DDRugging glioblastoma through the development of smart biomaterials

DDR通过开发智能生物材料来治疗胶质母细胞瘤

• 批准号: 2806147
• 金额: --
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2806147
• 关键词: DDRugging; glioblastoma; through; development; smart

From inception, the proposed project has been designed specifically with reference to the EPSRC HealthcareTechnologies Theme. In line with the first 'grand challenge' aim of this theme, the project is expected to tacklea number of engineering challenges to develop a new therapy, with the potential for future clinical translation.Since brain tumours are responsible for more years of life lost than any other cancer, we believe the clinicalcontext of the studies aligns strongly with the 'strong features' of the Theme's vision to focus on the highestpriority healthcare challenges. Previously developed surgically-delivered therapies for glioblastoma - the mostcommon and aggressive brain cancer - are not routinely used in the clinic due to a number of physical limitationswhich hamper their efficacy including: rapid, potentially toxic drug release profiles; physical properties includingstiffness which are not well matched with the human brain, and; the permanent, non-degradable nature ofcompounds used. A fresh, and multidisciplinary engineering perspective is required to develop new biomaterialsthat are fully attuned to the current unmet clinical need. As such, the proposed project will deal with a number ofcritical engineering challenges to provide a novel, composite biomaterial with the potential to improve patientoutcomes. Firstly, the properties of previous PLGA/PEG pastes will need to be substantially modified to enablethe delivery of a number of targeted drug therapies, and provide a stiffness much more comparable to brain thanin previous studies. Secondly, microbeads with properties that permit the ionizing radiation triggered release ofboth targeted drugs and temozolomide will need to be developed. Although we anticipate these may be based onuse of a poly-di(carboxylatophenoxy)phosphazene (PCPP) hydrogel with a selenocystamine cross-linked matrix, anumber of alternatives will be developed to provide optimal 'on/off' drug release, whilst also considering thepotential for 'drug recharge'. Thirdly, both components of the composite biomaterial will need to be improved aspart of iterative engineering process to ensure their use in combination does not adversely impact desiredproperties and to provide an overall drug release profile and duration which far exceeds materials published todate. This represents a significant challenge, but is critical to provide the durable treatment responses thatpatients desperately require. Fourthly, the project deals with the engineering challenge of developing potentialways to replenish drug compound(s) into the smart biomaterial. This provides a fresh problem, which to resolve,we expect the student will need to take inspiration from current implantable neurosurgical devices (such as anOmmaya reservoir, or a baclofen pump) and adapt these to develop a new device that can be used in conjunctionwith the smart biomaterial developed earlier in the studies. With our support, a particularly talented student maybe able to further advance this idea - for example, by developing a bioelectronic device with sensing capabilitiesto monitor drug concentration adjacent to the surgical resection cavity and alert the user when drugreplenishment is required and/or administer this in an automated manner. Finally, the studies will incorporatedevelopment of a 3D bioink printed resection cavity model to efficacy test the biomaterials against explantedglioblastoma cells or tissue. The 'to-scale' or 'near human scale' nature of this novel model will represent animportant advance in the 3D glioblastoma models our team are currently engineering and is likely to requirenumerous innovations to maintain cell viability at this scale, including integration of a 3D printed prototypevascular/perfusing network.

从一开始，拟议项目就专门参照EPSRC保健技术主题进行设计。根据这一主题的第一个“大挑战”目标，该项目预计将解决一系列工程挑战，以开发一种新的治疗方法，并具有未来临床转化的潜力。由于脑肿瘤比其他任何癌症都要导致更多的寿命损失，我们相信，这些研究的临床背景与主题愿景的“强有力的特征”密切相关，即关注最优先的医疗保健挑战以前开发的胶质母细胞瘤-最常见和最具侵袭性的脑癌-的经皮递送疗法由于许多妨碍其疗效的物理限制而未在临床中常规使用，这些物理限制包括：快速的、潜在毒性的药物释放曲线;物理性质，包括与人脑不匹配的硬度;以及所使用的化合物的永久性、不可降解性质。需要一个新的、多学科的工程视角来开发新的生物材料，以完全适应当前未满足的临床需求。因此，拟议的项目将处理一些关键的工程挑战，以提供一种新型的复合生物材料，具有改善患者预后的潜力。首先，需要对以前的PLGA/PEG糊剂的性质进行实质性修改，以实现许多靶向药物治疗的递送，并提供比以前的研究更接近大脑的硬度。其次，需要开发具有允许电离辐射触发释放靶向药物和替莫唑胺的特性的微珠。虽然我们预计这些可能是基于使用的聚-二（羧基苯氧基）磷腈（PCPP）水凝胶与硒代胱胺交联矩阵，将开发许多替代品，以提供最佳的“开/关”的药物释放，同时也考虑到潜在的“药物再充电”。第三，作为迭代工程过程的一部分，复合生物材料的两种组分都需要改进，以确保它们的组合使用不会对期望的性质产生不利影响，并提供远远超过迄今为止公布的材料的总体药物释放曲线和持续时间。这是一项重大挑战，但对于提供患者迫切需要的持久治疗反应至关重要。第四，该项目涉及开发潜力的工程挑战，以补充药物化合物到智能生物材料中。这提供了一个新的问题，要解决这个问题，我们希望学生需要从当前的植入式神经外科设备（如Ommaya储药器或巴氯芬泵）中获得灵感，并调整这些设备以开发一种新设备，该设备可以与研究早期开发的智能生物材料结合使用。在我们的支持下，一个特别有才华的学生可能能够进一步推进这一想法-例如，通过开发一种具有传感能力的生物电子设备来监测手术切除腔附近的药物浓度，并在需要药物补充时提醒用户和/或以自动化的方式管理。最后，这些研究将开发一种3D生物墨水打印的切除腔模型，以测试生物材料对胶质母细胞瘤细胞或组织的有效性。这种新模型的“按比例”或“接近人类规模”的性质将代表我们团队目前正在设计的3D胶质母细胞瘤模型的一个重要进展，并且可能需要大量的创新来维持这种规模的细胞活力，包括3D打印原型血管/灌注网络的整合。