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）是一个无法治愈的罐装事件 通过放射疗法和化学疗法使用替莫唑酚（TMZ）。 相比之下，辐照的功效受到这些干预措施的潜在损害。 将GBM敏感到TMZ是一种吸引人的策略，因为TMZ具有出色的大脑渗透和低的 毒性特征。 有望在GBM中增强TMZ敏感性。 CX43的末端，并且在促进急性和慢性方面具有治疗功效 已经开发了伤口，以探索靶向CX43并克服TMZ的潜力 GBM中的电阻。 ACT1肽，三个三阶段2人类临床，用于减少疤痕和慢性治疗 伤口。 GBM患者的存活率，并证明了体外和体内TMZ敏感性的提高， 因此，鼓励对其在将GBM肿瘤敏感的治疗潜力进行进一步研究。 第一阶段SBIR，以促进有效和有针对性的药物熟食，可控和持续可生物降解 ACT1纳米粒子的治疗递送系统是在体外和体内验证的 GBM。 优化和验证，特别具有针对性转换增强交付所必需的特征 （CED）GBM患者（FDA批准的共聚物；直径<150nm +\ -40，受控和持续ACT1 释放概况）。 通过更广泛的临床前开发。 GBM小鼠的大脑，然后进行TMZ治疗和作用机理。 使用MRI的生长和分析小鼠的存活将验证组合的功效 ACT1-NP ANDZ在高级自发犬胶质瘤中进行的兽医临床试验 神经胶质瘤具有人类肿瘤的许多特征，因此允许精确的外推术。 和从犬类疗法研究到人类试验的安全数据。 与TMZ相关的ACT1-NP的特定方案不相关的肿瘤。 涉及综合神经影像反应评估，神经be虫评估和生存。 安全分析将涉及出现报告和有毒动力学分析。 这些目标将验证ACT1-NP的CED递送，如致命GBM的新型组合疗法一样 在不久的将来，新诊断为GBM患者的潜在CLIAL基金会。