Multi-scale approach to designing novel colloidal drug delivery vehicles

目前正在开发的作为候选药物的大量小分子是疏水性的，并且因此这些药物中的许多可能由于由于水溶性差而遇到的问题而无法进入市场。因此，为了充分利用其治疗潜力，必须将此类药物掺入无毒、生物相容和/或生物可降解的制剂中，所述制剂既在体内运输期间保护药物又在靶组织处释放药物。在过去的几十年里，已经有越来越多的纳米颗粒制剂，其中许多已被研究其生物医学应用。在这些应用中，药物递送对于由有机分子组成的纳米颗粒而言是更普遍的应用之一，因为这样的颗粒可以用于增强包封分子的表观水溶性以及特异性地将分子引导至患病组织的部位。在药物递送中特别感兴趣的一类脂质是磷脂酰胆碱。磷脂酰胆碱主要被认为是细胞膜的主要成分，但它们也是可以自组装形成胶束的两亲性脂质。这些脂质具有低CMC，并且其疏水尾部长度的微小改变可导致其胶束性质的显著变化。这沿着它们的生物相容性，使它们成为有吸引力的化合物，以研究它们在递送难溶性药物中的用途，因为溶解度可以通过将它们包封在胶束的疏水核心内来增加。然后，所得胶束在体内降解以释放药物负载，并且这些分子的功能化可以允许靶向特定组织。该项目将原子和粗粒分子动力学（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NMR）相结合，以生成用于制备自组装纳米颗粒（SAN）的无规分子的基本化学性质如何影响所得药物递送载体的结构的非常详细的图片。该项目最初将涉及调查一系列两性离子脂质，包括不同长度的磷脂酰胆碱脂质，以评估它们形成的SAN的内部和界面结构。此外，我们还将研究SAN中小疏水性药物分子（包括睾酮庚酸酯和丙酸酯）的位置和数量。在了解这些初始分子的基本化学性质如何影响所得SAN作为药物递送载体的结构和能力之后，该项目将继续研究通过基于各自的强度选择脂质和单体来形成新型SAN，以实现SAN所需的最佳性能组合，这包括功能化这些SAN用于靶向药物递送的可能性，并观察这可能对纳米颗粒的影响。我们将能够辨别这些SAN的自组装和药物包封机制，并确定在这两个过程中关键的相互作用。MD模拟和实验技术都将被用于了解和模拟这些药物递送载体的降解，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.