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

项目摘要/摘要 每年，美国约有10,000名患者被诊断为多形性胶质母细胞瘤(GBM)， 这是这些脑肿瘤中最常见、最具侵袭性和最高级别的形式(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。尽管在不同的治疗方法(即放射治疗， 免疫治疗和化疗)，神经胶质瘤的预后并不显著。 多年来不断进步。对于位于大脑的肿瘤，全身给药必须 克服许多障碍，成功地将药物运送到现场，包括关键的 必须跨越血脑屏障(BBB)的步骤。由于难度大，相关成本高 为了开发新的治疗方法，应该把重点放在通过以下方式优化现有药物 比如用生物材料把它们送到当地。局部注射抗血管生成因子 (即米诺环素)和全身给药(即双氯乙基亚硝脲) (BCNU或替莫唑胺(TMZ))已被证明与 在啮齿动物脑胶质瘤模型中全身单独给药化疗药物。 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 系统地或一种系统地，另一种局部地治疗胶质瘤。然而， 通过将这两种制剂组合在可植入装置中进行局部递送尚未 被调查过了。假设局部给药既有化疗药物，也有 会阻碍癌细胞的生长和一种会阻塞血管的抗血管生成因子 与这些药物相比，药物形成可以更好地抑制癌症的进展 系统地或局部地单独进行。理想的治疗方法应该是靶向肿瘤细胞并避免损害 非肿瘤细胞，可导致记忆障碍、脑功能下降和质量低下 生活的一部分。CD44和CD105在人脑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 用针对这些标记物的抗体功能化可以减少非靶向性毒性和 提高靶细胞的生物活性。这项提案的总体目标是开发一种 具有维持化疗释放能力的可生物降解的复合系统 以及胶质瘤的抗血管生成剂和感兴趣的靶细胞，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 脑胶质瘤的有效治疗方法。

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.