Sustained release of PTH(1-34) from PLGA microspheres suppresses osteoarthritis progression in rats

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• 作者：Rajalakshmanan Eswaramoorthy^a ; ^b ; Chia-Chi Chang^a ; Shun-Cheng Wu^a ; Gwo-Jaw Wang^a ; ^c ; Je-Ken Chang^a ; ^d ; ¹ ; Mei-Ling Ho^a ; ^e ; ¹ ; ^{homelin@cc.kmu.edu.tw}
• 关键词：Controlled release ; Poly-(lactic-co-glycolic acid) (PLGA) microsphere ; Parathyroid hormone 1&ndash ; 34 ; Osteoarthritis (OA)
• 刊名：Acta Biomaterialia
• 出版年：2012
• 期刊代码：1_17427061
• 类别：ce
• 出版时间：July, 2012
• 卷：8
• 期：6
• 页码：2254-2262
• 文件大小：1335 K

摘要

We previously reported that PTH(1-34) inhibits the terminal differentiation of articular chondrocytes and, in turn, suppresses the progression of osteoarthritis (OA). However, this treatment requires an injection of PTH(1-34) once every 3 days over the treatment period. In this study, we studied the effect of sustained administration of PTH(1-34) in a papain-induced OA rat model. We developed an effective controlled-release system for prolonging the treatment duration of an intra-articular injection for OA treatment in rats. The effects of released PTH(1-34) from PLGA(65:35)-encapsulated PTH(1-34) microspheres (PTH/PLGA) on papain-induced OA in rat knees were studied. Microsphere morphology was observed in vitro by scanning electron microscopy, and microsphere size was determined with a particle size analyzer. The PTH(1-34) encapsulation efficiency and release profile, as well as the toxicity of PTH/PLGA, were examined. The bioactivity of released PTH(1-34) was tested by examining cAMP levels in MC3T3E1 cells. In vivo, we evaluated the changes of localized GAG, Col II, and Col X in the articular cartilage of rat knees. Our results demonstrated that the surface of the PLGA microspheres was smooth, and the size of the microspheres was in the range of 51-127 渭m. PTH/PLGA microspheres sustainably released PTH(1-34) for 19 days with a concentration range of 0.01-100 nM that covered the expected concentration of 10 nM at 37 掳C. The cAMP levels of MC3T3E1 cells were elevated in the response to released PTH(1-34) from PTH/PLGA microspheres, indicating that the released PTH(1-34) is bioactive. Most importantly, intra-articular treatment with either PTH(1-34) (0.1-100 nM) 3 days/injection or PTH/PLGA microspheres (15 days/injection) for 5 weeks revealed the similar effect on suppressing papain-induced OA changes (decreasing GAG and Col II and increasing Col X) in rat knee cartilage. The effect of PTH/PLGA microspheres on suppressing OA progression was similar to that of a once-every-three-day injection of PTH(1-34), indicating that both the sustained and intermittent action of PTH(1-34) effectively suppress OA progression. The developed PLGA microspheres with sustained release and long-term effect may be potent carriers for PTH(1-34) used to treat early OA.