿瘤转移中的重要作用，进一步探讨光热纳米材料在肿瘤微环境调控以及系统性免疫反应激活中的作用。结果表明，光热纳米材料能够诱导巨噬细胞极化，激活系统性免疫反应，并提高淋巴细胞的肿瘤浸润。进一步研究表明，光热纳米材料可以增敏低氧诱导化疗药物作用，激活免疫系统，提高抗肿瘤免疫应答并表现出对原位和远端肿瘤的协同抑瘤作用。该研究以肿瘤光疗法对肿瘤微环境调控作为切入点，通过多肽靶向修饰，提高纳米材料的靶向，并致力于探讨新型肿瘤光热治疗手段，在肿瘤诊疗一体化及肿瘤免疫微环境的调控方面的影响。综合上述结果，本研究为肿瘤诊疗一体化，光热与免疫协同治疗奠定了初步的工作基础。