利用纳米药物靶向干预炎性单核细胞和肿瘤相关巨噬细胞治疗脑胶质瘤

Glioblastoma (GBM) is the most common, aggressive and fatal primary brain tumor. A prominent feature of GBM is that GBM recruit large a quantity of inflammatory monocytes (IMC) from the peripheral circulation which are then differentiated into tumor associated macrophages (TAM). TAM not only provide vital support to GBM cells to promote cancer cell survival, aggression and metastasis, but also play key roles in the mechanisms of GBM chemoresistance. We have synthesized “nano chemodrugs” and “nano modulating drugs” on the basis of nanodiamond functionalized with polyglycerol (ND-PG). The present investigation is proposed to realize targeted GBM therapy through 1. delivery of nano chemodrugs to GBM using IMC and TAM as carriers and taking advantage of their intimate exchange mechanisms with the malignant cells. 2. blocking the recruitment of IMC and TAM and breaking their support to the malignant cells. Besides providing proof to the above concepts，this study will also delineate key cellular processes and molecular mechanisms involved, e.g. CCL2/CCR2 mediated IMC recruitment, macrophage secretion of lysosomes and extracellular vesicles induced by damage-associated molecular pattern, and a positive feedback loop of tumor damage. Of particular meaning is the proposed drug transport strategy that takes advantage of IMC transmigrating the blood brain barrier. If proven for its feasibility and effectiveness, this strategy would open a new approach for drug delivery into the central nervous system. Modulation of IMC and TAM will also hold great application potential for drug therapy of inflammatory diseases including cancers.

脑胶质母细胞瘤(GBM)是最常见、致死率最高的原发脑肿瘤。GBM大量招募炎性单核细胞(IMC)并使其分化为肿瘤相关巨噬细胞(TAM)，以促进GBM的发生发展和对化疗耐药。但IMC和TAM的招募为GBM的靶向化疗提供了新思路，而调控IMC和TAM也成为治疗GBM的新靶点。基于此，本课题利用“多聚甘油功能化纳米金刚石(ND-PG)”载体荷载效应分子，制备了靶向IMC和TAM的“纳米化疗药”和“纳米调控药”。拟在细胞和动物模型中探讨1.利用 IMC、TAM作为载体将“纳米化疗药”递送至肿瘤，通过IMC、TAM与肿瘤细胞的物质交换机制释放药物， 2.利用“纳米调控药物”靶向抑制IMC和TAM的功能，或阻断它们被肿瘤招募。我们将证明上述策略和相应手段靶向治疗GBM的可行性、有效性以及优势，并阐明其关键的细胞过程和分子机制。本课题可为GBM的治疗开辟新途径, 为纳米药物的抗肿瘤效应提供新的机制。

脑胶质瘤（GBM）是成年人中恶性度最高的脑部肿瘤，由于缺乏有效的治疗手段，多数患者预后极差。化疗是肿瘤治疗的常规手段，而免疫治疗则是新兴的肿瘤治疗手段，但多数化疗药物难以有效分布于GBM，而GBM的免疫抑制性微环境是其免疫治疗的严重障碍。本课题的主要研究目的是：利用GBM招募的免疫细胞作为运载工具向GBM递送化疗药物，同时逆转GBM的免疫抑制性微环境以实现GBM的化学免疫治疗。主要研究内容包括：1.以阿霉素（DOX）为模型化疗药物，以多聚甘油包被的纳米金刚石为载体，批量合成纳米金刚石-多聚甘油-阿霉素复合物（Nano-DOX），2. 以GBM相关的单核细胞、巨噬细胞或树突状细胞为运载工具，实现向GBM模型递送Nano-DOX， 3. 利用Nano-DOX刺激肿瘤细胞的免疫原性，逆转GBM的免疫抑制性微环境。主要研究结果如下：1. 证明人源和小鼠来源的单核细胞、巨噬细胞或树突状细胞均可可作为载体将Nano-DOX主动递送至小鼠GBM中并损伤、抑制肿瘤细胞。2. 证明Nano-DOX可刺激GBM细胞释放抗原和内源性佐剂（损伤相关分子模式，DAMPs）,并藉此活化作为药物递送载体的肿瘤相关巨噬细胞和树突状细胞，进而引发巨噬细胞介导的固有抗肿瘤免疫应答和树突状细胞驱动、淋巴细胞介导的适应性抗肿瘤免疫应答。3. 证明诱导自噬是Nano-DOX刺激肿瘤细胞免疫原性的重要机制。4. 发现Nano-DOX可阻断GBM细胞和星形胶质细胞之间由STAT3/IL-6信号介导的交互作用。5. 以小鼠三阴性乳腺癌（TNBC）细胞为模型，证明Nano-DOX可抑制肿瘤细胞与骨髓源性抑制性细胞（BMDSC）的交互作用。科学意义：1. 为GBM的药物递送，尤其是免疫细胞介导的药物递送提供了新理论和实验依据。2. 为GBM免疫微环境的调控及其化学免疫治疗提供了新的策略和手段。3. 为肿瘤细胞和免疫细胞之间的交互作用提供了新的洞见。4. 指出化疗药物的纳米递送形式与其游离形式在细胞效应和分布上存在显著差异，为纳米化疗药物的设计提供了新的知识。