Multi-scale approach to designing novel colloidal drug delivery vehicles

目前正在开发的大量作为候选药物的小分子是疏水性的，因此这些药物中的许多可能因为水溶解性差而无法上市。因此，为了充分发挥它们的治疗潜力，将这些药物结合到无毒、生物相容和/或可生物降解的制剂中是至关重要的，这些制剂既能在体内运输过程中保护药物，又能在靶组织中释放药物。在过去的几十年里，有越来越多的纳米颗粒制剂被创造出来，其中许多被研究用于生物医学应用。在这些应用中，药物输送一直是由有机分子组成的纳米颗粒更普遍的应用之一，因为这种颗粒可以用来增强包裹的分子的表观水溶解能力，以及专门将分子定向到病变组织的位置。磷脂酰胆碱是一类在药物输送中特别感兴趣的脂类。磷脂酰胆碱主要是已知的细胞膜的主要成分，但它们也是两亲性脂类，可以自组装形成胶束。这些脂类的CMC很低，其疏水性尾部长度的微小变化会导致其胶束性质的显著变化。这一点，加上它们的生物相容性，使它们成为研究它们在难溶药物输送中使用的有吸引力的化合物，因为可以通过将它们包裹在胶束的疏水核心中来增加溶解度。然后，产生的胶束在体内降解，释放药物负载，这些分子的功能化可以靶向特定的组织。该项目将原子分子动力学(MD)模拟和粗粒分子动力学(MD)模拟的相对优势与一系列先进的生物物理工具(如小角中子和光散射以及核磁共振)相结合，以生成用于制备自组装纳米颗粒(SAN)的脂类分子的基本化学性质如何影响最终药物输送载体的结构的非常详细的图片。该项目最初将包括研究一系列两性离子脂类，包括不同长度的磷脂酰胆碱脂类，以评估它们形成的SAN的内部和界面结构。此外，我们还将确定SANS中装载的疏水小药物分子(包括酮胡敏酸盐和本地酸)的位置和数量。在了解了这些初始分子的基本化学性质如何影响得到的SAN作为药物输送载体的结构和能力后，该项目将继续通过基于它们各自的强度选择脂质和单体来研究新型SAN的形成，以实现SAN所需的性能的最佳组合，这包括将这些SAN功能化以进行靶向药物输送的可能性，并观察这可能对纳米颗粒产生的影响。我们将能够辨别这些SAN的自组装和药物封装机制，并确定在这两个过程中关键的相互作用。此外，MD模拟和实验技术还将用于了解和模拟这些药物输送载体的降解，并调查降解产物的命运。

A large number of the small molecules currently under development as drug candidates are hydrophobic, and as a result many of these drugs may not make it to market because of problems encountered due to poor water solubility. Therefore, in order to fully exploit their therapeutic potential, it is essential to incorporate such drugs in nontoxic, biocompatible and/or biodegradable formulations that both protect the drug during transportation in the body and release it at the target tissue. In the past few decades, there have been an increasingly large number of nanoparticle formulations created, many of which have been investigated for their biomedical applications. Among these applications, drug delivery has been one of the more prevalent for nanoparticles composed of organic molecules, as such particles can be used to enhance the apparent aqueous solubility of the encapsulated molecules as well as specifically direct the molecules to the site of the diseased tissue. One class of lipid of particular interest in drug delivery is phosphatidylcholines. Phosphatidylcholines are predominantly known as the majority components of cell membranes but they are also amphiphilic lipids that can self-assemble to form micelles. These lipids have low CMCs and small alterations in their hydrophobic tail length can cause dramatic changes to their micelle properties. This, along with their biocompatibility, makes them attractive compounds to investigate with regards to their use in the delivery of poorly soluble drugs as solubility can be increased by encapsulating them within the hydrophobic core of the micelle. The resulting micelles are then degraded in the body to release the drug load and functionalisation of these molecules can allow targeting of specific tissues. This project combines the relative strengths of atomistic and coarse-grain molecular dynamics (MD) simulations with a range of advanced biophysical tools, such as small-angle neutron and light scattering and NMR, to generate a very detailed picture of how the underlying chemical properties of lipidic molecules used to prepare self-assembling nanoparticles (SANs) affect the architecture of the resulting drug delivery vehicle. This project will initially involve investigating a series of zwitterionic lipids, including phosphoatidylcholine lipids of different lengths, to evaluate the internal and interfacial structure of the SANs that they form. Additionally, we will characterise the location and amount of small hydrophobic drug molecules (including testerosterone enanthate and proprionate) loaded within the SANs. After understanding how the basic chemical properties of these initial molecules influence the architecture and ability of the resulting SANs to act as drug delivery vehicles the project will then go on to investigate the formation of novel SANs through selection of lipids and monomers based on their respective strengths in order to achieve the optimum combination of properties that the SANs require, this includes the possibility of functionalizing these SANs for targeted drug delivery and looking at the impact this may have on the nanoparticle.We will be able to discern the self-assembly and drug encapsulation mechanisms of these SANs, and determine the interactions which are key in both processes. Both MD simulations and experimental techniques will additionally be used to understand and model the degradation of these drug delivery vehicles and to investigating the fate of the degradation products.