Metal-organic frameworks as a modular platform for advanced drug delivery

纳米药物递送系统(DDS)因其极大地提高许多治疗药物的安全性和有效性而受到越来越多的关注。这些系统解决的关键挑战包括活性药物成分(API)不溶、稳定性差或具有显著的脱靶效应。这些对于癌症疗法和新的基因疗法尤其重要，前者往往毒性很高，后者不稳定，无法跨越生物障碍。通过在纳米载体中包裹或以其他方式持有原料药分子，治疗药物可以被赋予广泛的有益的药代动力学特性，包括缓释和靶向释放。然而，当前的技术提供了一个非互补性和高度碎片化的工具箱，单独的方法只能通过潜在原料药的子集来解决这些挑战的子集。其结果是，运营商需要对每一种应用进行艰苦的优化和表征。“即插即用”系统将大大简化这一领域，在这种系统中，一种新的原料药--无论其大小或化学成分--可以装载到一个通用载体中，然后根据其功能进行改变。该项目将开发一种基于金属有机骨架(MOF)的新型DDS，这是一种具有特别广泛功能的材料类别，并采用模块化的车辆设计方法。它们几乎可以接受任何API，并可以根据需要使用行业标准技术进行修改。这意味着，MOF载体一旦被特定药物证实，可能会被期望在新药物上表现出类似的行为；而表面修饰--一旦其影响被表征--可能会在应用于新载体时表现出类似的行为。因此，MOFS可能会提供一种“模块化工具箱”的载体设计方法，而且可能是迄今为止最接近真正的即插即用系统的技术。载体生物科学与药物发现弹射器一起，正在努力加快这项技术向临床的过渡。这个为期两年的项目将寻求展示该平台在传统小分子疗法、抗体靶向递送和新型siRNA基因疗法递送方面的功能。它将以临床相关的体内里程碑为目标，涵盖该技术的有效性、生物兼容性和药代动力学。在这样做的过程中，它将验证这项技术并将其降低到制药业的风险中，从而使协作得以组织起来，并在项目完成后继续平台的开发。这个项目的重点是胰腺癌。然而，该平台具有广泛的适用性，相邻区域将在项目后进行探索。

Nanoparticle drug delivery systems (DDS) are seeing growing attention for their potential to drastically improve the safety and efficacy of many therapeutics. Key challenges these systems address include active pharmaceutical ingredients (APIs) that are insoluble, have poor stability or have significant off-target effects. These are particularly important for cancer therapies, which are often highly toxic, and novel gene therapies, which are unstable and cannot cross biological barriers. By encapsulating or otherwise holding API molecules within a nanocarrier, therapeutics can be given a wide range of beneficial pharmacokinetic properties, including slow and targeted release.Current technologies, however, provide a non-complementary and highly fragmented toolbox, with individual approaches that are only able to address a subset of these challenges with a subset of potential APIs. The result is that carriers require painstaking optimisation and characterisation for each application. The field would be considerably streamlined by a "plug-and-play" system, in which a new API -- regardless of its size or chemistry -- could be loaded into a universal carrier, which is then altered to suit its function.This project will develop a novel DDS based on metal-organic frameworks (MOFs), a class of materials with exceptionally broad functionality and a modular approach to vehicle design. They can accept virtually any API and be modified as required using industry-standard techniques. This means that a MOF carrier, once proven with a particular drug, might be expected to behave similarly with a new drug; and a surface modification -- once its impact has been characterised -- might be expected to behave similarly when applied to a new carrier. MOFs may therefore offer a "modular toolbox" approach to carrier design and potentially the closest technology yet to a true plug-and-play system.Vector Bioscience, together with the Medicines Discovery Catapult, is working to accelerate the transition of this technology to the clinic. This 2-year project will seek to demonstrate the functionality of the platform across conventional small-molecule therapeutics, antibody-targeted delivery, and delivery of novel siRNA gene therapies. It will target clinically relevant _in vivo_ milestones covering the technology's efficacy, biocompatibility, and pharmacokinetics. In doing so, it will validate and de-risk the technology to the pharmaceutical industry, enabling collaborations to be structured and the development of the platform to continue once the project is complete. The focus of this project is pancreatic cancer. However, the platform has broad applicability and adjacent areas will be explored post-project.