Synthesis and Characterization of Polymeric Antioxidant microparticles for the pr

描述(申请人提供)：在美国，每年大约有132,000名接受抗癌治疗的患者患上口腔粘膜炎(OM)，这是一种痛苦的、使人虚弱的口腔创伤状况，据估计，这会使患者的护理成本增加17,000-43,000美元。大多数治疗方法侧重于姑息治疗或通过应用生长因子(GF)来加速伤口愈合过程。虽然生长因子，如Palifermin，在治愈OM方面显示出了希望，但它们具有肿瘤生长的潜力，并且不针对OM的根本原因。据报道，OM发生的最常见的分子机制是由于抗癌的化学辐射机制而过度产生的活性氧(ROS)。一种有效的抗氧化剂，如姜黄素，可能是预防OM的一种令人兴奋的治疗剂，因为它直接抑制OM发展的最早阶段，即氧化应激。事实上，它可以在抗癌机制之前应用，完全防止OM的发生。此外，姜黄素：1)显示了抑制癌细胞生长和不引发肿瘤生长的能力，2)显示了伤口愈合能力，3)证明了抗炎和抗菌特性，4)具有良好的口服耐受性，5)非常便宜。然而，由于姜黄素在生理环境和环境中的半衰期很短，因此在生理上给药是一个挑战。 水溶性能差。该项目的中心假设是，由天然抗氧化剂(C-PONA)组成的基于姜黄素的聚合物可以合成组织粘附性微粒，并预防性地应用于口腔粘膜表面，以减少局部细胞的氧化应激，从而降低放化疗诱发OM的可能性。作为实现这一假设的一部分，该研究计划被分为两个具体的目标，目标1：C-PONA微粒提供姜黄素的受控释放，以及目标2：C-PONA微粒附着在口腔粘膜组织上。第一个目标是抗氧化剂聚合物配方的开发和表征，第二个目标是通过体外模型展示将选定的配方输送到口腔粘膜表面的能力。在这项提案执行后，将确定C-PONA微粒子制剂(S)可以克服当前姜黄素给药策略的主要限制。将获得与粘蛋白紧密结合的微粒，同时允许长期局部释放。简而言之，这项提案的完成将为临床前动物试验的设计提供信息，使其进入第二阶段。

DESCRIPTION (provided by applicant): Every year in the United States, approximately 132,000 patients undergoing anti-cancer therapy develop oral mucositis (OM), a painful, debilitating oral wound condition, which is estimated to increase the patient's cost of care by $17,000-43,000. Most treatments have focused on either palliative care or accelerating the wound healing process through the application of growth factors (GF). Although growth factors, such as Palifermin, have shown promise in healing OM, they carrying the potential for neoplastic growths, and do not target the root cause of OM. The most commonly reported molecular mechanism for occurrence of OM is the excessive generation of reactive oxygen species (ROS) due to the anti-cancer chemo- radiation regimes. A potent antioxidant, such as curcumin, may represent an exciting therapeutic agent in OM prevention as a direct inhibitor of the earliest phase of OM development, i.e. oxidative stress. In fact, it can be applied before the anti-cancer regimes to prevent the occurrence of OM altogether. Additionally, curcumin: 1) has demonstrated ability to inhibit the growth of cancer cells and not trigger neoplastic growths, 2) has demonstrated wound healing capacity, 3) has proven anti-inflammatory and antimicrobial properties, 4) is well tolerated orally, and 5) is very inexpensive. However, delivery of curcumin physiologically represents a challenge due to its short half-life in physiological environments and poor aqueous solubility. The central hypothesis of this project is that curcumin-based polymers composed of natural antioxidants (C-PoNA) can be synthesized into tissue adhesive microparticles, and applied prophylactically to oral mucosal surfaces to decrease local cellular oxidative stress, and thereby decrease the likelihood of developing chemo/radio-therapy induced OM. As part of fulfilling this hypothesis, the research plan has been separated into two specific aims, Aim 1: C-PoNA microparticles provide controlled release of curcumin, and Aim 2: C-PoNA microparticles adhere to oral mucosal tissues. The first aim focuses on development and characterization of antioxidant polymer formulations, while the second aim focuses on demonstrating the ability to deliver select formulations to oral mucosal surfaces via an in vitro model. After the execution of this proposal, C-PoNA microparticle formulation(s) will be identified that can overcome the primary limitations of current curcumin delivery strategies. Microparticles that bond strongly to mucin while permitting long term local release will be obtained. In short, completion of this proposal will inform design of preclinical animal trials as e progress into phase II.