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.

项目摘要/摘要 每年，美国约有10,000名患者被诊断出患有胶质性多形性（GBM）， 这是这些脑肿瘤中最常见，侵略性和高级形式（占82％ 恶性神经胶质瘤）。目前，这种疾病的中位生存期在大约21个月后 诊断。尽管在不同的治疗方法方面取得了进步（即放射疗法， 免疫疗法和化学疗法），神经胶质瘤的预后尚未显着 这些年来有所改善。对于位于大脑中的肿瘤，剂的全身递送必须 克服许多障碍，成功将药物送到现场，包括关键 必须越过血脑屏障（BBB）的步骤。由于困难和成本高昂 要开发新的治疗剂，应将重点放在以方式上优化可用的药物 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）和全身递送化学疗法剂（即双氯乙基硝基库 （BCNU）或替莫唑胺（TMZ）已证明与相比 在啮齿动物神经胶质瘤模型中，单独递送化疗剂的全身递送。 到目前为止，已经进行了许多研究来研究这两个因素的传递 系统地或一个因素在系统上，另一个因素在本地以治疗神经胶质瘤。但是， 通过将这两种代理结合在可植入的设备中，这两个代理都没有 被调查。假设局部递送两种化学疗法剂 将阻碍癌细胞的生长和抗血管生成因子，该因子会阻止血管 与这些药物的递送相比，形成可以更好地抑制癌症的进展 全身或本地。理想的疗法应靶向肿瘤细胞并避免破坏 非肿瘤细胞可能导致记忆力障碍，脑功能下降和质量低 生活。 CD44和CD105已显示在人神经胶质瘤细胞系上高度表达 分别和内皮细胞，因此我们进一步假设生物材料 用抗体对这些标记的抗体功能化可以降低非靶向毒性和 增加对靶细胞的生物活性。该提议的总体目标是开发 可生物降解的复合系统，具有维持化学疗法的释放的能力 以及神经胶质瘤感兴趣的抗血管生成剂和靶细胞，也可以应用于 其他肿瘤类型。这项工作的结果将有助于发展更多 有效治疗脑神经胶质瘤的疗法。