MICA: Convection-enhanced delivery of encapsulated nanospheres for controlled delivery of chemotherapy to the brain

多形性胶质母细胞瘤(GBM)是最常见的原发性脑肿瘤。尽管化疗、放射治疗和外科技术取得了进步，但预后仍然很差。只有少数患者适合接受最大限度的治疗，包括手术切除、放射治疗和化疗，即使在最大限度的治疗之后，从诊断到确诊，平均生存期仍保持在大约14个月。GBM没有治愈的方法，患者不可避免地会复发和发展。大多数肿瘤复发发生在原发肿瘤部位2厘米以内，这是由于肿瘤细胞向周围脑组织的微小侵袭而逃脱了手术切除和放射治疗。脑肿瘤有效治疗的主要障碍之一是血脑屏障(BBB)的存在，它阻止药物从血液自由进入大脑。有时可以通过使用大剂量的药物来增加进入大脑的药物数量，但这通常会导致患者无法接受的严重副作用。我们的解决方案是绕过血脑屏障，在切除后直接将化疗输送到肿瘤周围的脑组织，使用一种名为对流增强递送(CED)的神经外科技术。CED描述了一种通过超细微导管将药物直接输送到大脑的方法。这项技术使我们能够以非常高的安全性和准确性对复发的脑肿瘤进行靶向化疗，并将有效的药物浓度分布在大脑的相关区域。这种方法还通过专门针对大脑的药物来降低副作用的风险。我们以前曾使用这种技术向帕金森氏症患者输送药物，在过去的5年里，我们一直在与行业合作者合作开发一种CED导管系统，使我们能够将重复剂量的药物输送到大脑。在这个项目中，我们建议将CED与纳米技术领域的最新进展结合起来。通过将化疗药物包裹在可生物降解的纳米球中，我们的目标是实现大脑内受控的药物释放，减少实现肿瘤消退所需的药物剂量，并限制副作用的风险。我们选择了一种在医疗行业广泛使用的纳米球配方，并被证明是安全无毒的。我们已经批准了无胶囊化疗的CED的临床试验，这项研究代表了一个合乎逻辑的进展。通过使用CED将化疗纳米粒输送到大脑，我们希望减少肿瘤的复发和进展，并改善这种毁灭性疾病患者的生活质量。我们的研究团队由神经外科医生、神经科学家、化学家和化学工程师组成，他们拥有开发这项新技术的知识和经验，为患者造福。

Glioblastoma multiforme (GBM) is the commonest primary malignant brain tumour. Despite advances in chemotherapy, radiotherapy and surgical technology, the prognosis remains poor. Only a minority of patients are suitable for maximal treatment comprising surgical excision, radiotherapy and chemotherapy, and even following maximal treatment, average survival remains at approximately 14 months from diagnosis. There is no cure for GBM and patients inevitably suffer from recurrence and progression of the disease. The majority of tumour recurrences occur within 2cm of the site of the original tumour due to microscopic invasion of tumour cells into surrounding brain tissue which escape surgical excision and radiotherapy. One of the major obstacles to the effective treatment of brain tumours is the existence of the blood-brain barrier (BBB), which prevents the free passage of drugs from the bloodstream into the brain. It is sometimes possible to increase the amount of drug which enters the brain by using high drug doses, but this often results in severe side-effects which are unacceptable to patients.Our solution is to bypass the BBB by delivering chemotherapy directly to brain tissue surrounding the tumour following excision, using a neurosurgical technique called convection-enhanced delivery (CED). CED describes a method of direct drug delivery to the brain through ultrafine microcatheters. This technique allows us to target the chemotherapy to recurrent brain tumours with very high safety and accuracy, and to distribute effective drug concentrations throughout relevant areas of the brain. This approach also reduces the risk of side-effects by specifically targetting drugs to the brain. We have previously used this technique to deliver drugs to patients with Parkinson's Disease, and over the last 5 years we have been working with industrial collaborators to develop a CED catheter system which allows us to deliver repeated drug doses to the brain. In this project we propose to combine CED with recent advances in the field of nanotechnology. By encapsulating chemotherapies in biodegradable nanospheres our aim is to achieve controlled drug release within the brain, to reduce the drug doses required to achieve tumour regression, and to limit the risk of side-effects. We have chosen a nanosphere formulation which is widely used in the medical industry and is proven to be safe and non-toxic. We have approval for a clinical trial of CED of unencapsulated chemotherapy, and this study represents a logical progression. By using CED to deliver chemotherapy nanoparticles to the brain we hope to reduce tumour recurrence and progression and to improve the quality of life of patients with this devastating disease. Our research team comprises a unique collaboration between neurosurgeons, neuroscientists, chemists and chemical engineers with the knowledge and experience to develop this novel technology for patient benefit.