A delivery system specifically approaching bone resorption surfaces to facilitate therapeutic modulation of microRNAs in osteoclasts
A delivery system specifically approaching bone resorption surfaces to facilitate therapeutic modulation of microRNAs in osteoclasts
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一种专门接近骨吸收表面的递送系统，以促进破骨细胞中 microRNA 的治疗调节
DOI：
10.1016/j.biomaterials.2015.02.007
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发表时间：
2015-06-01
期刊：
影响因子：
14
通讯作者：
Zhang, Ge
中科院分区：
文献类型：
--
作者：
Liu, Jin;Dang, Lei;Zhang, Ge
破骨细胞中microRNA的异常表达可导致多种骨骼疾病。这些致病性microRNA的治疗操作需要新的、有效的递送系统，以促进以最小脱靶效应靶向破骨细胞的microRNA调节剂。以高度结晶的羟基磷灰石为特征的骨吸收表面主要被破骨细胞占据。考虑到天冬氨酸的八个重复序列（D-Asp（8））可以优选地与高度结晶的羟基磷灰石结合，我们通过将D-Asp肽与脂质体缀合来开发靶向系统，用于将microRNA调节剂特异性地递送到骨吸收表面，并随后包封Escheromir-148 a（抑制破骨细胞生成miR-148 a的microRNA调节剂），即（D-Asp（8））-脂质体-miR-148 a。我们的研究结果表明，D-Asp（8）可以促进体内破骨细胞中miR-148 a的富集和随后的miR-148 a下调，从而减少骨吸收和减轻骨小梁结构的恶化。从机制上讲，破骨细胞靶向递送取决于骨吸收表面与D-Asp之间的相互作用（8）。单次/多次给药（D-Asp（8））-脂质体-阿司多莫-148 a后，在小鼠中未发现可检测到的肝脏和肾脏毒性。这些结果表明，（D-Asp（8））-脂质体作为一种很有前途的破骨细胞靶向给药系统，可以促进microRNA调节剂在破骨细胞功能障碍性骨骼疾病治疗中的临床应用。(C)2015爱思唯尔有限公司版权所有。
Dysregulated microRNAs in osteoclasts could cause many skeletal diseases. The therapeutic manipulation of these pathogenic microRNAs necessitates novel, efficient delivery systems to facilitate microRNAs modulators targeting osteoclasts with minimal off-target effects. Bone resorption surfaces characterized by highly crystallized hydroxyapatite are dominantly occupied by osteoclasts. Considering that the eight repeating sequences of aspartate (D-Asp(8)) could preferably bind to highly crystallized hydroxyapatite, we developed a targeting system by conjugating D-Asps peptide with liposome for delivering microRNA modulators specifically to bone resorption surfaces and subsequently encapsulated antagomir-148a (a microRNA modulator suppressing the osteoclastogenic miR-148a), i.e. (D-Asp(8))-liposome-antagomir-148a. Our results demonstrated that D-Asp(8) could facilitate the enrichment of antagomir-148a and the subsequent down-regulation of miR-148a in osteoclasts in vivo, resulting in reduced bone resorption and attenuated deterioration of trabecular architecture in osteoporotic mice. Mechanistically, the osteoclast-targeted delivery depended on the interaction between bone resorption surfaces and D-Asp(8). No detectable liver and kidney toxicity was found in mice after single/multiple dose(s) treatment of (D-Asp(8))-liposome-antagomir-148a. These results indicated that (D-Asp(8))-liposome as a promising osteoclast-targeting delivery system could facilitate clinical translation of microRNA modulators in treating those osteoclast-dysfunction-induced skeletal diseases. (C) 2015 Elsevier Ltd. All rights reserved.