Material-guided delivery and local activation of bioorthogonal prodrugs

生物正交前药的材料引导递送和局部激活

• 批准号: 10238760
• 负责人: Sangeetha Srinivasan
• 金额: $ 57.79万
• 依托单位: TAMBO, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238760
• 关键词: Address; Adverse Drug Experience Report; Adverse drug event; Adverse event; Alginates; Animal Model; Antibiotics; Antibodies; Area; Biological Process; Biopsy; Canis familiaris; Chemistry; Clinical; Combined Modality Therapy; Cortisone; Cyclooctenes; Cytotoxic agent; Data; Development; Disease; Dose; Doxorubicin; Drug Costs; Drug Delivery Systems; Drug Kinetics; Drug Modulation; Drug Packaging; Economics; Excision; Failure; Feedback; Formulation; Future; Gel; Goals; Health; Healthcare Systems; Hepatic; Immune response; Implant; In Vitro; Infection; Inflammation; Injectable; Injections; Intervention; Laboratories; Legal patent; Length of Stay; Localized Disease; Location; Lymphatic; Manufacturer Name; Maximum Tolerated Dose; Measures; Medical; Medicine; Methods; Morbidity - disease rate; Mus; Neoplasms; Operative Surgical Procedures; Oral; Pathologic; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phase I Clinical Trials; Price; Procedures; Prodrugs; Product Packaging; Program Development; Property; Rattus; Reaction; Renal clearance function; Reporting; Research; Research Personnel; Risk; Route; Safety; Site; Specificity; Steroids; Technology; Therapeutic; Therapeutic Index; Time; Tissues; Toxic effect; Toxicokinetics; Toxicology; Treatment Efficacy; United States Food and Drug Administration; Validation; Work; biocompatible polymer; biomaterial compatibility; cancer therapy; chemical reaction; combat; controlled release; cost; cycloaddition; design; dosage; drug candidate; drug development; drug discovery; experimental study; first-in-human; imaging probe; in vivo; interest; medication safety; meetings; mortality; mortality risk; novel; novel therapeutics; phase 2 study; response; safety study; scale up; side effect; small molecule therapeutics; spatiotemporal; stem; therapeutically effective; tumor

ABSTRACT Systemic administration of small molecule therapeutics to treat disease can be ineffective, and even hazardous, because the drugs distribute widely in the body. This lack of site-specificity means large systemic doses are needed to achieve effective concentrations in the diseased tissues, but these high doses often result in non- specific toxicity. Roughly 1 in 20 hospitalized patients experience adverse drug events (ADEs) and, throughout the U.S. healthcare system, over a million ADEs are reported every year. These unintended consequences of drug therapy double the risk of mortality and increase the length of hospital stays, with an economic toll that greatly exceeds $100 annually. In addition, ADEs have a crippling indirect effect on our therapeutic arsenal. Roughly 25% of drug development programs fail before completion of Phase II studies due to problems with clinical safety. Research groups have responded by developing drug delivery systems to optimize the localized and timely delivery of therapeutics, however, the approaches used have major limitations. For example, drugs that are conjugated to antibodies to achieve their target specificity can cause immune responses, and their therapeutic efficacy can be compromised by limited drug release. Other researchers are embedding drugs in biocompatible polymers, which allows them to be implanted where needed, but the technologies lack the capacity for repeated, optimal dosing without an invasive cycle of implant removal and replacement. Shasqi is developing a platform technology for efficient and modular drug-delivery that enables precise spatiotemporal localization of therapeutics, one that can combat localized diseases without causing systemic side effects, and that allows for the modulation of drug release. Built around a biocompatible gel that remains at the target site for >3 months, it relies on bio-orthogonal chemistry to concentrate systemic prodrugs (drugs modified to be quiescent) where they are needed and convert them to their therapeutic form. Our biodegradable gel can be implanted at the time of biopsy or surgery and would not require an additional invasive procedure for additional treatments or removal. In the future, our gel can be designed to have dual attachment chemistries for “catching” prodrugs, thus allowing for the controlled release (spatially and temporally) of combination therapies. While there is a market need for our technology in many therapeutic areas, Shasqi is initially focusing on developing chemotherapeutics for patients with neoplasms that are candidates for surgical intervention. To achieve these goals, we will pursue seven specific aims through the proposed Fast Track project. In Phase I, we will optimize gel dosage in combination with a prodrug for cancer treatment using tumor-bearing mice. We will also develop validated methods suitable for anticipated IND studies and expand our prodrug arsenal. In Phase II, we will conduct medium term (28 days) toxicity studies in canines guided by data from maximum tolerated dose (MTD) experiments and pharmacokinetics work in rats. We will also optimize prodrug formulation for stability and packaging of the drug product then manufacture GMP-grade gel for I eventual Phase 1 clinical trials.

抽象的 全身施用小分子疗法来治疗疾病可能是无效的，甚至是危险的， 因为药物在体内分布广泛，缺乏位点特异性意味着全身剂量很大。 需要在患病组织中达到有效浓度，但这些高剂量通常会导致非 大约每 20 名住院患者中就有 1 人经历过药物不良事件 (ADE)，并且在整个过程中。 在美国医疗保健系统中，每年都会报告超过一百万个不良事件。 药物治疗使死亡风险加倍并延长住院时间，造成的经济损失 每年的费用远远超过 100 美元。此外，ADE 对我们的治疗手段有严重的间接影响。 大约 25% 的药物开发项目在完成 II 期研究之前就因以下问题而失败： 研究小组已通过开发药物输送系统来优化局部治疗来应对。 然而，所使用的方法有很大的局限性，例如药物。 与抗体缀合以实现其目标特异性可以引起免疫反应，并且它们的 其他研究人员正在将药物嵌入其中，从而影响治疗效果。 生物相容性聚合物，可以将它们植入需要的地方，但技术缺乏能力 Shasqi 正在开发无需植入物移除和更换的侵入性循环的重复、最佳剂量。 一种高效、模块化药物输送的平台技术，可实现药物的精确时空定位 一种可以对抗局部疾病而不引起全身副作用的疗法，并且可以 它围绕生物相容性凝胶构建，可在目标部位保留超过 3 个月。 依靠生物正交化学将系统性前药（修饰为静态的药物）集中在它们需要的地方 我们的可生物降解凝胶可以在需要时将其转化为治疗形式。 活检或手术，不需要额外的侵入性手术来进行额外的治疗或切除。 将来，我们的凝胶可以设计为具有双重附着化学物质来“捕获”前药，从而允许 联合疗法的控释（空间和时间）虽然存在市场需求。 我们在许多治疗领域的技术，Shasqi 最初专注于开发化疗药物 为了实现这些目标，我们将追求手术干预的肿瘤患者。 通过拟议的快速通道项目的七个具体目标，我们将在第一阶段优化凝胶剂量。 我们还将开发经过验证的前药，用于使用荷瘤小鼠进行癌症治疗。 适合预期 IND 研究的方法并扩大我们的前药库 在第二阶段，我们将进行。 以最大耐受剂量 (MTD) 数据为指导的犬类中期（28 天）毒性研究 我们还将优化前药制剂的稳定性和药代动力学。 包装药品，然后制造 GMP 级凝胶，用于最终的一期临床试验。