Use of nanoparticles to deliver growth signals to the placenta

在怀孕期间，胎盘将营养物质转移到发育中的胎儿，同时保护其免受母体中存在的有害物质的影响。在早期，胎盘的快速生长建立了一个营养提取系统，有可能满足胎儿在怀孕后期的需求。与此同时，胎盘的保护屏障功能发展;这是通过在母体和胎儿循环之间插入几个细胞层来实现的。这些层以一种复杂的方式合作，检测母体循环中存在的生长信号，并将它们与所需的营养物质一起传递给胎儿，同时为胎盘本身的生长做好准备。尽管发达国家很富裕，但许多胎儿未能达到正常的生长潜力。这造成了严重的后果：最小的婴儿死亡，而那些存活下来的婴儿在儿童和成人时的健康前景都受到了严重损害。有令人信服的证据表明，高比例的妊娠生长受限是由胎盘生长异常引起的。然而，目前还没有办法纠正这些缺陷。制药公司回避开发用于怀孕的药物，因为他们担心新产品会伤害未出生的婴儿，并希望避免昂贵的诉讼。相反，他们投资于其他研究领域，使医生在治疗孕妇方面几乎没有选择。纳米颗粒是微小的合成珠粒-比体内的细胞小得多-原则上，可以注入母亲的血液中，并引导胎盘传递信号，使其生长。这种治疗模式应该间接地改善胎儿的生长，从而改善胎儿的健康前景，其巨大优势在于治疗颗粒将保留在胎盘屏障内，因此将在妊娠结束时被丢弃。在导致这一提议的工作中，我们已经开发出了在实验室中保持胎盘组织存活数天的方法，并表明载有生长刺激化学物质的纳米颗粒可以刺激常驻细胞生长。然而，我们现在需要找到一种方法，以确保如果纳米粒子被注射，他们将被输送到胎盘，而不是在母亲的身体的其他部位。最近发现，在身体的每个器官有一个独特的分子组合在其表面。这些蛋白质的作用就像一个“邮政编码”，可以用来“寻址”包裹-例如，药物-以便将它们发送到正确的地方。我们的初步工作已经确定了胎盘的邮政编码，在这项研究中，我们计划解决一个携带生长信号的纳米颗粒包，然后使用伦理上可接受的试管方法来探索人类胎盘内不同类型细胞的生长如何受到影响。我们还将研究不同细胞之间传递生长信号的分子机制，并通过跟踪纳米颗粒到达后发生的事情来检查包裹是否被胎盘保留，而不是传递给胎儿。我们知道其他形式的纳米颗粒可能对细胞产生不利影响，例如一些会导致DNA损伤，因此我们还将研究我们的包装是否具有类似的效果，如果必要的话，开发克服这些不必要的作用的方法。靶向药物输送系统的开发将帮助妇女相信她们在怀孕期间接受的任何药物都不会伤害她们未出生的孩子。该项目将定义一个框架，在该框架内，纳米颗粒疗法可以被表征并推进临床实施。

During pregnancy, the placenta transfers nutrients to the developing fetus while at the same time protecting it from harmful substances present in the mother. Very early on, rapid placental growth establishes a system for nutrient extraction that has the potential to meet the needs of the fetus later in pregnancy. At the same time, the protective barrier function of the placenta develops; this is achieved by interposing several cell layers between maternal and fetal circulations. These layers collaborate in a sophisticated way to detect growth signals present in maternal circulation and transmit them, together with the required nutrients, to the fetus, while at the same time making provision for the placenta itself to grow. Despite the affluence of developed countries, many fetuses fail to reach their normal growth potential. This has severe consequences: the smallest babies die, while those that survive have radically impaired health prospects both as children and adults. There is convincing evidence that a high proportion of pregnancies with growth restriction are caused by placental growth abnormalities. However currently, there is no way to correct these defects. Drug companies shy away from developing drugs for use in pregnancy because they are fearful of harming unborn babies with their new products, and want to avoid expensive lawsuits. Instead, they invest in other areas of research, leaving doctors with few alternatives for treating pregnant women. Nanoparticles are tiny synthetic beads - much smaller than cells in the body - which, in principle, could be injected into the mother's blood stream and directed to the placenta to deliver signals that cause it to grow. This mode of therapy should indirectly improve the growth - and hence health prospects - of the fetus, with the great advantage that the therapeutic particles would be retained within the placental barrier and so would be discarded at the end of pregnancy. In work leading up to this proposal, we have developed methods for keeping placental tissue alive in the laboratory for a few days, and have shown that nanoparticles loaded with growth-stimulatory chemicals, can stimulate the resident cells to grow. However we now need to find a way to ensure that if the nanoparticles were injected, they'd be delivered to the placenta and not to other sites in the mother's body.It has recently been discovered that every organ in the body has a unique combination of molecules on its surface. These proteins act like a "postcode" and can be used to "address" packages - for example, drugs - so that they are sent to the right place. Our preliminary work has identified the postcode for placenta and in this study we plan to address a package of nanoparticles carrying growth signals and then use ethically acceptable test tube methods to explore how the growth of the different types of cell within human placenta is affected. We will also investigate the molecular mechanisms involved in relaying growth signals between the different cells and will check that the package is retained by the placenta, and not passed to the fetus, by tracking what happens to the nanoparticles after they arrive. We know that other forms of nanoparticle can have adverse effects on cells, for example some cause DNA damage, so we will also investigate if our addressed packages have a similar effect and if necessary, develop ways to overcome these unwanted actions. Development of a targeted drug delivery system will help women feel confident that any drugs they receive during pregnancy will not harm their unborn child. This project will define a framework within which nanoparticle therapies can be characterised and advanced towards clinical implementation.