Abstract
Current intra-articular drug delivery methods do not guarantee sufficient drug penetration into cartilage tissue to reach cell and matrix targets at the concentrations necessary to elicit the desired biological response. Here, we provide our perspective on the utilization of charge–charge (electrostatic) interactions to enhance drug penetration and transport into cartilage, and to enable sustained binding of drugs within the tissue's highly negatively charged extracellular matrix. By coupling drugs to positively charged nanocarriers that have optimal size and charge, cartilage can be converted from a drug barrier into a drug reservoir for sustained intra-tissue delivery. Alternatively, a wide variety of drugs themselves can be made cartilage-penetrating by functionalizing them with specialized positively charged protein domains. Finally, we emphasize that appropriate animal models, with cartilage thickness similar to that of humans, must be used for the study of drug transport and retention in cartilage.
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Acknowledgements
This work was supported by NIH National Institute of Biomedical Imaging and Bioengineering grant EB017755, National Science Foundation Materials Research Science and Engineering Centers (MRSEC) grant DMR-1419807, NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) grant AR060331 and Department of Defense (DoD) Congressionally Directed Medical Research Programs (CDMRP) grant W81XWH-14-1-0544.
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A.G.B and A.J.G. declare that they are inventors on the US patent 9289506 B2 'Surface binding of nanoparticles-based drug delivery to tissue'.
Glossary
- Therapeutic levels
-
The drug doses necessary to elicit the desired biological response. For a particular drug this level can be estimated using a combination of in vitro assays and in vivo pharmacokinetic and pharmacodynamics studies.
- Diffusion time
-
Time for diffusion (τ) of a drug into cartilage of thickness 'L' is ∼ L2/D, where D is the diffusivity of the drug inside cartilage tissue.
- Electrostatic interaction
-
Non-covalent repulsive or attractive interaction between charged molecules (for example, proteins, glycosaminoglycan chains) in a physiological medium (for example, saline, synovial fluid) or inside highly charged tissues such as cartilage.
- Partition coefficient
-
The equilibrium concentration of unbound, free drug inside cartilage, normalized to drug concentration in the synovial fluid (denoted as k).
- Electrical potential
-
The potential energy of a charged particle at any location divided by the particle's charge. Sharp jumps in electrical potential result in high localized electric fields at that region.
- Steric hindrance
-
When the pore size of the tissue matrix is small enough, diffusion and transport of a drug or drug-carrier will be hindered simply because of its size.
- Donnan partitioning
-
The change in concentration of a charged drug across the synovial fluid–cartilage interface due to the drug's charge. The high negative fixed-charge density of glycosaimnoglycans inside cartilage results in a drop in the electrical potential at the tissue interface, causing a strong inwardly pointing electric field that enhances transport of positively charged species into cartilage and excludes penetration of negatively charged species such that the net charge inside the cartilage is zero. Thus, the concentration of positively charged drug can increase dramatically (i.e. partition upwards) across the interface as the drug enters the negatively charged cartilage.
- Dissociation constant, KD
-
Here, the concentration of the drug at which (in equilibrium) half of the binding sites are occupied by the drug. Generally, the lower the value of KD the tighter the binding.
- Binding site density, NT
-
Here, the local density of sites inside a tissue that can bind drug molecules.
- Binding affinity
-
Here, the strength of the binding interaction between a drug and its binding-site partner that bind together reversibly. High affinity means very tight binding.
- Dynamic loading
-
The mechanical loading of joints, which can occur across a wide range of frequencies (loading rates) depending on the type of physical activity. For example, joint loading frequencies can range from <1Hz in slow activities such as walking to 1,000 Hz for high rate activities such as jumping and high impact sports.
- Cationic drug nanocarriers
-
Biological or synthetic nano-particles (with diameters approximately <10 nm) that can be conjugated to small or large molecule drugs to enhance delivery.
- Electrostatic binding
-
Binding due to electrostatic interactions; generally nonspecific and much weaker than strong (for example, covalent) binding.
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Bajpayee, A., Grodzinsky, A. Cartilage-targeting drug delivery: can electrostatic interactions help?. Nat Rev Rheumatol 13, 183–193 (2017). https://doi.org/10.1038/nrrheum.2016.210
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DOI: https://doi.org/10.1038/nrrheum.2016.210
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