权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Porous 3D Silica Nanoparticle Assemblies as Post-surgical Drug Delivery Implants to Reduce Glioblastoma Recurrence

多孔 3D 二氧化硅纳米颗粒组件作为术后药物输送植入物以减少胶质母细胞瘤复发

基本信息

批准号：
EP/V009516/1
负责人：
Zhan Yuin Ong
金额：
$ 50.19万
依托单位：
University of Leeds
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FV009516%2F1
关键词：
Porous 3D Silica Nanoparticle Assemblies

项目摘要

Glioblastoma (GBM) is the most aggressive and common form of primary brain tumour in adults. GBM patients have an extremely poor median survival of < 15 months even with treatment. The occurrence of brain tumours is strongly related to age, and incidences worldwide and in the UK are rapidly rising; with a 39% rise in the UK since the 1990s to 12,071 new cases per year. The economic cost of brain tumours, including NHS treatment cost and loss of income, is ~£578 million per annum. Any technology that can improve the efficacy and safety of GBM treatment and patient outcomes will thus bear major cost savings for the UK economy. The treatment of GBM typically involves surgical tumour removal, radiotherapy, and chemotherapy. However, the aggressive tumour growth as finger-like tentacles in the brain often makes surgery ineffective, leading to unacceptably high tumour recurrence and mortality rates. As > 90% of tumour recurrences occur within 2 cm of the original tumour, the ability to prevent or delay local tumour regrowth after surgical removal of the bulk of the tumour mass will greatly improve patient outcomes. Indeed, the direct placement of a drug delivery device made from a drug-impregnated polymeric wafer (Glialdel) at the surgical site to kill residual cancer cells has modestly improved patient survival by 2 months. This approach also overcomes the usual challenge of drug delivery to the brain as it eliminates the need to transport the drug across the highly impermeable blood-brain barrier. However, the short acting nature of Glialdel has led to its small patient survival benefits, thus necessitating the development of more advanced drug delivery devices that could confer longer term drug release of more effective anticancer drugs to improve treatment outcomes.The aim of this project is to develop an implantable drug delivery technology to provide slow and sustained release of anticancer drugs in response to specific biological signals such as enzymes and chemicals after removal of the bulk of the tumour mass by neurosurgeons. This will be achieved by assembling 3D fibre-like structures from highly uniform porous silica nanoparticles. This system offers unprecedented porosity control for anticancer drugs to be loaded both inside the pores of the nanoparticles and in the spaces between the nanoparticles, thus enabling a high amount of anticancer drug to be delivered. As the pores between the nanoparticles are larger, faster initial drug release is expected, which will be followed by a slower sustained drug release from the smaller nanoparticle pores. The ability to precisely tune the interparticle pore sizes and surface area by varying the size and concentration of the nanoparticles and the inclusion of a natural polymer, hyaluronic acid, will allow the drug release to be more tightly regulated. This approach thus has the potential to provide steady long-term drug release which could improve the treatment safety and efficacy compared to other conventional local drug delivery systems. The 3D fibres will be formulated in a hydrogel to enhance their application at the brain cavity by neurosurgeons. The safety and efficacy of the 3D structures and hydrogel formulation will be studied in patient derived GBM and non-cancerous cells, which retain the native characteristics of the relevant human brain tissues.We have assembled a world-class multidisciplinary team of experts in materials chemistry, drug delivery, cancer biology, and neurosurgery to develop the drug delivery system. The complementary research expertise will ensure that the technology development is underpinned by a strong knowledge of cancer biology and clinical needs to maximise potential for technology translation and impact. The findings of this study will have wider applications for local drug delivery to other types of cancers and diseases for which the ability to control the release rates and provide long-term drug release is important.

胶质母细胞瘤（GBM）是成人中最具侵袭性和最常见的原发性脑肿瘤。即使接受治疗，GBM患者的中位生存期也极差，< 15个月。脑肿瘤的发生与年龄密切相关，全球和英国的发病率正在迅速上升;自20世纪90年代以来，英国的发病率上升了39%，达到每年12，071例新发病例。脑肿瘤的经济成本，包括NHS治疗成本和收入损失，每年约为5.78亿英镑。因此，任何能够提高GBM治疗效果和安全性以及患者结局的技术都将为英国经济节省大量成本。GBM的治疗通常包括手术切除肿瘤、放疗和化疗。然而，肿瘤在大脑中像手指一样的侵袭性生长往往使手术无效，导致不可接受的高肿瘤复发率和死亡率。由于> 90%的肿瘤复发发生在原始肿瘤的2cm内，因此在手术切除大部分肿瘤块后预防或延迟局部肿瘤再生长的能力将大大改善患者的预后。事实上，在手术部位直接放置由药物浸渍的聚合物薄片（Glialdel）制成的药物递送装置以杀死残留的癌细胞已经适度地提高了患者存活2个月。这种方法还克服了将药物递送到大脑的常见挑战，因为它消除了将药物运输穿过高度不可渗透的血脑屏障的需要。然而，Glialdel的短效性质导致其小的患者生存益处，因此，有必要开发更先进的药物释放装置，使更有效的抗癌药物能够长期释放，以改善治疗效果。本项目的目的是开发一种植入式药物释放技术，使抗癌药物能够响应特定的生物信号，如酶和化学物质后，切除大部分的肿瘤质量的神经外科医生。这将通过从高度均匀的多孔二氧化硅纳米颗粒组装3D纤维状结构来实现。该系统提供了前所未有的孔隙率控制，用于将抗癌药物装载在纳米颗粒的孔内和纳米颗粒之间的空间中，从而能够递送大量的抗癌药物。由于纳米颗粒之间的孔较大，预期初始药物释放较快，随后药物从较小的纳米颗粒孔中持续释放较慢。通过改变纳米颗粒的大小和浓度以及包含天然聚合物透明质酸来精确调节颗粒间孔径和表面积的能力将允许更严格地调节药物释放。因此，这种方法具有提供稳定的长期药物释放的潜力，与其他传统的局部药物递送系统相比，这可以提高治疗安全性和有效性。3D纤维将被配制成水凝胶，以增强神经外科医生在脑腔中的应用。该3D结构和水凝胶制剂的安全性和有效性将在患者来源的GBM和非癌细胞中进行研究，这些细胞保留了相关人脑组织的天然特征。我们组建了一个由材料化学，药物输送，癌症生物学和神经外科专家组成的世界一流的多学科团队来开发药物输送系统。互补的研究专业知识将确保技术开发得到癌症生物学和临床需求的强大知识的支持，以最大限度地发挥技术转化和影响的潜力。这项研究的结果将有更广泛的应用，局部药物输送到其他类型的癌症和疾病，其中控制释放速率和提供长期药物释放的能力是重要的。