OBJECTIVE: We are seeking Concept Clearance for a Program Announcement (PA) under the SBIR/STTR program. The purpose of this initiative is to encourage the design and development of novel delivery systems for rapid and/or sustained, on-demand release of therapeutic agents (e.g., antimicrobial, anti-inflammatory) in the oral cavity. The expected outcomes are the delivery of agents with more precise localization and appropriate half-lives to treat oral diseases such as caries and periodontal disease, oral mucositis and temporomandibular joint and muscle disorders and chronic pain.
The Small Business Innovation Research (SBIR) and Small Business Technology Transfer Research (STTR) are set-aside programs for small business to engage in commercially viable Research and Development (R&D) of relevance and importance to the funding institution. The federal mandates require 2.5% of the extramural R&D budget be allocated to SBIR and 0.3% of the budget to STTR. The goal of both programs is to accelerate the translational process from discovery science into application.
BACKGROUND: Tooth loss is the end result of advanced caries and severe periodontitis, both of which are common, especially in the aging population. It is widely accepted that the inflammation and tissue destruction that results in gingivitis and progresses to periodontitis is in large part caused by the inflammatory response to microbial pathogens sequestered in dental plaque biofilms. While many antibiotic and anti-inflammatory agents could be of benefit, penetrating the complex biofilm glycocalyx to achieve therapeutic doses is a significant challenge. Thus, there are major clinical problems in the long-term management of these diseases.
The etiology of caries is also highly related to oral bacteria which rapidly digest dietary sugars and secrete metabolites that generate an acidic environment at tooth surfaces, leading to breakdown of enamel. As decay progresses, restoration is eventually required to prevent erosion to the pulp and tooth loss. Long-term success of this intervention is largely dependent on the stability of the resin-dentin/resin-enamel bond that is susceptible to the regular mechanical and chemical stresses in the mouth. Microfissures and failure at the resin-tooth interface creates channels for deeper invasion of microorganisms, and further decay. Anti-cariogenic agents incorporated directly into the composite matrix could offer a significant therapeutic advantage.
Over 7 million people annually suffer from chronic pain of the temporomandibular joint (TMJ) tissues. Available drug therapies are largely limited to systemic anti-inflammatory drugs which may relieve symptoms, but do not address the underlying pathophysiology. Direct/localized delivery of anti-inflammatory agents will allow a greater diversity of therapeutics without the systemic side effects.
Oral mucositis refers to a toxic consequence of systemic intensive cancer chemotherapy and radiotherapy that affects the integrity of the epithelial linings of the oral cavity, esophagus, and the lower gastrointestinal tract. An impaired mucosal barrier predisposes patients to life threatening septic complications. The use of delivery systems will permit sustained delivery of molecules (e.g., of various epidermal growth factors, salivary antibacterial molecules such as lactoferrin) that have been shown to reduce the incidence, severity and/or duration of oral mucositis.
Current treatments are not always effective for these conditions. Effective delivery systems that optimize dosage and minimize systemic side effects, may be a better investment and more effective for patients than creating a new drug. Materials science and combinatorial chemistry have pushed the boundaries of understanding and manipulating complex macromolecules, enabling explorations of new drug delivery systems. The goal of such systems is to alter solubility, pharmacokinetics and/or distribution of therapeutic agents, or function as reservoirs for controlled availability. Some advanced drug delivery systems are already on the market, including liposome-encapsulated antifungals, poly-ethylene glycol (PEG)-conjugated anti-cancer drugs and antibiotics, and ligand-targeted anticancer molecules. Additionally, liposome delivery of DNA is a common research tool for gene modification. Recent developments and novel approaches include: i) on-demand activation of molecular interactions, ii) diffusion controlled delivery devices, iii) nanostructures based on functional polymers and dendrimers, and iv) coupling drug delivery to on-board sensing in implants. These formulations are generally for systemic administration, and so do not include considerations of stability in the oral cavity. Therefore, modifications of such systems so that they can perform in the oral environment may be needed.
This initiative will focus on the on the improvement and adaptation to the oral environment of existing drug delivery as well as on the design and development of new systems for sustained, controlled oral drug delivery via:
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tooth restorative materials with nanoscale-oriented deposition of materials, and biomimetic polymers that can deliver antimicrobial agents
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nanoparticles and other nanostructures that enable controlled released of therapeutic agents, antibodies, antisense oligonucleotides and genes into targeted cells
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encapsulated drugs within polymeric micelles or liposomes
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synthetic polymers with “tunable” degradation rates containing therapeutic small molecules embedded within their molecular structure
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novel drug delivery matrix materials with designed or on-demand drug release mechanisms, e.g. cell or receptor specific triggering mechanisms versus hydrolytic degradation or erosion in vivo
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drug delivery carriers integrating targeted delivery with imaging capabilities
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localized delivery by the use of tissue and cell specific molecular anchors and/or adhesives that prevent drug wash-out due to salivary flow or food intake
CURRENT PORTFOLIO OVERVIEW: The NIDCR SBIR/STTR program supports five grants in this area. They focus on: i) delivery of a non-steroidal anti-inflammatory agent to the TMJ; ii) topical delivery of agents to prevent gingivitis; iii) delivery of growth factors using transduced buccal epithelial cells; iv) use of denture adhesive gel to deliver antifungal agents, and v) a biocompatible, slowly degraded polymer matrix for delivery of a bone forming agent.
COLLABORATIVE ACTIVIES: It is expected that NHLBI, NIBIB and NIDDK would have an interest in a program with a strong emphasis on the unique challenges in drug delivery localized to the oral cavity.
FUNDING MECHANISMS: The funding mechanisms are the Phase I (R43 and R41) and the phase II (R44 and R42) SBIR/STTR.