Self-Assembling Camptothecin Nanofiber Hydrogels as Adjunct Therapy for Intraoperative Treatment of Malignant Glioma

项目总结 恶性胶质瘤，包括最常见的类型胶质母细胞瘤(GBM)，在组织学上是异质性的，并且 侵袭性肿瘤被称为最具破坏性的肿瘤，具有很高的发病率和死亡率。尽管是多式联运 治疗包括手术、放射治疗和化疗，这种疾病不可避免地复发并被证明是致命的。 局部应用卡莫司汀植入物(格列黛尔®晶片)作为手术和放射治疗的辅助手段 已被临床证明可以延长恶性胶质瘤患者的生存时间，强烈表明 肿瘤切除后局部化疗是治疗脑肿瘤的一种可行而有效的策略 病人。然而，卡莫司汀的快速消耗和低组织渗透率极大地限制了临床益处。 仅将接受治疗的患者的中位生存期延长了6个月 未经治疗。这项提议旨在开发一种新型的自组装纳米纤维水凝胶，它使用 抗癌药物喜树碱(CPT)作为分子构建块，可局部给药 切除肿瘤后的空洞，最终目标是为患者实现更有效的治疗 被诊断为恶性胶质瘤。我们假设被提议的纳米纤维水凝胶将分布在 大的组织面积和可持续释放的治疗药物对胶质瘤细胞的长期细胞毒性，从而 从而显著延长了我们的啮齿动物模型的存活时间。为了验证我们的假设，我们概述了 在三个具体目标中拟议的研究活动，寻求解决当地的三个关键挑战 将治疗药物输送到切除腔：1)纳米纤维的凝胶特性。凝胶形式使 延长了在递送部位的滞留时间，并最大限度地减少了原本会发生的游离药物的毛细血管损失 发生；2)长期持续释放免费药物。释放率和释放期限为 对有效消除胶质瘤细胞而不会造成破坏性副作用至关重要；3)扩散到 组织区域。在目标1中，我们将确定自组装CPT DAS设计中的关键分子参数 创造不同表面化学性质的CPT纳米纤维，以促进水凝胶的形成 接触体液。目标2的重点是评价和微调药物释放速率和 机制，他们克服MDR机制的能力，以及在器官型内的扩散距离 纸巾。在目标3中，我们将使用动物模型来评估纳米纤维在大组织中扩散的能力 两种已开发的纳米纤维水凝胶的面积、药代动力学、体内疗效和毒性 我们的最终目标是开发一种纳米纤维水凝胶平台 将延长携带人类脑癌的啮齿动物的存活时间的技术，并将这个平台 到临床前的方法。

Project summary Malignant gliomas, including the most common type glioblastoma (GBM), are histologically heterogeneous and invasive tumors known as the most devastating neoplasms with high morbidity and mortality. Despite multimodal treatment including surgery, radiotherapy, and chemotherapy, the disease inevitably recurs and proves fatal. Local application of carmustine implants (Gliadel® wafers) as an adjunct to surgery and radiation therapy has been clinically proven to extend the survival time for patients with malignant gliomas, strongly suggesting that local chemotherapy after tumor resection presents a feasible and effective strategy to treat brain tumor patients. However, the rapid depletion of carmustine and low tissue penetration greatly limit the clinical benefits of Gliadel® wafers, which only extend the median survival of treated patients by six months compared to those untreated. This proposal aims to develop a novel type of self-assembling nanofiber hydrogels that use the anticancer drug camptothecin (CPT) as the molecular building blocks and that can be locally administered to the resection cavities after tumor removal, with the ultimate goal to achieve more effective treatments for patients diagnosed with malignant gliomas. We hypothesize that the proposed nanofiber hydrogels will spread across large tissue areas and sustainably release therapeutic agents for long-term cytotoxicity against glioma cells, thus leading to significantly extended survival time in our rodent model. To test our hypothesis, we outlined the proposed research activities in the three specific Aims, seeking to address the three key challenges in local delivery of therapeutic drugs into resection cavities: 1) the nanofiber gelation properties. The gel form enables prolonged retention in the delivery sites and also minimizes capillary loss of free drugs that would otherwise occur; 2) the sustained release of free drugs over a long period of time. The release rate and period are critical for effective elimination of glioma cells without causing devastating side effects; 3) diffusion across large tissue areas. In Aim 1, we will identify the key molecular parameters in the design of self-assembling CPT DAs to create CPT nanofibers of varying surface chemistries that would promote the formation of hydrogels upon contact with body fluids. Aim 2 is focused on the evaluation and fine-tuning of the drug release rate and mechanism, their ability to overcome the MDR mechanisms, as well as diffusion distance within organotypic tissues. In Aim 3, we will use an animal model to evaluate the nanofibers’ ability to diffuse across large tissue areas, pharmacokinetics, in vivo efficacy and toxicity of two already developed nanofiber hydrogels and also those to be developed in Aim 1 and Aim 2. Our ultimate goal is to develop a nanofiber hydrogel platform technology that will extend the survival time of rodents bearing human brain cancer, and translate this platform to a pre-clinical approach.