Targeting mucositis with inflammation responsive hydrogel microparticles

描述（由申请人提供）：粘膜炎是许多形式的化疗和放疗的常见的使人衰弱的副作用。口腔粘膜炎导致弥漫性溃疡的发展，其严重程度使得需要改变饮食、通过静脉内或胃造口术途径补充营养、使用镇痛剂和调整癌症治疗的剂量。在接受清髓性化疗或头颈部放疗的患者中，粘膜炎是患者提到的最常见的令人不安的治疗副作用。除了其症状和功能影响外，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）和健康和经济负担，但预防和治疗口腔粘膜炎的选择是有限的。具有生物活性的局部应用剂具有潜力，但其效用受到以下因素的限制： 短暂粘膜驻留时间。为了解决这个问题，为了治疗癌症。口腔粘膜经常受到影响。我们已经开发了炎症响应性药物递送水凝胶微粒，其选择性地粘附到溃疡上，用于药物的受控和靶向释放。我们开发了这些运载工具，它们是从公认的安全材料中开发出来的，我们在没有化学修饰的情况下，将其诱导到水凝胶中，在组装过程中可以封装多种药物。在这里，我们的目的是证明在体外和体内的概念证明这种技术在啮齿动物模型的口腔粘膜炎。这项工作将 评估含有酶不稳定接头的自组装水凝胶微粒可以选择性地粘附到发炎的粘膜并响应于炎症释放药物以治疗口腔粘膜炎的假设。这些水凝胶颗粒将被测试用于选择性的 粘附、溃疡响应性药物释放和延长的药物释放持续时间。还将在口腔粘膜炎的啮齿动物模型中用抗炎药米诺环素测试水凝胶颗粒。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，并检查动态条件下水凝胶理化性质对粘附持续时间的影响。目的2：调节模型药物从GRAS水凝胶的刺激响应性释放，并检查在粘膜溃疡部位的释放。目标3：在仓鼠模型中比较通过口腔冲洗给予的负载米诺环素的GRAS水凝胶微粒与单独米诺环素的治疗功效。

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.