Local dual delivery of a chemotherapy and an anti-angiogenic agent from an injectable functionalized biodegradable biomaterial system for the treatment of gliomas

从可注射的功能化生物可降解生物材料系统局部双重递送化疗药物和抗血管生成药物，用于治疗神经胶质瘤

• 批准号: 10565921
• 负责人: Sue Anne Chew
• 金额: $ 10.9万
• 依托单位: UNIVERSITY OF TEXAS RIO GRANDE VALLEY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-16 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10565921
• 关键词: Alkylating Agents; Angiogenesis Inhibitors; Angiogenic Factor; Angiogenic Proteins; Antibodies; Apoptosis; Biocompatible Materials; Biological Assay; Brain; Brain Neoplasms; Bypass; CD44 gene; Cancer Cell Growth; Carmustine; Cell Survival; Cells; Chemotherapy and/or radiation; Defect; Development; Diagnosis; Disease; Drug Delivery Systems; ENG gene; Elements; Endothelial Cells; Environment; Glioma; Goals; Half-Life; High Pressure Liquid Chromatography; Human; Immunotherapy; Implant; In Vitro; Injectable; Kinetics; Local Therapy; Malignant Glioma; Malignant neoplasm of brain; Measures; Memory impairment; Methods; Minocycline; Modeling; Morphology; Mus; Nitrosourea Compounds; Operative Surgical Procedures; Organ; Outcome; Patients; Pharmaceutical Preparations; Prognosis; Proteins; Quality of life; Radiation therapy; Rattus; Rodent; Scanning Electron Microscopy; Site; System; Therapeutic Agents; Toxic effect; Tumor Volume; Tumor Weights; Western Blotting; Work; antibody conjugate; blood vessel development; blood-brain barrier crossing; chemotherapy; cost; cytotoxic; design; drug efficacy; effective therapy; glioma cell line; implantable device; improved; in vivo; in vivo Model; interest; light scattering; neoplastic cell; new technology; novel therapeutics; particle; patient prognosis; response; scaffold; subcutaneous; temozolomide; tumor; tumor growth; tumor progression

PROJECT SUMMARY/ABSTRACT Each year, around 10,000 patients in the US are diagnosed with gliobastoma multiforme (GBM), which is the most common, aggressive and high-grade form of these brain tumors (82% of malignant gliomas). Currently, the median survival for this disease is around 21 months after diagnosis. Despite advances in the different methods of therapy (i.e. radiotherapy, immunotherapy and chemotherapy), the prognosis for gliomas has not been dramatically improved through the years. For tumors located in the brain, systemic delivery of agents has to overcome many obstacles for the successful delivery of the drug to the site including the critical step of having to cross the blood brain barrier (BBB). Due to the difficulty and high cost related to developing new therapeutics, focus should be placed on optimizing available drugs by ways such as delivering them locally using biomaterials. Local delivery of an anti-angiogenic factor (i.e. minocycline) and systemic delivery of a chemotherapy agent (i.e. bis-chloroethylnitrosourea (BCNU) or temozolomide (TMZ)) has been shown to improve median survival compared to the delivery of the systemic delivery of the chemotherapy agent alone in a rodent glioma model. Thus far, a lot of studies have been performed to study the delivery of both of these factors systemically or one factor systemically and the other factor locally to treat gliomas. However, the local deliver of both of these agents by combining both of them in an implantable device has not been investigated. It is hypothesized that the local delivery of both a chemotherapy agent that will impede the growth of cancer cells and an anti-angiogenic factor that will block blood vessel formation can better inhibit cancer progression compared to the delivery of these drugs systemically or locally alone. An ideal therapy should target tumor cells and avoid damaging non-tumor cells which can result in memory impairment, decline in brain function and low quality of life. CD44 and CD105 have been shown to be highly expressed on human glioma cell lines and endothelial cells, respectively and thus we further hypothesized that biomaterials functionalized with antibody against these markers can decrease non-targeted toxicity and increase bioactivity on targeted cells. The overall goal of this proposal is to develop a biodegradable composite system that has the ability to sustain the release of a chemotherapy and an anti-angiogenic agent and target cells of interest for glioma which may also be applied to other tumor types. The results from this work will contribute to the development of more effective therapies for the treatment of brain gliomas.

项目概要/摘要 每年，美国约有 10,000 名患者被诊断患有多形性胶质母细胞瘤 (GBM)， 这是这些脑肿瘤中最常见、最具侵袭性的高级形式（82% 恶性胶质瘤）。目前，这种疾病的中位生存期约为 21 个月。 诊断。尽管不同的治疗方法（即放射治疗、 免疫疗法和化疗），神经胶质瘤的预后尚未显着 这些年来有所改善。对于位于大脑的肿瘤，药物的全身递送必须 克服了将药物成功运送到现场的许多障碍，包括关键的 必须穿过血脑屏障（BBB）的步骤。由于难度大、成本高 为了开发新疗法，重点应放在通过以下方式优化现有药物上： 例如使用生物材料在本地交付它们。抗血管生成因子的局部递送 （即米诺环素）和化疗药物（即双氯乙基亚硝基脲）的全身递送 （BCNU）或替莫唑胺（TMZ））已被证明与其他药物相比可提高中位生存期 在啮齿动物神经胶质瘤模型中单独全身递送化疗药物。 到目前为止，已经进行了大量研究来研究这两个因素的传递 全身治疗或全身治疗一种因素而局部治疗另一种因素来治疗神经胶质瘤。然而， 通过将这两种药物组合在可植入装置中来进行局部递送尚未见报道。 被调查。据推测，两种化疗药物的局部递送 会阻碍癌细胞的生长，抗血管生成因子会阻塞血管 与这些药物的输送相比，形成可以更好地抑制癌症进展 系统地或局部地单独进行。理想的治疗应该针对肿瘤细胞并避免损伤 非肿瘤细胞，可导致记忆障碍、脑功能下降和质量低下 的生活。 CD44 和 CD105 已被证明在人胶质瘤细胞系中高表达 和内皮细胞，因此我们进一步假设生物材料 用针对这些标记的抗体进行功能化可以降低非靶向毒性 增加靶细胞的生物活性。该提案的总体目标是开发一个 可生物降解的复合系统，能够持续释放化疗药物 以及神经胶质瘤的抗血管生成剂和靶细胞，其也可应用于 其他肿瘤类型。这项工作的成果将有助于开发更多 治疗脑胶质瘤的有效疗法。