Exploiting microorganism biomimicry to interact with critical blood-tissue barriers

虽然纳米粒子是非常有前途的药物输送系统，但在携带有效剂量的药物到某些组织区域方面，纳米粒子并没有被证明是有效的。例如，将药物用于大脑，治疗脑肿瘤或阿尔茨海默病仍然非常困难。其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，组织被保护免受一般毒性。不幸的是，在血液中循环的药物，无论是游离的还是装入纳米颗粒的，都很难穿过这些屏障。另一方面，一些病原体，如病毒和细菌（它们在物理上与纳米颗粒相似）能够穿过这些复杂的血液组织屏障。例如，HIV-1（导致艾滋病的病毒）可以感染脑组织。这种病毒使用的一种方法是通过特定的进入点（例如受体）非常强烈地附着在内皮细胞的膜上。病毒包膜含有一种蛋白质，这种蛋白质能够同时与细胞膜结合两次。由于这种强结合，细胞吸收了病毒颗粒，并将其完整地运送到另一边。***本程序旨在模拟这种行为，并触发纳米颗粒在复杂的血液组织屏障上的完全运输，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，这些元素协同作用于内皮细胞膜的两个独立的共受体。以艾滋病毒为模型，我们将组装这些模拟粒子，并在细胞培养中筛选它们，以确定它们的功效。稍后，我们将在小鼠身上使用最好的配方，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还可以用于将更多的抗逆转录病毒药物从母体血液转移到艾滋病毒阳性新生儿的母乳中。如果取得成功，该项目将为了解传染病和物质通过母乳从母亲传给孩子提供有力的工具。

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.