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）是最常见的原发性恶性脑肿瘤。尽管化疗、放疗和手术技术取得了进展，但预后仍然很差。只有少数患者适合最大限度的治疗，包括手术切除、放疗和化疗，即使在最大限度的治疗后，平均生存期仍保持在诊断后约14个月。GBM无法治愈，患者不可避免地遭受疾病的复发和进展。大多数肿瘤复发发生在原始肿瘤部位的2cm内，这是由于肿瘤细胞显微镜下侵入周围脑组织而逃避手术切除和放疗。有效治疗脑肿瘤的主要障碍之一是血脑屏障（BBB）的存在，它阻止药物从血流自由进入大脑。有时可以通过使用高剂量的药物来增加进入大脑的药物量，但这通常会导致患者无法接受的严重副作用。我们的解决方案是在切除肿瘤后通过将化疗药物直接输送到肿瘤周围的脑组织来绕过BBB，使用称为对流增强输送（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。这种技术使我们能够以非常高的安全性和准确性将化疗靶向复发性脑肿瘤，并将有效的药物浓度分布在大脑的整个相关区域。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病患者输送药物，在过去的5年里，我们一直在与工业合作者合作开发CED导管系统，使我们能够向大脑输送重复的药物剂量。在这个项目中，我们建议将联合收割机CED与纳米技术领域的最新进展相结合。通过将化疗药物封装在可生物降解的纳米球中，我们的目标是实现脑内药物的受控释放，减少实现肿瘤消退所需的药物剂量，并限制副作用的风险。我们选择了一种广泛用于医疗行业的纳米球配方，并被证明是安全无毒的。我们已经批准了一项未封装化疗的CED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将化疗纳米颗粒输送到大脑，我们希望减少肿瘤复发和进展，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之间的独特合作组成，他们拥有知识和经验来开发这种新技术，以造福患者。

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.