Targeting tumor microenvironment by nanoimmunodrugs for glioma treatment

胶质母细胞瘤(GBM)是最致命的脑癌。治疗选择有限，部分原因是 跨血脑屏障(BBB)的药物输送效率低下。GBM微环境致癌作用 生长、入侵和逃脱免疫监视。我们将制定一种全新的GBM战略 肿瘤微环境靶向与激活脑癌特权免疫同步治疗 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 与胶质母细胞瘤的异质性基因突变无关。它比传统技术有潜在的优势。 银杏叶提取物用小分子药物治疗，放射和靶向分子标志物(S)抑制。在…的框架内 FOA《走向癌症纳米技术干预的翻译》，我们将发展癌症的翻译 使用能够跨越生物屏障的新型纳米药物的干预措施，如血脑屏障、细胞膜和内膜， 并调节肿瘤微环境以进行有效的治疗，不仅可以治疗脑原发肿瘤(GBM) 但其他难以治疗的脑部继发性/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(A4b1g1)之间的相互作用 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例GBM患者的临床资料显示，肿瘤层粘连蛋白-411与肿瘤侵袭性有关， 患者存活率低，早期复发。我们开发了以天然聚合物聚(β-L-苹果酸)为基础的纳米药物 酸)，能够在体内阻断三聚体蛋白质层粘连蛋白-411的合成。我们还使用了同基因小鼠模型 用纳米免疫药物治疗，向GBM检查点抑制物抗体抗CTLA-4或抗PD-1 在自由状态下不跨越血脑屏障，这增加了动物的存活率。Nanodrugs具有良好的特性，并且不是 对小鼠和兔子的毒性(与纳米技术表征实验室合作)。纳米聚合物药物 生产规模扩大到了1克。在灵长类动物身上成功地进行了毒性和PK研究， 雄性/雌性食蟹猴使用治疗性1倍和急性10倍静脉注射剂量。 我们还在同一平台上开发了抗CTLA-4或抗PD-1的纳米免疫递送系统 穿过血脑屏障的抗体，激活了当地的大脑免疫系统，延长了动物的存活时间。新的 初步数据表明，层粘连蛋白-411调节Notch通路和NK、NKT、IFNG+NKT的激活， 和巨噬细胞，而检查点抑制剂在纳米平台上传递到大脑调节这两种先天的 和适应性免疫系统。我们的翻译研究致力于开发适用于临床的 有效治疗脑胶质瘤的跨血脑屏障纳米药物组合。 目的1.合成用于脑癌联合治疗的新型纳米药物变异体。目标2.铅纳米药物测试 对于脑胶质瘤的治疗效果。目的3.纳米铅的药理(PK、Pd)及毒理学检测 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.