Treatment of glioma with nanocombretastatin with MRI monitoring

 描述（由申请人提供）：胶质母细胞瘤（GBM）是一种高度侵袭性的过度血管化脑肿瘤，其特征是尽管进行了高级治疗，但复发率高且预后差。GBM的血管系统与正常血管系统有着根本的不同，并为抗癌治疗提供了独特的靶点。因此，用血管阻断剂（VDA）直接靶向肿瘤血管系统与抗血管生成策略明显不同，并为标准治疗提供了补充方法。Combretastatin A4（CA 4）是一种有效的血管阻断药物。CA 4诱导肿瘤血液供应的快速关闭，通常促进肿瘤核心的坏死，但在周边留下存活肿瘤细胞的边缘，然后可以快速重新生长。然而，CA 4在GBM肿瘤的核心处不能有效地诱导坏死。小分子化疗药物在治疗恶性脑肿瘤中的无效性已归因于血脑屏障（BBB）是药物部分穿过屏障进入肿瘤组织的血管外隔室的经血管外渗的显著障碍，并且高肿瘤间质液压力也提供了额外的递送屏障。纳米技术已经 有利于药物穿过血脑屏障进入脑肿瘤。我们已经设计了纳米尺寸的聚合物CA 4缀合物，其表现出高的水溶性。初步静脉注射（i. v.）在原位神经胶质瘤模型中递送G3-CA 4显示肿瘤核心坏死，留下存活组织的边缘。通过应用所设计的纳米前药策略和肿瘤特异性前药活化机制，我们首次在原位U-251胶质瘤动物模型中观察到在肿瘤核心诱导坏死的真正成功。当与细胞毒性化疗和放疗联合治疗其他肿瘤模型时，肿瘤-VDA具有显著的潜力。与放射的组合治疗是有吸引力的，因为放射治疗（RT）代表护理标准，并且RT应该有效地杀死灌注良好的肿瘤边缘中的良好氧合的癌细胞。我们已经表明，GBM癌干细胞对培养中的辐射暴露敏感，并且在原代GBM大鼠模型中，单剂量50 Gy的辐射产生坏死。因此，本研究扩展至包括SRS和标准细胞毒性替莫唑胺（TMZ）治疗与G3-CA 4。我们假设G3-CA 4与SRS和TMZ的组合将在临床相关的原发性GBM模型中显示协同细胞毒性作用。我们提出的研究的目的是A）将CA 4分子与在水性介质中显示出完全溶解性的基于树枝状聚合物的纳米颗粒（G3-CA 4）结合，B）确定小分子CA 4、CA 4-P和G3-CA 4纳米前药在U251神经胶质瘤肿瘤模型中的功效和安全性，C）确定G3-CA 4单独或与SRS组合在原发性GBM中的功效和安全性，D）确定G3-CA 4和标准TMZ组合疗法在原发性GBM模型中的功效和安全性。将通过对长期存活大鼠的图像引导MRI监测来评价G3-CA 4单独或与SRS/TMZ组合的总体治疗效果。

 DESCRIPTION (provided by applicant): Glioblastoma (GBM) is a highly aggressive hypervascularized brain tumor characterized by high recurrence rates and poor prognosis despite advanced treatment. The vasculature of GBM is fundamentally different from that of normal vasculature and offers a unique target for anti-cancer therapy. Therefore, direct targeting of tumor vasculature with vascular disrupting agents (VDAs) is distinctly different from anti-angiogenic strategies, and offers a complementary approach to standard therapies. Combretastatin A4 (CA4) is a potent vascular disrupting drug. CA4 induces rapid shutdown of tumor blood supply, typically promoting a necrosis at the core of the tumor, but leaves a rim of viable tumor cells at the periphery which can then rapidly re-grow. However, CA4 is not effective in inducing necrosis at the core of GBM tumor. The ineffectiveness of small molecule chemotherapy drugs in treating malignant brain tumors has been attributed to the blood-brain barrier (BBB) being a significant impediment to the transvascular extravasation of drug fraction across the barrier into the extravascular compartment of tumor tissue and the high tumor interstitial fluid pressure also presents an additional delivery barrier. Nanotechnology is already benefiting to deliver drugs across the BBB and into brain tumors. We have engineered a nano-sized polymeric CA4 conjugate which demonstrates high water solubility. Preliminary intravenous (i.v.) delivery of G3-CA4 in an orthotopic glioma model demonstrated necrosis at the core of the tumor leaving a rim of viable tissue. By applying the designed nanoprodrug strategy and tumor- specific prodrug activation mechanism, we observed the true success of inducing necrosis at the core of the tumor in an orthotopic U-251 glioma animal model first time. Tumor-VDAs have significant potential when combined with cytotoxic chemotherapy and radiotherapy in treating other tumor models. Combined treatment with radiation is attractive, as radiation therapy (RT) represents a standard of care and RT should effectively kill the well-oxygenated cancer cells in the well-perfused tumor rim. We have shown that GBM cancer stem cells are sensitive to radiation exposure in culture and a single dose of 50Gy irradiation yielded necrosis in primary GBM rat model. Therefore, this study is extended to include SRS and standard cytotoxic temozolomide (TMZ) therapies with G3-CA4. We hypothesize that the combination of G3-CA4 with SRS and TMZ will show synergistic cytotoxic effect in clinical relevant primary GBM model. Our objectives of the proposed research are A) To incorporate CA4 molecules with dendrimer-based nanoparticles (G3-CA4) that demonstrates full solubility in aqueous media, B) To determine the efficacy and safety of small molecule CA4, CA4-P and G3-CA4 nanoprodrug in U251 glioma tumor model, C) To determine the efficacy and safety of G3- CA4 alone or in combination with SRS in primary GBM, D) To determine the efficacy and safety of a combined G3-CA4 and standard TMZ therapy in primary GBM model. The overall therapeutic effect from G3-CA4 alone or in combination with SRS/TMZ will be evaluated by image-guided MRI monitoring of long-term survival rats.