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 恶性胶质瘤，包括最常见类型的胶质母细胞瘤（GBM），在组织学上是异质的， 侵袭性肿瘤是最具破坏性的肿瘤，具有很高的发病率和死亡率。尽管多式联运 虽然治疗包括手术、放疗和化疗，但这种疾病不可避免地会复发，并证明是致命的。 局部应用卡莫司汀植入剂（Gliadel® wafer）作为手术和放射治疗的辅助治疗， 临床证明，它可以延长恶性胶质瘤患者的生存时间，这强烈表明， 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 患者然而，卡莫司汀的快速消耗和低组织渗透性极大地限制了临床益处 Gliadel®晶片，与那些治疗患者相比，仅延长了6个月的中位生存期。 未经治疗。该提案旨在开发一种新型的自组装水凝胶， 抗癌药物喜树碱（CPT）作为分子结构单元，并且可以局部给药于 肿瘤切除后的切除腔，最终目标是为患者实现更有效的治疗 被诊断为恶性神经胶质瘤我们假设，所提出的水凝胶将扩散到 大的组织面积和可持续释放的治疗剂，用于对神经胶质瘤细胞的长期细胞毒性，因此 从而显著延长了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 在三个具体目标的拟议研究活动，寻求解决当地的三个关键挑战， 将治疗药物递送到切除腔中：1）凝胶化性质。凝胶形式使得 延长了药物在输送部位的滞留时间，并使游离药物的毛细血管损失最小化， 2）药物在长时间内持续释放。释放速率和时间为 对于有效消除神经胶质瘤细胞而不引起破坏性副作用至关重要; 3）扩散穿过大的 组织区域。在目标1中，我们将确定自组装CPT DA设计中的关键分子参数 以产生不同表面化学的CPT纳米纤维，其将促进水凝胶的形成， 与体液接触。目的2集中于药物释放速率的评估和微调， 机制，它们克服MDR机制的能力，以及器官型内的扩散距离。 组织中在目标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 区域，药代动力学，体内疗效和毒性的两个已经开发的水凝胶， 在目标1和目标2中制定的目标。我们的最终目标是开发一个可降解的水凝胶平台 这项技术将延长携带人类脑癌的啮齿动物的生存时间，并将这个平台 临床前的方法。