Treatment of glioma with nanocombretastatin with MRI monitoring

MRI监测下纳米康布他汀治疗神经胶质瘤

• 批准号: 9251794
• 负责人: Meser M. Ali
• 金额: $ 34.26万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9251794
• 关键词: Address; Animal Model; Animals; Autacoids; Biodistribution; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood Volume; Blood flow; Brain; Brain Neoplasms; Cancer Model; Cancerous; Cerebral Neoplasm; Clinical; Clinical Oncology; Cohort Effect; Combined Modality Therapy; Combretastatin A-4; Combretastatin A4 Phosphate; Cytotoxic Chemotherapy; Dendrimers; Development; Dose; Drug Extravasation; Effectiveness; Engineering; Esters; Extensive Necrosis; Generations; Glioblastoma; Glioma; Goals; Growth; Human; Implant; In Vitro; Intercellular Fluid; Intravenous; KDR gene; Magnetic Resonance; Magnetic Resonance Imaging; Malignant Glioma; Malignant neoplasm of brain; Measures; Methods; Modeling; Monitor; Nanotechnology; Necrosis; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Nude Rats; Patients; Perfusion; Pharmaceutical Preparations; Polymers; Prodrugs; Radiation exposure; Radiation therapy; Radiosurgery; Rattus; Recurrence; Reporting; Research; Research Project Grants; Resistance development; Safety; Solid Neoplasm; Solubility; Spin Labels; Therapeutic Agents; Therapeutic Effect; Time; Tissue Viability; Tumor Cell Invasion; Tumor Markers; Tumor Tissue; U251; Vascular Endothelial Growth Factors; Vascular blood supply; Water; angiogenesis; antiangiogenesis therapy; aqueous; base; cancer cell; cancer stem cell; cancer therapy; chemotherapy; clinical application; clinically relevant; compare effectiveness; cytotoxic; design; drug testing; extracellular; image guided; improved; in vivo; inorganic phosphate; irradiation; killings; nano; nanoformulation; nanoparticle; nanosized; neoplastic cell; novel; novel strategies; outcome forecast; pre-clinical; pressure; public health relevance; small molecule; standard of care; success; targeted delivery; targeted treatment; temozolomide; tool; treatment planning; treatment response; tumor; tumor growth; tumor vascular supply; vascular bed; water solubility

 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.

 描述（由申请人提供）：胶质母细胞瘤（GBM）是一种高度侵袭性的血管丰富的脑肿瘤，其特征是尽管经过先进的治疗，仍具有高复发率和不良预后。GBM的血管系统与正常血管系统根本不同，并提供了独特的抗肿瘤靶点。因此，用血管破坏剂（VDA）直接靶向肿瘤血管系统与抗血管生成策略明显不同，并且为标准疗法提供了补充方法。 Combretastatin A4 (CA4) 是一种有效的血管破坏药物，CA4 会导致肿瘤血液供应快速关闭，通常会促进肿瘤核心坏死，但会在周围留下存活的肿瘤细胞，然后这些细胞可以迅速重新生长。然而，CA4不能有效诱导GBM肿瘤核心坏死。小分子化疗药物治疗恶性脑肿瘤的无效性归因于血脑屏障。 (BBB) 是药物成分跨血管外渗进入肿瘤组织血管外室的重大障碍，而高肿瘤间质液压力也已经成为纳米技术的额外输送障碍。 我们设计了一种纳米级聚合 CA4 缀合物，该缀合物具有高水溶性，在原位神经胶质瘤模型中进行的初步静脉注射 (i.v.) 证实了 G3-CA4 的核心坏死。通过应用设计的纳米前药策略和肿瘤特异性前药激活机制，我们观察到诱导坏死的真正成功。首次在原位 U-251 神经胶质瘤动物模型中发现肿瘤核心，当与细胞毒性化疗和放疗联合治疗其他肿瘤模型时，与放射治疗 (RT) 一样，放射治疗具有巨大的潜力。代表护理标准，RT 应有效杀死灌注良好的肿瘤边缘中氧合良好的癌细胞。我们已经证明，GBM 癌症干细胞对培养物中的辐射暴露和单剂量 50Gy 敏感。辐射在原发性 GBM 大鼠模型中产生坏死，因此，本研究扩展到包括 SRS 和标准细胞毒性替莫唑胺 (TMZ) 疗法与 G3-CA4，我们认为 G3-CA4 与 SRS 和 TMZ 的组合将在模型中显示出协同细胞毒性作用。临床相关的原发性 GBM 模型的目的是 A) 将 CA4 分子与基于树枝状聚合物的纳米粒子 (G3-CA4) 结合起来。证明在水介质中完全溶解，B) 确定小分子 CA4、CA4-P 和 G3-CA4 纳米前药在 U251 神经胶质瘤肿瘤模型中的功效和安全性，C) 确定单独或联合使用 G3-CA4 的功效和安全性在原发性 GBM 中使用 SRS，D) 确定 G3-CA4 和标准 TMZ 联合治疗在原发性 GBM 模型中的有效性和安全性，单独使用 G3-CA4 或在原发性 GBM 模型中的总体治疗效果。与 SRS/TMZ 的组合将通过对长期存活大鼠的图像引导 MRI 监测进行评估。