Targeting mucositis with inflammation responsive hydrogel microparticles

用炎症反应性水凝胶微粒治疗粘膜炎

• 批准号: 8634092
• 负责人: Jeffrey Michael Karp
• 金额: $ 26.51万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8634092
• 关键词: Acute Disease; Address; Adhesions; Adrenal Cortex Hormones; Adverse effects; Affect; Analgesics; Anti-Inflammatory Agents; Anti-inflammatory; Anus; Biocompatible; Caring; Charge; Chemicals; Colitis; Colon; Development; Diet; Diffuse; Dose; Drug Delivery Systems; Economic Burden; Encapsulated; Environment; Enzymes; Exhibits; Flare; Frequencies; Gastrointestinal tract structure; Gastrostomy; Gelatinase A; Gelatinase B; Genes; Hamsters; Head and neck structure; Hydrogels; In Vitro; Incubated; Inflammation; Intravenous; Lipopolysaccharides; Mediator of activation protein; Minocycline; Modeling; Modification; Mucins; Mucositis; Mucous Membrane; Mus; Myeloablative Chemotherapy; Non-Small-Cell Lung Carcinoma; Nutritional; Oral; Oral cavity; Oral mucous membrane structure; Patients; Pharmaceutical Preparations; Pilot Projects; Prevention; Process; Property; Radiation; Radiation therapy; Rodent Model; Route; Severities; Simulate; Site; Steroids; Stimulus; Supplementation; Surface; Technology; Testing; Time; Tissues; Topical application; Transferrin; Treatment Efficacy; Ulcer; Ulcerative Colitis; Work; cancer therapy; cost; cytokine; enema administration; esterase; experience; health economics; in vivo; local drug delivery; macrophage; mucosal site; oral mucositis; particle; public health relevance; response; surface coating

DESCRIPTION (provided by applicant): Mucositis is a common, debilitating side effect of many forms of chemo- and radiation therapy used Oral mucositis results in the development of diffuse ulcerations of such severity as to necessitate changes in diet, nutritional supplementation through intravenous or gastrostomy routes, analgesic use, and dose modifications in cancer therapy. Among patients receiving myeloablative chemotherapy or head and neck radiation, mucositis was the most consistently mentioned troubling side effect of treatment mentioned by patients. Aside from its symptomatic and functional impact, oral mucositis significantly escalates the cost of care: the incremental cost of mucositis in patients with head and neck or non- small cell lung cancers is over $17,000. Despite its frequency (there will be about 450.000 new cases of oral mucositis in the U.S. this year) and health and economic burden, options for the prevention and treatment of oral mucositis are limited. Biologically active, topically-applied agents have potential, but their utility has been limited by transient mucosal resident time. To address this, for the treatment of cancer. The oral mucosa is frequently affected. we have developed inflammation responsive drug delivery hydrogel microparticles that selectively adhere to ulcers for controlled and targeted release of drugs. We developed these delivery vehicles from generally recognized as safe materials that we have coaxed, without chemical modification, to self-assemble in hydrogels that can encapsulate multiple classes of drugs during the assembly process. Here we aim to demonstrate an in vitro and in vivo proof of concept for this technology in rodent models of oral mucositis. This work will assess the hypothesis that self-assembled hydrogel microparticles containing enzyme-labile linkers can selectively adhere to the inflamed mucosa and release drugs in response to inflammation for treatment of oral mucositis. These hydrogel particles will be tested for selective adhesion, ulcer-responsive drug release, and extended duration of drug release. The hydrogel particles will also be tested with anti-inflammatory drug minocycline in the rodent models of oral mucositis. This proposal will focus on addressing the following aims: Aim 1: Characterize selective adhesion of hydrogel particles to inflamed mucosa and examine the influence of hydrogel physicochemical properties on duration of adhesion under dynamic conditions. Aim 2: Tune stimulus responsive release of model drugs from GRAS hydrogels and examine release at sites of mucosal ulcers. Aim 3: Compare the therapeutic efficacy of minocycline-loaded GRAS hydrogel microparticles versus minocycline alone administered via oral rinse in a hamster model.

描述（由申请人提供）：粘膜炎是多种形式的化疗和放射治疗的常见副作用，口腔粘膜炎会导致弥漫性溃疡，其严重程度导致需要改变饮食、通过静脉或胃造口途径补充营养、使用镇痛剂以及在癌症治疗中调整剂量。在接受清髓性化疗或头颈放疗的患者中，粘膜炎是患者提到的最令人不安的治疗副作用。除了对症状和功能的影响外，口腔粘膜炎还显着增加了护理费用：头颈癌或非小细胞肺癌患者的粘膜炎增量费用超过 17,000 美元。尽管口腔粘膜炎的发病率很高（今年美国将新增约 45 万例口腔粘膜炎病例）以及健康和经济负担，但预防和治疗口腔粘膜炎的选择仍然有限。生物活性的局部用药具有潜力，但其效用受到以下因素的限制： 短暂粘膜停留时间。为了解决这个问题，用于治疗癌症。口腔粘膜经常受到影响。我们开发了炎症反应性药物输送水凝胶微粒，可以选择性地粘附在溃疡上，以控制和靶向释放药物。我们利用公认的安全材料开发了这些运载工具，无需进行化学修饰，即可在水凝胶中自组装，在组装过程中可以封装多种药物。在这里，我们的目标是在口腔粘膜炎的啮齿动物模型中展示该技术的体外和体内概念证明。这项工作将 评估以下假设：含有酶不稳定连接体的自组装水凝胶微粒可以选择性地粘附在发炎的粘膜上，并响应炎症释放药物以治疗口腔粘膜炎。这些水凝胶颗粒将进行选择性测试 粘附、溃疡反应性药物释放和药物释放持续时间延长。水凝胶颗粒还将在啮齿动物口腔粘膜炎模型中与抗炎药物米诺环素一起进行测试。该提案将重点解决以下目标： 目标 1：表征水凝胶颗粒对发炎粘膜的选择性粘附，并检查水凝胶理化性质对动态条件下粘附持续时间的影响。目标 2：调节 GRAS 水凝胶中模型药物的刺激响应释放，并检查粘膜溃疡部位的释放。目标 3：在仓鼠模型中比较负载米诺环素的 GRAS 水凝胶微粒与仅通过口腔冲洗施用的米诺环素的治疗效果。