Use of nanoparticles to deliver growth signals to the placenta

使用纳米颗粒向胎盘传递生长信号

• 批准号: MR/K01126X/1
• 负责人: John Aplin
• 金额: $ 60.96万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK01126X%2F1
• 关键词: Use; nanoparticles; deliver; growth; signals

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.

在怀孕期间，胎盘将营养物质传递给发育中的胎儿，同时保护胎儿免受母体有害物质的侵害。在很早的时候，胎盘的快速生长建立了一个营养提取系统，有可能满足怀孕后期胎儿的需求。同时，胎盘的保护屏障功能发育；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，并将它们连同所需的营养物质一起传递给胎儿，同时为胎盘本身的生长提供条件。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。这产生了严重的后果：最小的婴儿死亡，而那些存活下来的婴儿从根本上损害了儿童和成人的健康前景。有令人信服的证据表明，很大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。制药公司不愿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。纳米颗粒是一种微小的合成珠子——比人体细胞小得多——原则上，它可以被注射到母亲的血液中，并被引导到胎盘中，以传递导致胎盘生长的信号。这种治疗方式将间接改善胎儿的生长，从而改善其健康前景，其巨大优势是治疗颗粒将保留在胎盘屏障内，因此在怀孕结束时将被丢弃。在提出这一建议的工作中，我们已经开发出了在实验室中使胎盘组织存活几天的方法，并证明了携带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来确保如果注射了纳米粒子，它们会被输送到胎盘，而不是母体的其他部位。最近人们发现，身体的每个器官表面都有独特的分子组合。这些蛋白质就像一个“邮政编码”，可以用来“定位”包裹——比如药物——以便它们被送到正确的地方。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，我们计划解决一包携带生长信号的纳米颗粒，然后使用道德上可接受的试管方法来探索人类胎盘中不同类型细胞的生长是如何受到影响的。我们还将研究在不同细胞之间传递生长信号的分子机制，并将通过跟踪纳米颗粒到达后的情况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会对细胞产生不利影响，例如一些会导致DNA损伤，所以我们也将研究我们的包装是否有类似的影响，如果必要的话，开发出克服这些有害作用的方法。开发一种靶向给药系统将有助于妇女确信她们在怀孕期间服用的任何药物都不会伤害未出生的孩子。这个项目将定义一个框架，在这个框架内，纳米颗粒疗法可以被表征并推进到临床实施。

项目成果

In vitro placenta barrier model using primary human trophoblasts, underlying connective tissue and vascular endothelium.

使用原代人滋养层、底层结缔组织和血管内皮的体外胎盘屏障模型。

• DOI: 10.1016/j.biomaterials.2018.08.025
• 发表时间: 2019
• 期刊: Biomaterials
• 影响因子: 14
• 作者: Nishiguchi A

Targeted Delivery of Epidermal Growth Factor to the Human Placenta to Treat Fetal Growth Restriction.

• DOI: 10.3390/pharmaceutics13111778
• 发表时间: 2021-10-25
• 期刊: Pharmaceutics
• 影响因子: 5.4
• 作者: Renshall LJ;Beards F;Evangelinos A;Greenwood SL;Brownbill P;Stevens A;Sibley CP;Aplin JD;Johnstone ED;Teesalu T;Harris LK
• 通讯作者: Harris LK

Delivery and intracellular turnover of insulin-like growth factor I (IGF-I) delivered to human placenta using quantum dots

使用量子点将胰岛素样生长因子 I (IGF-I) 递送至人胎盘并进行细胞内周转

• DOI: 10.1016/j.placenta.2014.06.168
• 发表时间: 2014
• 期刊: Placenta
• 影响因子: 3.8
• 作者: Karolczak-Bayatti M

Selective Targeting of a Novel Vasodilator to the Uterine Vasculature to Treat Impaired Uteroplacental Perfusion in Pregnancy.

• DOI: 10.7150/thno.19678
• 发表时间: 2017
• 期刊: Theranostics
• 影响因子: 12.4
• 作者: Cureton N;Korotkova I;Baker B;Greenwood S;Wareing M;Kotamraju VR;Teesalu T;Cellesi F;Tirelli N;Ruoslahti E;Aplin JD;Harris LK
• 通讯作者: Harris LK

IGF-I INTRACELLULAR SIGNALLING IN THE HUMAN PLACENTA IS DEPENDENT ON CLATHRIN- AND CAVEOLIN-DEPENDENT ENDOCYTOSIS

人胎盘中的 IGF-I 细胞内信号传导依赖于网格蛋白和小窝蛋白依赖性内吞作用

• 发表时间: 2015
• 期刊: PLACENTA
• 影响因子: 3.8
• 作者: Karolczak-Bayatti Magdalena