Targeting mucositis with inflammation responsive hydrogel microparticles

描述(申请人提供)：粘膜炎是一种常见的，衰弱的副作用，多种形式的化疗和放射治疗口腔粘膜炎会导致弥漫性溃疡的发展，严重到需要改变饮食，通过静脉或胃造口途径进行营养补充，止痛剂的使用，以及癌症治疗中的剂量调整。在接受清髓性化疗或头颈部放射治疗的患者中，粘膜炎是患者提到的最令人不安的副作用。除了对症状和功能的影响外，口腔粘膜炎还显著增加了护理成本：头颈部或非小细胞肺癌患者的粘膜炎增量成本超过17,000美元。尽管它的频率(今年美国将有大约450.000例新的口腔粘膜炎病例)以及健康和经济负担，但预防和治疗口腔粘膜炎的选择有限。生物活性、局部应用的药物具有潜力，但它们的用途受到以下因素的限制 暂时性粘膜停留时间。来解决这个问题，用于癌症的治疗。口腔粘膜经常受到影响。我们已经开发了具有炎症反应的药物传递水凝胶微粒，这种微粒选择性地附着在溃疡上，实现药物的受控和靶向释放。我们开发了这些被普遍认为是安全的材料，我们已经诱使这些材料在没有化学修饰的情况下在水凝胶中自组装，在组装过程中可以包裹多种药物。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这项技术的体外和体内概念验证。这项工作将 评估含有酶不稳定连接物的自组装水凝胶微粒可以选择性地附着在炎症的粘膜上并在炎症反应中释放药物治疗口腔粘膜炎的假说。这些水凝胶颗粒将进行选择性测试 粘连、对溃疡有反应的药物释放，以及药物释放持续时间延长。这种水凝胶颗粒还将在口腔粘膜炎的啮齿动物模型中与抗炎药物米诺环素进行测试。这项建议将集中于解决以下目标：目标1：表征水凝胶颗粒对炎症黏膜的选择性黏附，并检测动态条件下水凝胶的物理化学性质对黏附持续时间的影响。目的2：调节GRAS水凝胶对模型药物的刺激反应释放，并考察其在粘膜溃疡部位的释放情况。目的：比较米诺环素GRAS水凝胶微球与米诺环素单独口腔冲洗对金黄地鼠的治疗效果。

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.