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Cartilage-targeting drug delivery: can electrostatic interactions help?

Nature Reviews Rheumatology volume 13, pages 183193 (2017) | Download Citation


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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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.

Author information


  1. Department of Bioengineering, Northeastern University, 360 Huntington Avenue, Boston, Massachusetts 02115, USA.

    • Ambika G. Bajpayee
  2. Departments of Biological Engineering, Mechanical Engineering, and Electrical Engineering and Computer Science, Massachusetts Institute of Technology, 77 Massachusetts Ave, Cambridge, Massachusetts 02139, USA.

    • Alan J. Grodzinsky


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Both authors researched data for the article, provided substantial contributions to discussion of its content, wrote the article and undertook review and/or editing of the manuscript before submission.

Competing interests

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'.

Corresponding author

Correspondence to Alan J. Grodzinsky.


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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