SapC-DOPS Nanovesicles for Treating Glioblastoma Multiforme

SapC-DOPS 纳米囊泡用于治疗多形性胶质母细胞瘤

• 批准号: 7611436
• 负责人: XIAOYANG QI
• 金额: $ 27.31万
• 依托单位: BEXION PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-25 至 2010-06-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7611436
• 关键词: Ablation; Address; Adverse effects; Affinity; American; Animal Model; Animals; Antibodies; Autopsy; Benchmarking; Binding; Biodistribution; Biological Assay; Biological Sciences; Bone Marrow; Brain; Brain Neoplasms; C-Peptide; Catabolism; Cell Line; Cell surface; Cells; Characteristics; Colon; Data; Development; Devices; Diagnosis; Diagnostic; Dose; Drug Formulations; Drug Kinetics; Drug resistance; Duodenum; Employee Strikes; Engineering; Evaluation; Excision; Fluorescence; Frozen Sections; Genus Cola; Glioblastoma; Glioma; Glucosylceramides; Growth; Head; Health behavior; Heart; Human; Image; Imaging Techniques; Implant; In Vitro; Injection of therapeutic agent; Intracranial Neoplasms; Invasive; Kidney; Label; Life; Liver; Luciferases; Lung; Magnetic Resonance Imaging; Malignant Glioma; Malignant Neoplasms; Marketing; Measures; Mediating; Membrane; Methods; Microscopic; Modeling; Monitor; Morbidity - disease rate; Mus; Muscle; Neurologic; Normal Cell; Normal tissue morphology; Nude Mice; Ohio; Operative Surgical Procedures; Organ; Output; Pathology; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phosphatidylserines; Phospholipids; Preparation; Procedures; Property; Proteins; Proteolipids; Public Health; Quality Control; Radiation therapy; Radiosurgery; Range; Research; Resistance; Resolution; Route; Safety; Saline; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Speed; Spleen; Staining method; Stains; Stomach; Surface; Technology; Testing; Therapeutic; Time; Tissues; Toxic effect; Tumor-Derived; Universities; Variant; Vesicle; Vimentin; Water consumption; Week; Weights and Measures; Xenograft Model; base; beta-Glucosidase Stimulating Protein; brain tissue; cancer cell; cancer therapy; chemotherapy; commercialization; day; digital imaging; drug development; drug testing; expectation; fluorophore; food surveillance; improved; in vivo; innovation; iron oxide; killings; luciferin; luminescence; lysosomal proteins; mouse model; neoplastic cell; neurobehavior; novel; novel therapeutics; red fluorescent protein; research clinical testing; research study; scale up; size; success; tool; tumor; tumor growth; whole body imaging

DESCRIPTION (provided by applicant): We are proposing to develop a new treatment for targeting and eliminating glioblastoma multiforme (GBM, high grade glioma), a deadly and invasive brain tumor with no effective treatment. Of the 12,000 patients expected to be diagnosed with GBM this year, most will succumb within the first year. GBM tumors have proven to be resistant to existing anti-cancer therapies. Complete surgical ablation is nearly impossible because invasive cells remain hidden in the brain. The tumor returns rapidly. There is an urgent demand and a growing market for an efficacious anti-glioma drug. To address this need, we are planning to determine the feasibility of using novel proteolipid nanovesicles to target and destroy glioma tumor cells. Composed of the small lysosomal protein saposin C (SapC, 80 aa) and the phospholipid dioleoylphosphatidylserine (DOPS); the stable 200 nm SapC-DOPS nanovesicles have unusually high affinity for phosphatidylserine-enriched membrane surfaces which are common in many types of tumor cells. To check whether the nanovesicles could be used for targeting and attacking tumor cells, we conducted preliminary in vitro and in vivo assays and discovered that, indeed, the nanovesicles have high propensity to accumulate in tumors, and very importantly, in gliomas. Upon repeated SapC-DOPS injection in tumor-bearing mice, we noticed a reduction in tumor size and improved survival. These intriguing observations prompted us to explore the use of SapC-DOPS as a potentially therapeutic drug for treating aggressive brain tumors. In Phase I of this proposal, our specific aims are: (1) Confirm that Saposin C (SapC) is necessary for delivery of nanovesicles to intracranial gliomas and evaluate the biodistribution of the nanovesicles in vivo, (2) Using a bioluminescent glioma xenograft model, determine the dose-dependent elimination of tumor cells by SapC-DOPS nanovesicles, and (3) Evaluate the anti-tumor activity of SapC-DOPS nanovesicles against a second type of glioma with aggressive and invasive growth properties. Tissues from treated mice will be analyzed to confirm that the nanovesicles are relatively nontoxic at useful doses. Neurological evaluation will be performed, monitoring for evidence of toxicity. Upon the completion of these studies, we expect to have compelling evidence to support further development of SapC-DOPS nanovesicles as a first-line anti-glioma therapeutic. In Phase II, detailed optimization, efficacy, distribution, pharmacokinetics, scale-up, and safety studies will be conducted, while in Phase III, the emphasis will be on IND-enabling studies to move the product toward clinical testing. This research is innovative because SapC-DOPS nanovesicles offer a unique approach for imaging and eliminating hidden brain tumors. Eventually, we expect to adapt our technology for targeting different types of tumors and for developing tumor-targeted diagnostics. PUBLIC HEALTH RELEVANCE: We are developing a new treatment for glioblastoma multiforme, a deadly form of brain tumor that kills over 90% of afflicted patients. Current treatment methods, consisting of surgery, radiation, and chemotherapy, have not been effective in significantly reducing morbidity. Our strategy involves using new proteolipid nanovesicles that can penetrate the tumors and selectively destroy malignant cells without harming normal cells. Success in the proposed animal models will enable us to test the product in humans.

描述(申请人提供)：我们建议开发一种新的治疗方法，用于靶向和消除多形性胶质母细胞瘤(GBM，高级别胶质瘤)，这是一种致命的侵袭性脑瘤，没有有效的治疗方法。预计今年将有1.2万名患者被诊断为GBM，其中大多数将在第一年内死亡。GBM肿瘤已被证明对现有的抗癌治疗具有耐药性。完全的外科消融几乎是不可能的，因为侵袭性细胞仍然隐藏在大脑中。肿瘤很快就会复发。人们迫切需要一种有效的抗胶质瘤药物，市场也在不断增长。为了满足这一需求，我们正计划确定使用新型蛋白脂纳米微囊靶向并摧毁胶质瘤肿瘤细胞的可行性。由小的溶酶体蛋白皂苷C(SapC，80aa)和磷脂二油酰磷脂酰丝氨酸(DOPS)组成；稳定的200 nm SapC-DOPS纳米胶囊对富含磷脂酰丝氨酸的膜表面具有异常高的亲和力，这在许多类型的肿瘤细胞中都很常见。为了验证纳米微囊是否可以用于靶向和攻击肿瘤细胞，我们进行了初步的体外和体内测试，发现确实，纳米微囊在肿瘤中积累的倾向很高，而且非常重要的是，在胶质瘤中。在荷瘤小鼠身上反复注射SapC-DOPS后，我们注意到肿瘤体积缩小并提高了存活率。这些有趣的观察促使我们探索使用SapC-DOPS作为一种潜在的治疗药物来治疗侵袭性脑瘤。在这项建议的第一阶段，我们的具体目标是：(1)确认皂苷C(SapC)是向颅内胶质瘤运送纳米微囊所必需的，并评估纳米微囊在体内的生物分布；(2)利用生物发光的胶质瘤异种移植模型，确定SapC-DOPS纳米微囊对肿瘤细胞的剂量依赖消除；(3)评价SapC-DOPS纳米微囊对第二种具有侵袭性和侵袭性生长特性的胶质瘤的抗肿瘤活性。将对处理过的小鼠的组织进行分析，以确认纳米胶囊在有效剂量下是相对无毒的。将进行神经学评估，监测毒性证据。在这些研究完成后，我们期望有令人信服的证据来支持SapC-DOPS纳米胶囊作为一线抗胶质瘤治疗的进一步发展。在第二阶段，将进行详细的优化、疗效、分布、药代动力学、扩大规模和安全性研究，而在第三阶段，重点将放在支持IND的研究上，以使该产品进入临床测试。这项研究具有创新性，因为SapC-DOPS纳米微囊为成像和消除隐藏的脑瘤提供了一种独特的方法。最终，我们希望调整我们的技术，以针对不同类型的肿瘤，并开发针对肿瘤的诊断。公共卫生意义：我们正在开发一种治疗多形性胶质母细胞瘤的新方法，这是一种致命的脑瘤，90%以上的患者死亡。目前的治疗方法，包括手术、放疗和化疗，在显著降低发病率方面并不有效。我们的策略包括使用新的蛋白脂纳米囊，这种纳米囊可以穿透肿瘤，在不损害正常细胞的情况下选择性地摧毁恶性肿瘤细胞。拟议中的动物模型的成功将使我们能够在人体上测试该产品。