GSK3787-Loaded Poly(Ester Amide) Particles for Intra-Articular Drug Delivery
Ian J Villamagna1,2, Danielle M McRae3, Aneta Borecki3
1School of Biomedical Engineering, The University of Western Ontario, London, ON N6A 5B9, Canada.
Abstract:
Osteoarthritis (OA) is a debilitating joint disorder affecting more than 240 million people. There is no disease modifying therapeutic, and drugs that are used to alleviate OA symptoms result in side effects. Recent research indicates that inhibition of peroxisome proliferator-activated receptor δ (PPARδ) in cartilage may attenuate the development or progression of OA. PPARδ antagonists such as GSK3787 exist, but would benefit from delivery to joints to avoid side effects. Described here is the loading of GSK3787 into poly(ester amide) (PEA) particles. The particles contained 8 wt.% drug and had mean diameters of about 600 nm. Differential scanning calorimetry indicated the drug was in crystalline domains in the particles. Atomic force microscopy was used to measure the Young's moduli of individual particles as 2.8 MPa. In vitro drug release studies showed 11% GSK3787 was released over 30 days. Studies in immature murine articular cartilage (IMAC) cells indicated low toxicity from the drug, empty particles, and drug-loaded particles and that the particles were not taken up by the cells. Ex vivo studies on murine joints showed that the particles could be injected into the joint space and resided there for at least 7 days. Overall, these results indicate that GSK3787-loaded PEA particles warrant further investigation as a delivery system for potential OA therapy.
Insights
New poly(ester amide) particles loaded with GSK3787 show potential for osteoarthritis therapy. These particles deliver the drug to joints, offering a promising approach to manage osteoarthritis progression with low toxicity.
Area of Science:
- Biomaterials Science
- Pharmacology
- Orthopedics
Background:
- Osteoarthritis (OA) affects over 240 million people globally, with no current disease-modifying treatments.
- Existing OA symptom treatments have side effects, necessitating novel therapeutic strategies.
- Inhibiting peroxisome proliferator-activated receptor delta (PPARδ) in cartilage shows potential for attenuating OA development.
Purpose of the Study:
- To develop and characterize poly(ester amide) (PEA) particles for targeted intra-articular delivery of the PPARδ antagonist GSK3787.
- To evaluate the safety, drug release kinetics, and in vivo joint retention of GSK3787-loaded PEA particles.
Main Methods:
- GSK3787 was loaded into PEA particles (8 wt.% drug, ~600 nm diameter).
- Particle characterization included differential scanning calorimetry and atomic force microscopy (Young's modulus: 2.8 MPa).
- In vitro drug release, cytotoxicity assays (IMAC cells), and ex vivo murine joint injection studies were performed.
Main Results:
- GSK3787 was present in crystalline domains within the PEA particles.
- In vitro studies showed slow drug release (11% over 30 days) and low toxicity to cartilage cells.
- Ex vivo studies demonstrated successful intra-articular injection and retention in murine joints for at least 7 days.
Conclusions:
- GSK3787-loaded PEA particles are a viable system for intra-articular drug delivery.
- The developed particles exhibit low toxicity and sustained drug release, suggesting potential for OA therapy.
- Further investigation of these particles as a targeted OA treatment is warranted.
