Formulations for Convection-Enhanced Delivery of Therapeutics in Diffuse Intrinsic Pontine Glioma

对流增强输注（CED）是一种通过手术植入小导管将药物直接输注到大脑特定且难以到达的区域的技术。CED已被应用于许多神经系统疾病，包括一系列脑肿瘤和神经退行性疾病。与许多市售导管相关的输液回流问题意味着通过这种方法输送的药物溶液体积有限。因此，使用高浓度的化疗药物大剂量注射，而局部的场外神经毒性是药物快速扩散离开肿瘤部位的结果。我们假设将药物配制成能够形成肿瘤内储库的长效输注剂将导致更低的脱靶毒性和更好的治疗效果。虽然针对CED的重新配方药物适用于许多疾病，但在本项目中，配方将针对弥漫性内生性脑桥胶质瘤（DIPG），这是一种侵袭性的儿科脑肿瘤，无法手术治疗，目前的治疗方案也很差。本项目旨在了解如何合理制定api以通过CED交付，重点是DIPG的治疗交付。以下目标是该项目的优先事项：-了解通过CED给药时在肿瘤部位局部和扩展持久性的配方特性-通过CED给药时产生最小回流的配方项目结果将是了解如何通过CED制定用于一般给药的api，以及可应用于DIPG中CED的特定配方。

Convection-Enhanced Delivery (CED) is a technique in which a direct infusion of drugs to the specific and difficult to reach areas of the brain is achieved via small catheters implanted surgically. CED has been applied to a number of neurological conditions, including a suite of brain tumours and neurodegenerative diseases. The issue of infusate backflow associated with many commercially available catheters means that drug solution volume delivered via this method is limited. As a result, high concentration bolus injections of chemotherapeutics are used, and local off-site neurotoxicity is a consequence of rapid drug diffusion away from the tumour site. We hypothesise that formulating drugs into long-acting infusates capable of forming intratumoural depots will lead to lower off-target toxicity and better treatment outcomes. Whilst reformulating drugs for CED is applicable to a number of diseases, in this project, formulations will be targeted towards Diffuse Intrinsic Pontine Glioma (DIPG), an aggressive paediatric brain tumour which is inoperable and for which current treatment options are poor. This project will aim to understand how to rationally formulate APIs for delivery via CED, with a focus on delivery of treatments for DIPG. The following aims are priorities for this project:- Understanding of formulation properties for local and extended persistence at the tumour site when administered via CED- Generation of formulations with minimal backflow when administered through CEDProject outcomes will be an understanding of how to formulate APIs for general administration via CED, and specific formulations that can be applied to CED in DIPG.