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: 8060382
• 负责人: XIAOYANG QI
• 金额: $ 67.04万
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8060382
• 关键词: SapC; DOPS; nanovesicles; Treating; Glioblastoma

DESCRIPTION (provided by applicant): Our goal is to develop a new molecular entity with a novel mechanism of action 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. Clearly, there is an urgent demand for an efficacious anti-glioma drug. To address this need, we are developing a new class of therapeutic proteolipid nanovesicle that can target and destroy glioma tumors. Composed of the small lysosomal, sphingolipid activator 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 that occur widely in many types of tumor cells and tumor neovasculature. In a mechanism consistent with activation of sphingolipid protein function, SapC- DOPS also appears to selectively induce tumor cells to undergo apoptosis. In Phase I of this proposal, we demonstrated the feasibility of using SapC-DOPS nanovesicles to target and kill intracranial gliomas in mouse models. Injections of SapC-DOPS in mice with orthotopically implanted gliomas resulted in dose-dependent improvement in survival. Specific targeting of SapC-DOPS to the tumor mass was demonstrated using fluorescently-tagged nanovesicles in live animal imaging experiments. We also showed that saposin C protein, in specific association with DOPS is essential for targeting. Anticancer activity of SapC-DOPS was confirmed in a second orthotopic glioma model, derived from an aggressive and invasive glioma line. Pilot toxicity data indicated SapC-DOPS to be relatively nontoxic with no evidence of behavioral abnormalities or pathological lesions. Our objective in Phase II proposal is to identify and select optimized SapC-DOPS formulations and treatment methods suitable for advancing toward planned human testing. The specific aims of Phase II are: (1) optimize protein expression and purification, and develop clinically suitable formulation; (2) conduct preclinical pharmacokinetics, stability, and brain and tissue distribution analysis in animal models to determine in vivo disposition of the nanovesicles; and (3) carry out toxicity studies in two animal models to assess safety, towards filing of the IND. Upon the completion of these studies, we expect to have compelling evidence to progress clinical development of SapC-DOPS nanovesicles as a potent new anti-cancer therapeutic (during SBIR Phase III). This research is innovative because SapC-DOPS nanovesicles offer a unique approach for slowing tumor growth and eliminating deep-seated brain tumors. Ultimately, 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 molecular entitity for treating glioblastoma multiforme, a deadly form of brain tumor that kills over 90% of afflicted patients. Current standards of treatment, 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（由申请人提供）： 我们的目标是开发一种新的分子实体，具有靶向和消除多形性胶质母细胞瘤（GBM，高级别胶质瘤）的新作用机制，这是一种致命的侵袭性脑肿瘤，没有有效的治疗方法。预计今年将有12，000名患者被诊断患有GBM，其中大多数将在第一年内死亡。显然，迫切需要一种有效的抗神经胶质瘤药物。为了满足这一需求，我们正在开发一类新的治疗性蛋白脂质纳米囊泡，可以靶向和破坏胶质瘤肿瘤。由小的溶酶体、鞘脂激活蛋白saposin C（SapC，80 aa）和磷脂二油酰磷脂酰丝氨酸（DOPS）组成;稳定的200 nm SapC-DOPS纳米囊泡对广泛存在于许多类型的肿瘤细胞和肿瘤新生血管中的富含磷脂酰丝氨酸的膜表面具有异常高的亲和力。在与鞘脂蛋白功能活化一致的机制中，SapC-DOPS似乎也选择性地诱导肿瘤细胞经历凋亡。在该提案的第一阶段，我们证明了使用SapC-DOPS纳米囊泡在小鼠模型中靶向和杀死颅内胶质瘤的可行性。在原位植入胶质瘤的小鼠中注射SapC-DOPS导致存活率的剂量依赖性改善。在活体动物成像实验中使用荧光标记的纳米囊泡证明了SapC-DOPS对肿瘤块的特异性靶向。我们还表明，saposin C蛋白，与DOPS特异性相关是必不可少的靶向。SapC-DOPS的抗癌活性在源自侵袭性和侵袭性胶质瘤系的第二原位胶质瘤模型中得到证实。初步毒性数据表明SapC-DOPS相对无毒，没有行为异常或病理学病变的证据。我们在II期提案中的目标是确定和选择适合推进计划的人体测试的优化SapC-DOPS制剂和治疗方法。II期的具体目标是：（1）优化蛋白质表达和纯化，并开发临床适用的制剂;（2）在动物模型中进行临床前药代动力学、稳定性以及脑和组织分布分析，以确定纳米囊泡的体内分布;和（3）在两种动物模型中进行毒性研究以评估安全性，以提交IND。在完成这些研究后，我们期望有令人信服的证据来推进SapC-DOPS纳米囊泡作为有效的新抗癌治疗剂的临床开发（在SBIR III期期间）。这项研究具有创新性，因为SapC-DOPS纳米囊泡为减缓肿瘤生长和消除深部脑肿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和开发肿瘤靶向诊断。 公共卫生相关性： 我们正在开发一种新的分子实体来治疗多形性胶质母细胞瘤，这是一种致命的脑瘤，超过90%的患者死亡。目前的治疗标准，包括手术，放疗和化疗，并没有有效地显着降低发病率。我们的策略包括使用新的蛋白脂质纳米囊泡，可以穿透肿瘤并选择性地破坏恶性细胞而不伤害正常细胞。动物模型的成功将使我们能够在人类中测试该产品。