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

胶质母细胞瘤(GBM)是成人最具侵袭性和最常见的原发脑肿瘤。即使接受治疗，GBM患者的中位生存期也非常低，只有15个月。脑瘤的发生与年龄密切相关，全球和英国的脑瘤发病率正在迅速上升；自20世纪90年代以来，英国的脑瘤发病率上升了39%，达到每年12,071例新病例。脑肿瘤的经济成本，包括NHS的治疗费用和收入损失，每年为5.78亿GB。因此，任何可以提高GBM治疗的有效性和安全性以及患者结果的技术都将为英国经济节省大量成本。基底膜的治疗通常包括手术切除肿瘤、放射治疗和化疗。然而，像手指一样的触须在大脑中侵略性生长的肿瘤往往使手术无效，导致令人无法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2厘米以内，在手术切除大部分肿瘤后，预防或延缓局部肿瘤再生长的能力将极大地改善患者的预后。事实上，直接将由药物浸渍的聚合物晶片(Glialdel)制成的药物输送装置放置在手术部位以杀死残留的癌细胞，略微提高了患者2个月的存活率。这种方法还克服了将药物输送到大脑的常见挑战，因为它消除了将药物运送到高度不渗透的血脑屏障的需要。然而，Glialdel的短效特性导致其对患者生存的好处很小，因此需要开发更先进的药物输送装置，使更有效的抗癌药物能够更长期地释放，以改善治疗结果。该项目的目的是开发一种植入式药物输送技术，在神经外科医生切除大部分肿瘤后，提供针对特定生物信号的缓慢和持续的抗癌药物释放，如酶和化学物质。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，使抗癌药物既可以装载在纳米颗粒的孔内，也可以装载在纳米颗粒之间的空间中，从而能够输送大量抗癌药物。由于纳米颗粒之间的孔较大，预计初始药物释放较快，随后较小的纳米颗粒孔将较慢地持续释放药物。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，将使药物释放得到更严格的控制。因此，这种方法有可能提供稳定的长期药物释放，与其他传统的局部给药系统相比，可以提高治疗的安全性和有效性。神经外科医生将把3D纤维制成水凝胶，以增强其在脑腔中的应用。3D结构和水凝胶配方的安全性和有效性将在患者来源的GBM和非肿瘤细胞中进行研究，这些细胞保留了相关人脑组织的天然特征。我们组建了一支由材料化学、药物输送、癌症生物学和神经外科专家组成的世界级多学科专家团队，以开发药物输送系统。互补的研究专业知识将确保技术开发得到对癌症生物学和临床需求的深厚知识的支持，以最大限度地发挥技术转化和影响的潜力。这项研究的结果将在其他类型的癌症和疾病的局部药物输送中得到更广泛的应用，对这些疾病来说，控制释放速率和提供长期药物释放的能力是重要的。

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.