Development and evaluation of hyaluronic acid-based drug delivery system for promoting articular cartilage repair
Refereed conference paper presented and published in conference proceedings

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AbstractObjective: To design and evaluate a hyaluronic acid-based small molecule delivery system for promoting articular cartilage repair in osteoarthritis (OA) model of mouse.
Methods: Hyaluronic acid (HA), the ligand of CD44 receptor abundantly existing on the surface of articular chondrocytes, is considered as a potential carrier for targeted drug delivery to cartilage tissues. Here, hyaluronic acid-based drug delivery system HA-DFO was synthesized by chemical modification approach to carry deferoxamine (DFO), a small molecule inhibitor of prolyl hydroxylase to stabilize hypoxia inducible factor-1α (HIF-1α) in cells. 1H NMR was performed to evaluate the synthesis of HA-DFO. HA-DFO was added to iron containing solution and Ultra-Visible spectroscopy was performed to determine the ability of HA-DFO to chelate iron. The effects of HA-DFO on proliferation of chondrogenic or chondroprogenitor cells were examined by MTT and colony formation assays. Western blot and real-time PCR were performed to evaluate the effects of HA-DFO on the protein and mRNA levels of HIF-1α in chondrocytes, respectively. Chondrocytes micro mass cultures were performed and the molecular markers of chondrogenic cell proliferation or differentiation were detected by real-time PCR. OA model in mouse was established by surgical dissection of the medial meniscus and anterior cruciate ligament of the knee joint. The knee joints of the model mice were treated with intra-articular cavity injection of different molecules including HA-DFO, DFO, HA, mixture of HA and DFO (HA+DFO), with saline as the control. The pharmacological effects of the above treatments on articular cartilage repair were evaluated by histological examination, immunohistochemistry, OARSI and ICRS II scoring systems.
Results: The 1H NMR spectrum showed that HA-DFO was synthesized successfully with a grafting degree about 15%. The UV spectrum indicated that HA-DFO formed HA-DFO-iron chelate when mixed with iron containing solution. The MTT and colony formation assays indicated that HA-DFO increased proliferation of chondrocytes or chondroprogenitors. Real-time RCR and Western blot analyses revealed that HA-DFO upregulated mRNA and protein levels of HIF-1α in chondrocytes, respectively. In the chondrocyte micromass culture, HA-DFO upregulated the expression of chondrogenic marker genes including Sox5, Sox6, Sox9, Col2α1 and Bapx1. In vivo histological examinations including Safranin O staining, H&E staining and Alcian blue staining indicated that HA-DFO enhanced proteoglycan synthesis and protected the articular cartilage from degeneration more efficiently compared with that of all other treatments. OARSI and ICRS II score analyses indicated that HA-DFO had advantages in inhibiting the deterioration of OA pathology and promoted articular cartilage repair than that of other groups.
Conclusions and Discussion: The newly synthesized HA-DFO reserves the properties of free DFO to chelate iron and activate the HIF-1α pathway in chondrogenic cells, which subsequently enhanced proliferation and differentiation of chondrogenic cells in vitro. In vivo, HA-DFO exhibited advantages to promote articular cartilage repair in the mouse OA model than that of DFO, HA or HA+DFO treatments. The results indicate that HA-DFO may serve as a promising targeted drug delivery system for promoting articular cartilage repair or regeneration in degenerative joint diseases.
All Author(s) ListLin WANG, Fengjie ZHANG, Wing Pui TSANG, Chi WU, Chao WAN
Name of ConferenceThe 12th International Congress on Orthopaedic Advanced Techniques and Clinical Translational Research
Start Date of Conference04/05/2018
End Date of Conference06/05/2018
Place of ConferenceShanghai
Country/Region of ConferenceChina
LanguagesEnglish-United Kingdom

Last updated on 2018-27-11 at 11:33