Targeting tumor microenvironment by nanoimmunodrugs for glioma treatment

胶质母细胞瘤（GBM）是最致命的脑癌形式。治疗选择有限，部分原因是 通过血脑屏障（BBB）的药物递送效率低。GBM微环境有助于恶性肿瘤 生长、入侵和逃避免疫监视。我们将制定一个全新的GBM战略 同时靶向肿瘤微环境和激活脑癌特权免疫的治疗 系统这种新的组合方法旨在调节肿瘤微环境成分，这些成分在很大程度上是 与胶质母细胞瘤中的异质性基因突变无关。它具有传统技术无法比拟的潜在优势 用小分子药物、放射和靶向分子标记物抑制治疗GBM。框架下 FOA“癌症纳米技术干预的翻译”，我们将开发癌症的翻译 - 使用能够穿过生物载体（例如BBB、细胞和内体膜）的新型纳米药物的干预， 并调节肿瘤微环境以进行有效治疗，不仅可以治疗脑原发性肿瘤（GBM）， 但是其他难以治疗的脑继发性/转移性肿瘤。 我们计划了解细胞外基质（ECM）蛋白层粘连蛋白-411（a4 b1 g1） 表达和脑局部免疫系统作为GBM促进免疫抑制微环境的一部分。 我们对130名GBM患者的临床数据显示，肿瘤层粘连蛋白-411与肿瘤侵袭性相关， 患者生存率低和早期复发。我们开发了基于天然聚合物聚（β-L-苹果酸）的纳米药物 酸），能够在体内阻断三聚体蛋白层粘连蛋白-411的合成。我们还使用了同基因小鼠模型 用递送GBM检查点抑制剂抗体抗CTLA-4或抗PD-1的纳米免疫药物治疗， 游离形式不穿过BBB，这增加了动物存活率。纳米药物被很好地表征， 对小鼠和兔子有毒（与纳米技术表征实验室合作）。纳米高分子药物 生产规模扩大到克。在灵长类动物中成功进行了毒性和PK研究， 雄性/雌性食蟹猴，使用治疗性1X和急性10 X静脉内剂量。 我们还在同一平台上开发了携带抗CTLA-4或抗PD-1的纳米免疫递送系统 抗体穿过血脑屏障，激活局部脑免疫系统，延长动物存活时间。新 初步数据表明，层粘连蛋白-411调节Notch途径和NK、NKT、IFNg+ NKT的活化， 和巨噬细胞，而在纳米平台上传递到大脑的检查点抑制剂调节先天性和巨噬细胞， 和适应性免疫系统我们的转化研究旨在开发临床适用的 用于有效神经胶质瘤治疗的BBB交叉纳米药物的组合。 目标1.用于脑癌联合治疗的新型纳米药物变体的合成。目标2.铅纳米药物检测 神经胶质瘤的治疗效果目标3.纳米铅的药理学（PK、PD）和毒理学检查 免疫聚合物。

Glioblastoma (GBM) is the most lethal form of brain cancer. Treatment options are limited, in part because of inefficient drug delivery across the blood-brain barrier (BBB). GBM microenvironment contributes to malignant growth, invasion, and escape from immune surveillance. We will develop a radically new strategy of GBM treatment by simultaneous targeting of tumor microenvironment and activating brain cancer privileged immune system. This new combination approach aims to regulate tumor microenvironment components that are largely independent of heterogeneous genetic mutations in glioblastoma. It has potential advantage over conventional GBM treatment with small molecule drugs, radiation and targeted molecular marker(s) inhibition. In the frame of the FOA "Toward Translation of Cancer Nanotechnology Interventions", we will develop the translation of cancer interventions using novel nanomedicines able to cross biobarriers, such as BBB, cell and endosomal membranes, and modulate tumor microenvironment for effective therapy that may treat not only brain primary tumors (GBM) but other poorly treatable brain secondary/metastatic tumors. We plan to understand the interactions between extracellular matrix (ECM) protein laminin-411 (a4b1g1) expression and brain local immune system as parts of GBM-promoting immunosuppressive microenvironment. Our clinical data on 130 GBM patients showed that tumor laminin-411 correlated with tumor aggressiveness, poor patient survival and early recurrence. We developed nano drugs based on natural polymer, poly(β-L-malic acid), able to block the synthesis of trimer protein laminin-411 in vivo. We also used syngeneic mouse models treated with nano immuno drugs delivering to GBM checkpoint inhibitor antibodies anti-CTLA-4 or anti-PD-1 that in free form do not cross BBB, which increased animal survival. Nanodrugs were well characterized and non- toxic in mice and rabbits (collaboration with Nanotechnology Characterization Laboratory). Nano polymeric drugs production was scaled up to grams. Toxicity and PK studies were successfully performed on primates, male/female Cynomolgus macaques using therapeutic 1X and acute 10X intravenous dosages. We also developed a nano immuno delivery system on the same platform bearing anti-CTLA-4 or anti-PD-1 antibodies that traversed BBB, activated local brain immune system and prolonged animal survival. New preliminary data demonstrate that laminin-411 regulates Notch pathway and activation of NK, NKT, IFNg+ NKT, and macrophages, whereas checkpoint inhibitors delivered to the brain on nanoplatform regulate both innate and adaptive immune system. Our translational research is geared towards developing clinically suitable combinations of BBB-crossing nanomedicines for efficient glioma treatment. Aim 1. Synthesis of novel nano drug variants for combination brain cancer therapy. Aim 2. Lead nano drug testing for glioma treatment efficacy. Aim 3. Pharmacological (PK, PD) and toxicological examination of lead nano immunopolymers.