Novel therapeutic approach in treatment of glioblastoma using sustained delivery of Connxin43 carboxy-terminal peptide encapsulated in biodegradable nanoparticles in combination with temozolomide

使用可生物降解纳米粒子持续递送封装在可生物降解纳米颗粒中的 Connxin43 羧基末端肽与替莫唑胺联合治疗胶质母细胞瘤的新方法

• 批准号: 10063657
• 负责人: Christina Grek
• 金额: $ 10万
• 依托单位: XEQUEL BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-22 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063657
• 关键词: Adult; Adverse event; Alkylating Agents; Animals; Apoptosis; Astrocytoma; Biodistribution; Brain; Brain Glioblastoma; Brain Neoplasms; Bypass; Caliber; Canis familiaris; Cell Line; Cell Survival; Cell physiology; Cells; Characteristics; Cicatrix; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; Communication; Companions; Complex; Connexin 43; Connexins; Convection; Cytotoxic Chemotherapy; DNA; Data; Disease; Drug Delivery Systems; Drug Targeting; Effectiveness; Encapsulated; Enrollment; Enzymes; Etiology; Evaluation; Excision; FDA approved; Failure; Formulation; Foundations; Future; Gel; Glioblastoma; Glioma; Glycolates; Heterogeneity; Human; Human Characteristics; Immunocompromised Host; In Vitro; Injections; Intervention; Investigation; Link; MGMT gene; Magnetic Resonance Imaging; Malignant Neoplasms; Methods; Microscopy; Mission; Modeling; Monitor; Mus; Nature; Newly Diagnosed; Operative Surgical Procedures; Outcome; PIK3CB gene; Patient-Focused Outcomes; Patients; Penetration; Peptides; Phase; Phase II Clinical Trials; Population; Proteins; Protocols documentation; Public Health; Radiation; Radiation therapy; Recurrence; Refractory; Regulation; Reporting; Research; Resistance; Resolution; Rodent; Rodent Model; Role; Safety; Small Business Innovation Research Grant; Survival Analysis; System; Tail; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Toxic effect; Toxicokinetics; Toxicology; Translating; Treatment Efficacy; Treatment Protocols; Tumor Tissue; Tumor Volume; United States National Institutes of Health; Work; Xenograft procedure; acute wound; aggressive therapy; base; chemotherapy; chronic wound; combinatorial; copolymer; effective therapy; efficacy evaluation; healing; improved; in vivo; in vivo Model; intraperitoneal; irradiation; meetings; migration; nanoparticle; neoplastic cell; neuroimaging; new combination therapies; novel; novel strategies; novel therapeutic intervention; novel therapeutics; outcome forecast; phase III trial; preclinical development; prevent; repaired; research and development; response; stem cells; success; synthetic peptide; temozolomide; therapeutic evaluation; treatment strategy; tumor; tumor growth; tumor progression

PROJECT SUMMARY Glioblastoma (GBM) is an incurable cancer even with aggressive therapies such as surgical resection followed by radiotherapy and chemotherapy using temozolomide (TMZ). Efforts to improve surgical resection or the efficacy of irradiation are limited by the potential damage these interventions cause to the brain. In contrast, sensitizing GBM to TMZ is an appealing strategy because TMZ has excellent brain penetration and a low toxicity profile. Recent research suggests that targeting the gap junction protein connexin 43 (Cx43) holds promise for enhancing TMZ sensitivity in GBM. A synthetic peptide, aCT1, which comprises the carboxy- terminus of Cx43, and has demonstrated therapeutic efficacy in promoting healing of acute and chronic wounds, has been developed in order to explore the potential of targeting Cx43 and overcoming TMZ resistance in GBM. FirstString Research has currently advanced Granexin® gel, the topical formulation of aCT1 peptide, through three Phase 2 human clinical trials for scar reduction and the treatment of chronic wounds. Preliminary data demonstrated that Cx43 expression inversely correlates with TMZ sensitivity and GBM patient survival, and demonstrated that aCT1 significantly increases TMZ sensitivity in vitro and in vivo, thus encouraging further investigation into its therapeutic potential in sensitizing GBM tumors to TMZ. During the Phase I SBIR, to facilitate efficient and targeted drug delivery, a controlled and sustained biodegradable aCT1 nanoparticle system of therapeutic delivery was developed and validated in vitro and in vivo models of GBM. Biodegradable aCT1-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were developed, optimized and validated, specifically with characteristics necessary for targeted convection-enhanced delivery (CED) in GBM patients (FDA approved copolymer; <150nm +\- 40 in diameter, controlled and sustained aCT1 release profile). The objective of this Phase II SBIR proposal is to translate the success of our Phase I data through more extensive pre-clinical development. Aim I will involve intracranial injection of aCT1-NPs into the brains of GBM mice followed by TMZ treatment and mechanism of action studies. We will monitor tumor growth using MRI and analyze mouse survival. Aim II will validate the efficacy and safety of combinatorial aCT1-NP and TMZ treatment in a veterinary clinical trial in high-grade spontaneous canine gliomas. Canine gliomas have many of the characteristics of human tumors, thus permitting precise extrapolation of efficacy and safety data from canine therapy studies to human trials. We will enroll companion dogs with spontaneous tumors into a specific protocol involving CED of aCT1-NPs in association with TMZ. Efficacy evaluation will involve comprehensive neuroimaging response assessment, neurobiobehavioral evaluation, and survival. Safety analyses will involve adverse event reporting and toxicokinetic analyses. Successful completion of these aims will validate CED delivery of aCT1-NP as a novel combinational therapy for lethal GBM and will lay foundation for potential clinical trials in newly diagnosed GBM patients in the near future.

项目摘要 胶质母细胞瘤（GBM）是一种无法治愈的癌症，即使采用积极的治疗，如手术切除， 通过使用替莫唑胺（TMZ）的放疗和化疗。努力改善手术切除或 辐射的功效受到这些干预对大脑造成的潜在损害的限制。与此相反， 使GBM对TMZ敏感是一种有吸引力的策略，因为TMZ具有极好的脑渗透性和低的脑损伤。 毒性特征最近的研究表明，靶向差距连接蛋白连接蛋白43（Cx43） 有望提高TMZ在GBM中的敏感性。一种合成肽aCT 1，其包含羧基- Cx43末端，并已证明在促进急性和慢性 为了探索靶向Cx43和克服TMZ的潜力， GBM中的抗性。FirstString Research目前拥有先进的Granexin®凝胶，这是一种外用制剂， aCT 1肽，通过三个2期人体临床试验，用于减少疤痕和治疗慢性 伤口初步数据表明，Cx43表达与TMZ敏感性呈负相关， GBM患者存活率，并证明aCT 1在体外和体内显著增加TMZ敏感性， 从而鼓励进一步研究其在使GBM肿瘤对TMZ敏感方面的治疗潜力。期间 第一阶段SBIR，以促进有效和有针对性的药物输送，控制和持续的生物可降解 开发了治疗递送的aCT 1纳米颗粒系统，并在体外和体内模型中进行了验证。 GBM。开发了可生物降解的载aCT 1的聚（乳酸-共-乙醇酸）（PLGA）纳米颗粒（NP）， 经过优化和验证，特别是具有针对性对流增强输送所需的特性 (CED)在GBM患者中（FDA批准的共聚物;直径<150 nm ± 40，控制和持续aCT 1 释放曲线）。第二阶段SBIR提案的目标是将第一阶段数据的成功转化为 通过更广泛的临床前开发。目的I将涉及将aCT 1-NPs颅内注射到 GBM小鼠的脑，随后进行TMZ处理和作用机制研究。我们将监测肿瘤 生长并分析小鼠存活率。目的二是验证联合化疗的有效性和安全性。 在高级别自发性犬神经胶质瘤的兽医临床试验中使用aCT 1-NP和TMZ治疗。犬 神经胶质瘤具有人类肿瘤的许多特征，因此可以精确地推断疗效 以及从犬类治疗研究到人体试验的安全数据。我们将招募自发性的伴侣犬， 在一个实施方案中，本发明涉及将aCT 1-NPs与TMZ联合CED的特异性方案用于治疗肿瘤。疗效评估 包括全面的神经影像反应评估、神经生物行为评估和生存率。 安全性分析将涉及不良事件报告和毒代动力学分析。成功完成 这些目的将验证aCT 1-NP的CED递送作为致死性GBM的新型组合疗法， 为在不久的将来在新诊断的GBM患者中进行潜在的临床试验奠定了基础。