Sustained release of PTH(1-34) from PLGA microspheres suppresses osteoarthritis progression in rats
Sustained release of PTH(1-34) from PLGA microspheres suppresses osteoarthritis progression in rats
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DOI：
10.1016/j.actbio.2012.03.015
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发表时间：
2012-07-01
影响因子：
9.7
通讯作者：
Ho, Mei-Ling
中科院分区：
文献类型：
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作者：
Eswaramoorthy, Rajalakshmanan;Chang, Chia-Chi;Ho, Mei-Ling
我们先前报道甲状旁腺素(1-34)抑制关节软骨细胞的终末分化，进而抑制骨关节炎(OA)的进展。然而，这种治疗需要在治疗期间每3天注射一次甲状旁腺素(1-34)。在本研究中，我们研究了持续给予甲状旁腺素(1-34)对木瓜蛋白酶诱导的骨性关节炎大鼠模型的影响。我们开发了一种有效的控释系统，以延长关节腔内注射治疗OA的大鼠的治疗持续时间。研究了PLGA(65：35)包裹的PTH(1-34)微球(PTH/PLGA)释放的PTH(1-34)对木瓜蛋白酶诱导的大鼠膝关节骨性关节炎的影响。用扫描电子显微镜观察微球的体外形态，用粒度分析仪测定微球的大小。考察了PTH(1-34)的包封率和释药特性，以及PTH/PLGA的毒性。通过检测MC3T3E1细胞内cAMP水平检测释放的甲状旁腺素(1-34)的生物活性。在体内，我们评价了GAG、Col II和Col X在大鼠膝关节软骨中的定位变化。PTH/PLGA微球可持续释放甲状旁腺素(1-34)19天，浓度范围为0.01-100 nm，37℃时释放浓度为10 nM。PTH/PLGA微球释放甲状旁腺素(1-34)后，MC3T3E1细胞内cAMP水平升高，表明释放的甲状旁腺素(1-34)具有生物活性。最重要的是，关节腔内注射PTH(1-34)(0.1-100 NM)3d/次或PTH/PLGA微球(15d/次)注射5周，在抑制木瓜酶诱导的大鼠膝关节软骨OA改变(降低GAG和Col II，增加Col X)方面显示出类似的效果。PTH/PLGA微球对骨性关节炎的抑制作用与甲状旁腺素(1-34)三天一次注射的作用相似，表明甲状旁腺素(134)的持续性和间歇性作用均能有效地抑制骨性关节炎的进展。所研制的PLGA微球具有缓释和长效作用，有望成为PTH(1-34)治疗早期骨性关节炎的有效载体。(C)2012 Acta Materialia Inc.由爱思唯尔有限公司出版。保留所有权利。
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 mu 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 degrees 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(134) 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. (C) 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.