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 全身给予小分子治疗以治疗疾病的治疗可能是无效的，甚至是危险的， 因为这些药物在体内广泛分布。缺乏现场特异性意味着大型全身剂量是 需要在解剖组织中实现有效浓度，但是这些高剂量通常会导致非 - 特异性毒性。大约有20名住院患者中有1个经历了不良毒品事件（ADE），并且在整个过程中 美国医疗保健系统每年都有超过100万个ADE。这些意外的后果 药物疗法的死亡风险增加了一倍，增加了住院时间，经济损失是 每年大大超过100美元。此外，ADE对我们的治疗库有间接效果。 由于问题的问题 临床安全。研究小组的回应是开发药物输送系统以优化本地化的 但是，及时提供治疗的方法，使用的方法有重大局限性。例如，药物 与抗体结合以实现其靶特异性的抗体可能会导致免疫复杂，及其 有限的药物释放可能会损害治疗效率。其他研究人员正在将药物嵌入 生物相容性的聚合物，可以在需要的地方植入它们，但是该技术缺乏能力 对于重复，最佳剂量，无侵入性的植入物去除和替换循环。 Shasqi正在发展 一种用于高效和模块化药物传递的平台技术，可实现精确的时空定位 治疗，一种可以打击局部疾病而不会引起全身性副作用的治疗，这允许 药物释放的调节。围绕一个生物相容性的凝胶建造，该凝胶在目标部位保持> 3个月， 依靠生物正交化学来浓缩全身前药（被修饰为静止的药物） 需要并将其转换为他们的治疗形式。我们的可生物降解凝胶可以在 活检或手术，不需要额外的侵入性手术来进行其他治疗或去除。 将来，我们的凝胶可以设计为具有双重依恋化学家用于“捕捉”前药，从而允许 对于组合疗法的受控释放（空间和临时）。虽然市场需要 我们在许多治疗领域的技术，Shasqi最初专注于开发化学治疗剂 肿瘤的患者是候选手术干预的患者。为了实现这些目标，我们将追求 通过拟议的快速轨道项目的七个特定目标。在第一阶段，我们将优化凝胶剂量 与使用肿瘤小鼠的前药结合癌症治疗。我们还将开发经过验证的 适用于预期的IND研究的方法并扩大了我们的前药。在第二阶段，我们将进行 在最大耐受剂量（MTD）的数据引导的犬类中的中期（28天）毒性研究 实验和药代动力学在大鼠中起作用。我们还将优化稳定性的前药公式和 然后，该药物的包装为I最终1期临床试验生产GMP级凝胶。