Synthesis and Characterization of Polymeric Antioxidant microparticles for the pr

聚合物抗氧化剂微粒的合成与表征

• 批准号: 8592983
• 负责人: Nihar Manilal Shah
• 金额: $ 21.77万
• 依托单位: BLUEGRASS ADVANCED MATERIALS, LLC
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-24 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8592983
• 关键词: Acrylates; Address; Adherence; Adhesions; Adverse effects; Amines; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Biological; Cancer Cell Growth; Caring; Cells; Chemistry; Complication; Curcumin; Development; Drug Formulations; Economics; Environment; Esters; Gel; Generations; Growth Factor; Half-Life; Head and Neck Cancer; Healed; Health Care Costs; In Vitro; Injury; Interruption; Kinetics; Lead; Life; Liquid substance; Lubricants; Malignant Neoplasms; Mechanics; Molecular; Mucins; Mucous Membrane; Neoplasms; Oral; Oral Ulcer; Oral cavity; Oral mucous membrane structure; Oxidative Stress; Pain; Palliative Care; Particle Size; Patients; Pharmaceutical Preparations; Phase; Physiological; Plant Roots; Polymers; Powder dose form; Prevention; Process; Property; Protons; Radiation; Radio; Reaction; Reactive Oxygen Species; Reporting; Research; Severities; Solubility; Speed; Surface; Suspension substance; Suspensions; Technology; Therapeutic Agents; Thick; Time; Tissue Adhesives; Tissue Model; Tissues; Treatment Cost; Uncertainty; United States; Vertebral column; Wound Healing; antimicrobial; aqueous; base; biodegradable polymer; cancer therapy; chemical cleavage; compliance behavior; controlled release; cost; crosslink; cryogenics; cytotoxicity; design; healing; improved; in vitro Model; inhibitor/antagonist; keratinocyte growth factor; nano; novel therapeutics; oral mucositis; oxidation; pre-clinical; premature; prevent; public health relevance; small molecule; treatment strategy; wound

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.

描述（由申请人提供）：在美国，每年约有132，000名接受抗癌治疗的患者发生口腔粘膜炎（OM），这是一种疼痛、使人虚弱的口腔伤口病症，估计会使患者的护理成本增加17，000 - 43，000美元。大多数治疗都集中在姑息治疗或通过应用生长因子（GF）加速伤口愈合过程。虽然生长因子，如Palifermin，已显示出治愈OM的希望，但它们具有肿瘤生长的潜力，并且不针对OM的根本原因。最常报道的OM发生的分子机制是由于抗癌化疗-放射方案导致的活性氧（ROS）的过度产生。一种有效的抗氧化剂，如姜黄素，可以代表一个令人兴奋的治疗剂在OM预防作为一个直接抑制剂的最早阶段的OM发展，即氧化应激。事实上，它可以在抗癌方案之前应用，以完全预防OM的发生。此外，姜黄素：1）已经证明能够抑制癌细胞的生长并且不触发肿瘤生长，2）已经证明具有伤口愈合能力，3）已经证明具有抗炎和抗微生物特性，4）口服耐受性良好，以及5）非常便宜。然而，姜黄素的生理递送是一个挑战，因为它在生理环境中的半衰期短， 水溶性差。 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为组织粘附性微粒，并粘附性地应用于口腔粘膜表面以降低局部细胞氧化应激，从而降低发生化疗/放疗诱导的OM的可能性。作为实现这一假设的一部分，研究计划已被分成两个具体目标，目标1：C-PoNA微粒提供姜黄素的控释，目标2：C-PoNA微粒粘附于口腔粘膜组织。第一个目标侧重于抗氧化剂聚合物制剂的开发和表征，而第二个目标侧重于证明通过体外模型将选择的制剂递送至口腔粘膜表面的能力。 在执行该提案后，将确定可以克服当前姜黄素递送策略的主要限制的C-PoNA微粒制剂。将获得与粘蛋白牢固结合同时允许长期局部释放的微粒。简而言之，本提案的完成将为临床前动物试验的设计提供信息，以进入II期。