Abstract
The efficient delivery of therapeutic molecules to the cartilage of joints is a major obstacle in developing useful therapeutic interventions; hence, a targeted drug delivery system for this tissue is critical. We have overcome the challenge by developing a system that employs electrostatic attraction between the negatively charged constituents of cartilage and a positively charged polymer, poly-beta amino esters (PBAEs). We have demonstrated cartilage uptake of dexamethasone (DEX) covalently bound to the PBAE was doubled and retention in tissues prolonged compared to the equivalent dose of the commercial drug formulation. Moreover, no adverse effects on chondrocytes were found. Our data also show that PBAEs can bind not only healthy cartilage tissues but also enzymatically treated cartilage mimicking early stages of OA. Our PBAEs-prodrug technology's advantages are fourfold; the specificity and efficacy of its targeting mechanism for cartilage, the ease of its production and the low-cost nature of the delivery system.
Highlights
Cartilage is the connective tissue that constitutes the load-bearing surfaces of synovial joints; they allow the synovial joints' low friction and pain-free movements.[1]
Fluoro-tagging of poly-beta amino esters (PBAEs) with FITC revealed that PBAE were able to penetrate the cartilage tissues used (Figure 3) in about 1 min; it appeared that A1 penetrates cartilage easier than A2 as little fluorescent dye was noticed in the cartilage sample far from the surface exposed to PBAE
The effective diffusion coefficient (DÞ depends on the structure of the PBAE and is connected to the time necessary to the PBAE to cross the full thickness of the sample as shown in (Figure 3); in cartilage samples with original level of GAG, the diffusion coefficient for A1 (DA1Þwas greater than for A2 (DA2Þ (p b 0.05), 8 × 10−6 cm2/s and 5.5 × 10−6 cm2/s respectively
Summary
Cartilage is the connective tissue that constitutes the load-bearing surfaces of synovial joints; they allow the synovial joints' low friction and pain-free movements.[1] The structure of the extracellular matrix of cartilage is characterized by the presence of glycosaminoglycans (GAGs). The resulting structure is highly negatively charged allowing cartilage to perform the required functions of shock absorber and low friction surface. Osteoarthritis (OA) is the most common disease affecting joint in the USA, with a reported 10% and 13% of male and female population, respectively, over 60 years old experiencing symptomatic OA,[2] similar incidence was found in the UK,[3] with about 8.7 millions of patients.[4] Some of the most common predictors of OA are obesity and age[5,6]; the number of OA diagnoses is expected to increase in light of the aging population along with growing obesity.[4] At present, therapies.
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