That’s the spot! A precision drug delivery for improving tendon healing
A recent study has leveraged nanoparticle drug delivery to directly administer treatment to the site of injured tendons.
Researchers from the University of Rochester (NY, USA) and University of Oregon (OR, USA) have collaborated on a recent study combining their expertise in tendon cell biology and drug delivery systems to investigate a promising new approach to improve tendon healing. By reducing scar tissue formation using a targeted nanoparticle-based drug delivery system approach, this innovation aims to enhance regenerative, rather than fibrous, healing that naturally occurs in injured tendons.
Tendons are complex in nature; the recovery process for tendon injuries, which can take a long time to heal, can be disruptive to daily life and regaining near-native movement can take even longer. Surgical procedures are usually performed to treat minor tendon injuries and with just over 300,000 tendon repair surgeries performed annually, there is a critical need for more effective treatment strategies.
Current drug delivery methods often fail to sufficiently reach the injured tendon, with less than 1% of systemically administered medications typically reaching the target area. Local administration, while more direct, poses risks of tissue damage and lacks precise control over drug concentrations at the injury site, as noted by co-author Alayna Loiselle (University of Rochester).
For the past several years, Loiselle and her team have focused on advancing therapeutic strategies beyond systemic and local drug delivery, exploring alternative pharmacological approaches. They utilized findings from their previous study, where they had performed spatial transcriptomic profiling to define the molecular map of a healing tendon and discovered something momentous: high levels of Acp5 gene expression at the site of a healing tendon.
The ACP5 gene encodes a protein usually associated with bone-remodeling osteoclasts known as tartrate resistant acid phosphate (TRAP). Due to the high levels of TRAP, the researchers were able to harness this activity to directly deliver medication to the site of injury. They employed a subnanomolar peptide, TRAP binding peptide (TBP) that has a high affinity for TRAP. By incorporating TBP with a nanoparticle (NP) delivery system, called the PSMA-b-PS NP delivery system, the team hypothesized they had developed a TBP-NP system that would be ideal for efficiently targeting the injured site of the tendon.
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With a system for targeting the injured tendon site designed, the team needed to select a therapeutic molecule to address scar formation. In another previous study, the team had demonstrated that inhibiting S100a4 – a gene that produces a protein involved in the formation of fibrosis in tissues – improved fibrotic tendon healing in mouse models. This lead them to select a transcriptional inhibitor of S100a4: niclosamide ethonolamine salt, also termed niclosamide.
As S100a4 is involved in many tissues such as the liver, heart and lungs, the team ran additional tests to compare the difference in performance between loading niclosamide into their TBP-NP system for administration and systemic administration of the therapeutic. The team found that by encapsulating niclosamide into their nanoparticle delivery system, they achieved enhanced solubility and efficacy, resulting in reduced S100a4 levels and improved tendon healing.
This approach not only enhanced healing but also improved range of motion recovery and mechanical integrity of tendons over both short- and long-term periods in a single treatment in the mouse model.
“The beauty of this system is that it can be loaded with different kinds of drugs to target different molecular processes or pathways,” remarked Emmanuela Adjei-Sowah (University of Rochester).
Looking ahead, the researchers plan to explore broader applications of their system beyond tendon injuries, potentially treating other types of tissue injuries characterized by scar formation. Their findings represent a significant advancement in targeted drug delivery for improving tissue regeneration, offering promising prospects for clinical translation.
