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.
This research will develop a new therapeutic strategy to prevent the occurrence of oral mucositis (OM). OM is a common side effect to the chemo-radiation treatment against head and neck cancers. These painful and debilitating mouth ulcers result in an increased treatment cost of $17,000 to $43,000 per patient. The proposed research plan will yield powdered formulations of biodegradable polymers of natural antioxidants that can be applied to the oral cavity via simple mouth rinses. The long term and local release of the potent antioxidant curcumin is expected to prevent the initiation of OM, thus drastically improving patient comfort and compliance, and preventing interruptions in the critically required anti-cancer therapy.
|Gupta, Prachi; Jordan, Carolyn T; Mitov, Mihail I et al. (2016) Controlled curcumin release via conjugation into PBAE nanogels enhances mitochondrial protection against oxidative stress. Int J Pharm 511:1012-21|