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

自组装喜树碱纳米纤维水凝胶作为恶性胶质瘤术中治疗的辅助疗法

• 批准号: 10738545
• 负责人: Honggang Cui
• 金额: $ 52.11万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-04 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10738545
• 关键词: Address; Animal Experiments; Animal Model; Animals; Antineoplastic Agents; Area; Behavior; Blood capillaries; Body Fluids; Brain; Brain Neoplasms; Camptothecin; Carmustine; Cells; Chemicals; Chemistry; Clinical; Clinical Trials; Combined Modality Therapy; Diagnosis; Diffuse; Diffusion; Disease; Distant; Drug Carriers; Drug Design; Drug Exposure; Drug Kinetics; Evaluation; Excision; Exhibits; Feedback; Foundations; Gel; Gliadel Wafers; Glioblastoma; Glioma; Goals; Histologic; Human; Hydrogels; Implant; In Vitro; Infiltration; Investigation; Laboratories; Location; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Modeling; Molecular; Monitor; Morbidity - disease rate; Mus; Neoplasms; Newly Diagnosed; Operative Surgical Procedures; Patient-Focused Outcomes; Patients; Penetration; Pharmaceutical Preparations; Phase; Play; Primary Brain Neoplasms; Property; Radiation therapy; Recurrence; Recurrent disease; Recurrent tumor; Reproducibility of Results; Research Activity; Rodent; Rodent Model; Role; Safety; Series; Site; Surface; Surgically-Created Resection Cavity; Survival Rate; System; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Topotecan; Toxic effect; Translating; Translations; Tumor Tissue; Viscosity; Work; amphiphilicity; biomaterial compatibility; cancer cell; cancer type; chemotherapy; clinical development; clinical translation; combat; controlled release; critical period; cytotoxicity; design; drug release kinetics; drug release profile; effective therapy; experimental study; functional group; human disease; immunogenicity; implantation; improved; in vivo; irinotecan; millimeter; mortality; mouse model; nanofiber; novel; pre-clinical; rational design; residence; self assembly; side effect; technology platform; translational potential; treatment strategy; tumor

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.

项目摘要 恶性神经胶质瘤，包括最常见的类型胶质母细胞瘤（GBM），在组织学上是异质的， 侵入性肿瘤被称为最毁灭性的肿瘤，具有高发病率和死亡率。尽管有多模式 治疗包括手术，放疗和化学疗法，这种疾病不可避免地复发并证明是致命的。 局部应用Carmustine Imprans（Gliadel®Wavers）作为手术和放射治疗的辅助 在临床上被证明可以延长恶性神经胶质瘤患者的生存时间，强烈表明 肿瘤切除后局部化疗提出了一种可行有效的治疗脑肿瘤的策略 患者。但是，卡莫斯汀和低组织渗透的迅速部署极大地限制了临床益处 Gliadel®波，仅将治疗患者的中位存活率延长了六个月 未经处理。该建议旨在开发一种新型的自组装纳米纤维水凝胶，用于使用 抗癌药物camptothecin（CPT）作为分子构建块，可以局部给药 肿瘤切除后切除腔，最终目标是为患者获得更有效的治疗方法 被诊断为恶性神经胶质瘤。我们假设所提出的纳米纤维水凝胶将遍布 大组织区域，可持续释放针对神经胶质瘤细胞长期细胞毒性的治疗剂，因此 在我们的啮齿动物模型中导致显着延长生存时间。为了检验我们的假设，我们概述了 在三个特定目标中提出的研究活动，试图应对本地的三个主要挑战 将治疗药物递送到切除腔中：1）纳米纤维胶凝特性。凝胶形式启用 长期保留在交货地点，还可以最大程度地减少免费药物的毛细管损失 发生; 2）长时间持续释放免费药物。释放率和周期是 对于有效消除神经胶质瘤细胞而不会引起毁灭性副作用至关重要； 3）扩散大型 组织区域。在AIM 1中，我们将确定自组装CPT DAS设计中的关键分子参数 创建各种表面化学的CPT纳米纤维，以促进水凝胶的形成 与体液接触。 AIM 2的重点是对药物释放率的评估和微调， 机制，他们克服MDR机制的能力以及有机体内的扩散距离 组织。在AIM 3中，我们将使用动物模型来评估纳米纤维在大型组织中扩散的能力 区域，药代动力学，两个已经开发的纳米纤维水凝胶的体内效率和毒性 那些在AIM 1和AIM 2中开发的。我们的最终目标是开发纳米纤维水凝胶平台 将延长带有人脑癌的啮齿动物的生存时间的技术，并翻译此平台 采用临床前方法。