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

项目总结/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）， 这是最常见的，侵略性和高级别的形式，这些脑肿瘤（82%的 恶性神经胶质瘤）。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， 免疫疗法和化学疗法），神经胶质瘤的预后并不显着 这些年来有所改善。对于位于脑中的肿瘤，药剂的全身递送必须 克服了许多障碍，成功地将药物输送到该部位，包括关键的 必须穿过血脑屏障（BBB）的步骤。由于相关的难度和高成本 为了开发新的治疗方法，重点应该放在优化现有的药物上， 例如使用生物材料局部递送它们。抗血管生成因子的局部递送 (i.e.米诺环素）和化疗剂（即双-氯乙基亚硝基脲）的全身递送 （BCNU）或替莫唑胺（TMZ））已被证明可以改善中位生存期相比， 在啮齿动物神经胶质瘤模型中单独全身递送化疗剂的递送。 到目前为止，已经进行了大量的研究来研究这两种因素的传递 系统地或一种因素系统地和另一种因素局部地治疗神经胶质瘤。但 通过在可植入装置中组合这两种药剂来局部递送这两种药剂， 被调查了假设局部递送化疗剂， 会阻碍癌细胞的生长，并且是一种抗血管生成因子， 与这些药物的递送相比， 系统地或局部地单独地。理想的治疗方法应该靶向肿瘤细胞， 非肿瘤细胞，可导致记忆障碍，脑功能下降和低质量 生命CD 44和CD 105在人脑胶质瘤细胞系中高度表达 和内皮细胞，因此我们进一步假设， 用针对这些标志物的抗体功能化可以降低非靶向毒性， 增加对靶细胞生物活性。本提案的总体目标是制定一个 具有持续释放化疗药物的能力的可生物降解的复合系统 以及抗血管生成剂和神经胶质瘤的目标靶细胞， 其他肿瘤类型这项工作的成果将有助于发展更多的 治疗脑胶质瘤的有效方法。

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.