Osteoarthritis is a debilitating disease of the joint which manifests as a loss of articular cartilage, causing serious pain and impeding mobility. Currently, no disease modifying osteoarthritis drug (DMOAD) capable of preserving cartilage exists and the standard of care is merely palliative. The approval of a DMOAD has been hindered by repeated clinical trial failures, due in considerable part to inadequate drug delivery to cartilage, even with local injection directly into the affected joint. Recent work has identified that cationic nanomaterials display increased binding to and penetration throughout anionic cartilage tissue via electrostatic interactions. In this research, to develop an intra-articular drug delivery vehicle for DMOADs, we screened a small library of partially PEGylated cationic dendrimers (20-60% end group functionalization) to identify an optimally charged dendrimer with high cartilage binding and no toxicity. The lead PEGylated dendrimer was conjugated to insulin like growth factor 1 (IGF-1) without loss in bioactivity and tested for penetration into bovine cartilage, pharmacokinetics following intra-articular injection in rats, and efficacy in a surgically induced rat osteoarthritis model. 71% of the lead dendrimer-IGF-1 conjugate incubated with bovine cartilage explants bound to the tissue within 2 days. The conjugate penetrated through the entire 1000 µm depth of the tissue, on the order of human cartilage thickness. In contrast, free IGF-1 displayed around 2% binding to the tissue and could only penetrate ~20 µm in 2 days. Free IGF-1 and dendrimer-IGF-1 were injected into rat joints and monitored by in vivo imaging (IVIS) over 28 days. Half-lives were calculated for each based on single phase exponential decay fits of the data. Free IGF-1 had a joint half-life of 0.41 days whereas dendrimer-IGF-1 had a joint half-life of 4.21 days, 10 times that of free IGF-1. We evaluated if dendrimer-IGF-1 could rescue cartilage in a surgically induced rat model of osteoarthritis. 48 hours after surgery, dendrimer-IGF-1, free IGF-1, or no treatment was injected. 4 weeks later, the rats were sacrificed and quantitative measurements of cartilage and bone degeneration were taken from histology and µCT images. While IGF-1 alone was ineffective, injection of the dendrimer-IGF-1 conjugate led to significantly reduced cartilage degeneration width and osteophyte (bone spur) volume at 30 days post-surgery, relative to the untreated animals.

Cartilage penetrating nanocarriers enhance drug delivery and efficacy in osteoarthritis

256th National Meeting (2018)

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