Osteoarthritis (OA) is a degenerative joint disease associated with impaired activity and pain for the affected joints. Intra-articular injection of smll molecule drugs has great potential to treat both disease progression and symptoms of OA, but fails due to the very rapid clearance of small drugs from the joint space. Previous work in the Sponsor laboratory has advanced use of injectable drug depots for intra-articular delivery of protein drugs that can provided for sustained and local release of drug. The goal of the current project is to develop injectable, intra-articular carriers for small-molecule drugs that have potential to treat OA. I have adopted methods to synthesize nano- and micro-particles from silk fibroin (SF) towards the goal of coupling to small molecule drugs. SF is attractive as a drug depot for its extensive history of safe clinical use, and it is inexpensive to prepare in large quantities. Curcumin is a small di-phenol that inhibits inflammation in many cell types and will be used as a model drug here. A very low solubility and oral bioavailability for curcumin is very limiting, however, as it is difficult to achieve nanomolar curcumin concentrations following oral dosing as high as 10 grams. In this study, we will work with a novel curcumin variant - monofunctional curcumin carbamate (MCC) - that was synthesized at Duke to allow for increased drug solubility and to provide a reactive amine for coupling to silk. The hypothesis of this project and training period is that intra-articular delivery of SF particles conjugated to MCC will enhance drug efficacy in pre-clinical models of OA, by prolonging drug half-lives in the joint space while retaining bioactivity. Work in Aim 1 will optimize SF modification to enable MCC coupling (SF-MCC) and synthesize two groups of drug carriers: (1) nanoparticles (<1 micron);or (2) microparticles. For each group, I will: (a) study in vitro MCC release and bioactivity against IL-1b, (b) determine in vivo half-life of SF particles following delivery to the joint spac using in vivo fluorescence imaging;and (c) measure in vivo clearance of MCC following intra-articular injection of SF-MCC in plasma via HPLC. This work will demonstrate if nano- or microparticles provide a preferred drug depot for the delivery of a small molecule to the joint space. Work in Aim 2 will evaluate an ability for SF-MCC particles to attenuate disease development and pain-related sensitivity in a rat joint instability model of OA. Rats with OA will be treated with intra-articular injection of curcumin, MCC, SF-MCC, or SF particles alone, and I will measure and compare (a) hind limb weight-bearing;(b) pain-related sensitivity (mechanical allodynia);(c) histopathology grade;and (d) serum and synovial fluid biomarkers of OA. Results from these studies should reveal if local and sustained delivery of a modified curcumin and delivery vehicle has potential to modify disease or symptoms associated with OA. I will work with my Sponsor and interdisciplinary mentoring team to learn fundamentals and applications of materials science, drug delivery, pre-clinical model outcomes that will extend my interest in translational bioengineering and prepare me for an academic career in bioengineering.
This project will advance use of a safe and inexpensive biomaterial carrier for small molecule drug delivery to the joint space. Nano and microparticles of silk fibroin will be conjugated to a small molecule inflammatory antagonist, curcumin, and evaluated as a sustained release drug depot following injection into the knee joint for the treatment of osteoarthritis. A goal of this project is to provide novel learning in translational bioengineering in order to further the applicant's potential for a successful academic career in biomedical research.
|Bowles, Robby D; Mata, Brian A; Bell, Richard D et al. (2014) In vivo luminescence imaging of NF-?B activity and serum cytokine levels predict pain sensitivities in a rodent model of osteoarthritis. Arthritis Rheumatol 66:637-46|