Targeted pathological collagen delivery of sustained-release rapamycin to prevent heterotopic ossification
Targeted pathological collagen delivery of sustained-release rapamycin to prevent heterotopic ossification
复制标题
持续释放雷帕霉素的靶向病理胶原递送以防止异位骨化
DOI：
10.1126/sciadv.aay9526
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发表时间：
2020-04-01
期刊：
影响因子：
13.6
通讯作者：
Chen, Xiao
中科院分区：
文献类型：
--
作者：
Chen, Yangwu;Shen, Weiliang;Chen, Xiao
我们揭示了mTOR在肌腱HO中的重要性，并建立了靶向病理性胶原的药物递送系统。肌腱和韧带等结缔组织中的异位骨化（HO）严重破坏组织结构。HO的发病机制尚不清楚，但可能涉及mTOR。这里呈现的结果表明，肌腱干/祖细胞不经历骨软骨分化时，mTOR信号被基因敲除或雷帕霉素（RAPA）治疗失活。同时，将RAPA输送到损伤部位，避免干扰正常肌腱。使用胶原蛋白杂交肽（CHP）修饰聚（乳酸-羟基乙酸）（PLGA）纳米颗粒表面开发的RAPA递送系统，将RAPA特异性靶向病理性肌腱胶原蛋白。CHP-PLGA-RAPA纳米粒具有良好的病理胶原亲和性、缓释性和生物活性。在肌腱HO的小鼠模型中，CHP-PLGA-RAPA纳米颗粒特异性地结合到病理性肌腱并强烈抑制HO进展。mTOR信号通路似乎是肌腱HO的可行治疗靶点，并且CHP-PLGA纳米颗粒可能对肌腱相关疾病的治疗有价值。
We revealed the importance of mTOR in tendon HO and established a drug delivery system that targets pathological collagen. Heterotopic ossification (HO) in connective tissues like tendons and ligaments severely damages tissue structure. The pathogenesis of HO remains unclear but may involve mTOR. The results presented here indicate that tendon stem/progenitor cells do not undergo osteochondrogenic differentiation when mTOR signaling is inactivated by gene knockout or rapamycin (RAPA) treatment. Meanwhile, it is necessary to deliver RAPA to the injured sites and avoid disturbing the normal tendon. A RAPA delivery system, developed using collagen hybrid peptide (CHP) to modify the surface of poly(lactic-co-glycolic acid) (PLGA) nanoparticles, targeted RAPA specifically to pathological tendon collagen. The CHP-PLGA-RAPA nanoparticles showed excellent pathological collagen affinity, sustained-release ability, and bioactivity. In a mouse model of tendon HO, CHP-PLGA-RAPA nanoparticles specifically bound to pathological tendon and strongly suppressed HO progression. The mTOR signaling pathway appears to be a viable therapeutic target for tendon HO, and CHP-PLGA nanoparticles may be valuable for the treatment of tendon-related diseases.