Exploiting microorganism biomimicry to interact with critical blood-tissue barriers

利用微生物仿生学与关键的血液组织屏障相互作用

• 批准号: RGPIN-2018-06636
• 负责人: ROULLIN, VGaëlle
• 金额: $ 4.08万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=762041
• 关键词: Exploiting; microorganism; biomimicry; interact; critical

Although very promising drug delivery systems, nanoparticles have failed to prove efficient in carrying effective amounts of drugs to certain tissue areas. For instance, it is still very difficult to address drugs to the brain, to cure brain tumors or Alzheimer's disease. The main reason lies in the existence of a protective barrier around those tissues. These barriers are constituted from endothelial cells making up the vessel walls, and are reinforced by other cell layers. Hence the tissues are protected from general toxicity. Unfortunately, it is very difficult for drugs circulating in the blood, either free or loaded into nanoparticles, to cross those barriers. On the other hand, some pathogens like viruses and bacteria (which are physically similar to nanoparticles) are able to cross those complex blood-tissue barriers. For example, HIV-1 (the virus responsible for AIDS) can infect the brain tissue. One way used by this virus is to attach very strongly via specific entry points (e.g. receptors) to the membrane of endothelial cells. The virus envelope contains a protein that is able to bind twice at the same time onto the cell membrane. As a consequence of this strong binding, the cell uptakes the viral particle and transports it, intact, to the other side. This program intends to mimic this behaviour and trigger a complete transport of nanoparticles across complex blood-tissue barriers, without deterioration. To that end, we will synthetize nanoparticles bearing two different elements of recognition acting cooperatively on two separate co-receptors of the endothelial cell membranes. Using HIV as a model, we will assemble those mimetic particles and screen them on cell cultures to determine their efficacy. Later, we will use the best formulations in mice, in order to transfer anticancer, antiviral or psychotropic drugs into the brain tissue. This kind of doubly-decorated nanoparticles could also be used to transfer higher quantity of antiretroviral drugs from the maternal blood to the breastfeeding milk of HIV-positive newborns. If successful, this program should provide powerful tools to understand infectious diseases and the transfer of substances from mother to child through breastfeeding.

虽然非常有前途的药物输送系统，纳米粒子未能证明有效携带有效量的药物到某些组织区域。例如，仍然很难将药物用于大脑，治愈脑瘤或阿尔茨海默病。主要原因在于这些组织周围存在保护屏障。这些屏障由构成血管壁的内皮细胞构成，并由其他细胞层加强。因此，保护组织免受一般毒性。不幸的是，在血液中循环的药物，无论是游离的还是装载到纳米颗粒中的，都很难穿过这些屏障。 另一方面，一些病原体，如病毒和细菌（物理上类似于纳米颗粒）能够穿过这些复杂的血液组织屏障。例如，HIV-1（艾滋病病毒）可以感染脑组织。这种病毒使用的一种方式是通过特定的进入点（例如受体）非常强烈地附着到内皮细胞的膜上。病毒包膜含有一种蛋白质，能够同时结合到细胞膜上两次。由于这种强结合，细胞摄取病毒颗粒并将其完整地运输到另一边。 该计划旨在模拟这种行为，并触发纳米颗粒穿过复杂的血液组织屏障的完整运输，而不会恶化。为此，我们将合成具有两种不同识别元素的纳米颗粒，它们协同作用于内皮细胞膜的两种单独的辅助受体。使用HIV作为模型，我们将组装这些模拟颗粒，并在细胞培养物上筛选它们，以确定它们的功效。随后，我们将在小鼠中使用最佳配方，以便将抗癌、抗病毒或精神药物转移到脑组织中。这种双重修饰的纳米颗粒也可以用于将更多的抗逆转录病毒药物从母体血液转移到HIV阳性新生儿的母乳中。如果成功的话，这个项目将提供强有力的工具来了解传染病和通过母乳喂养将物质从母亲转移到孩子身上。