Developing Impermeable Nanocapsules for Efficient Remote Delivery of Cytotoxic Drugs at Precise Locations

癌症治疗对健康组织有显著的副作用。一个突出的研究领域集中在封装细胞毒性药物靶向递送到癌症组织，从而减少脱靶副作用。然而，对于包封的临床药物仍然存在重大挑战。载药量低，制造过程效率低且昂贵2。一旦包封，药物随时间的浸出通常很高（特别是在稀释时）3。最近开发的用于金属壳微胶囊的方法能够永久地保留小分子并通过基于超声的远程激活突发释放有效载荷，最近已经发展到产生纳米胶囊（50- 120 nm），其可以永久地包封化疗药物（Paclitaxel）。这种递送方法同时解决了上述挑战，确保纳米胶囊核心内存在高药物含量，在到达作用部位之前不会发生浸出，从而防止任何副作用，并且可以通过使用超声波实现药物的局部释放。该项目将进一步发展这种方法并解决该技术的非常重要的方面，该项目通过专注于开发纳米物体，以不同的方式解决细胞毒性药物递送的关键方面，其目的是通过阻止药物浸出来防止副作用，这是大多数当前纳米物体的典型缺点化疗治疗功效仍然受到我们不能递送足够高的剂量以允许完全控制癌细胞的限制，这是由于由于需要限制由于非靶组织中的毒性引起的全身药物水平。然而，目前的（低）全身剂量仍然引起患者生活质量的显著降低，其中大多数施用的药物对身体的其余部分引起副作用而不是到达肿瘤。开发了一种仅在肿瘤附近以高剂量递送高毒性化疗药物的新方法，壳纳米胶囊，防止任何药物浸出前激活。在这个项目中负责任的创新是基于两个方面：1）了解金属纳米胶囊在体外对人细胞和在体内对小鼠模型的潜在毒性，以及2）考虑到“潜在的杂散”纳米胶囊对环境的毒性。

Cancer therapeutics have dramatic side effects on healthy tissues. A prominent research area focuses on encapsulating cytotoxic drugs for targeted delivery to cancer tissues thereby reducing off-target side-effects. However, significant challenges remain for encapsulated clinical drugs.1. Drug loading is low and the manufacturing process is inefficient and expensive2. Once encapsulated, drug leaching over time is often high (especially on dilution)3. Typically, release specifically within tumours is not achieved.Recently developed methods for metallic-shell microcapsules able to permanently retain small molecules and to burst release payloads via ultrasound-based remote activation have recently evolved to produce nanocapsules (50-120nm) that can permanently encapsulate a chemotherapeutic drug (Paclitaxel). This delivery method addresses the above challenges simultaneously by ensuring that a high drug content is present within the nanocapsule cores, that no leaching occurs prior to reaching the site of action, thus preventing any side-effects and that local release of the drugs can be achieved through the use of ultrasound.This project will further develop this methodology and address very important aspects of the technology, which are key for working towards uptake of this delivery method by industry.This project addresses key aspects of cytotoxic drug delivery in a different manner by focusing on developing nano-objects, which aim to prevent side-effects by stopping leaching of the drugs, which is a typical drawback of most current nano-objects (e.g. liposomes, vesicles, micelles, nanoparticles), particularly upon dilution in the bloodstream.Chemotherapy treatment efficacy is still restricted by our inability to deliver high enough doses to allow complete control of cancer cells, resulting from the need to limit systemic drug levels due to toxicity in non-target tissues. Nevertheless, current (low) systemic doses still induce dramatic patient life quality reduction with the majority of administered drugs causing side effects to the rest of the body rather than reaching tumours.Here, a new method for delivering highly toxic chemotherapy drugs at high doses only within the tumour vicinity is developed by locally/remotely releasing drugs encapsulated within metal-shell nanocapsules that prevent any drug leaching prior to activation.Responsible innovation in this project is based on two aspects: 1) understanding the potential toxicity of the metal nanocapsules on human cells in-vitro and on mouse models in-vivo and 2) considering the toxicity of 'potentially stray' nanocapsules on the environment.