Exploiting microorganism biomimicry to interact with critical blood-tissue barriers

尽管纳米粒是非常有希望的药物输送系统，但在将有效剂量的药物运送到某些组织区域方面，却未能证明是有效的。例如，针对大脑的药物、治疗脑瘤或阿尔茨海默病的药物仍然非常困难。主要原因在于这些组织周围存在一道保护性屏障。这些屏障是由构成血管壁的内皮细胞构成的，并由其他细胞层加强。因此，这些组织受到保护，不受一般毒性的影响。不幸的是，血液中循环的药物，无论是游离的还是负载到纳米颗粒中的，都很难越过这些屏障。*另一方面，一些病原体，如病毒和细菌(在物理上与纳米颗粒相似)能够越过这些复杂的血液-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式是通过特定的入口点(例如受体)非常强烈地附着在内皮细胞的膜上。病毒被膜含有一种能够同时结合两次到细胞膜上的蛋白质。这种强结合的结果是，细胞吸收病毒颗粒，并将其原封不动地输送到另一边。*这个程序打算模仿这种行为，并触发纳米颗粒完全跨越复杂的血液-组织屏障，而不会恶化。为此，我们将合成含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个单独的共同受体。以HIV为模型，我们将组装这些模拟颗粒，并在细胞培养上筛选它们，以确定它们的有效性。稍后，我们将在老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母亲血液中较高数量的抗逆转录病毒药物转移到艾滋病毒阳性新生儿的母乳中。如果成功，这个项目应该会为了解传染病和通过母乳喂养将物质从母亲转移到孩子提供强大的工具。

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.