Hyaluronan derived nanoparticle for simvastatin delivery: evaluation of simvastatin induced myotoxicity in tissue engineered skeletal muscle
Hyaluronan derived nanoparticle for simvastatin delivery: evaluation of simvastatin induced myotoxicity in tissue engineered skeletal muscle
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DOI：
10.1039/c9bm00986h
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发表时间：
2020-01-01
影响因子：
6.6
通讯作者：
Mudera, Vivek
中科院分区：
文献类型：
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作者：
Jones, Julia M.;Player, Darren J.;Mudera, Vivek
他汀类药物是目前世界上最常用的降高胆固醇药物，估计使用量接近六分之一的人口。然而，已知他汀类药物在1.5%至10%的患者中引起多效性骨骼肌病，并且他汀类药物诱导这种反应的机制尚未完全了解。在这项研究中，一种基于胶原蛋白的3D组织工程化骨骼肌构建体被用作筛选平台，以测试一种新的递送系统的功效和毒性。设计了一种载辛伐他汀的透明质酸衍生纳米粒（HA-SIM-NPs），并研究了游离辛伐他汀和HA-SIM-NPs对细胞、分子和组织反应的影响。在最高浓度（333.33 μ M）下，肌管的形态学消融和从头肌管形成（再生）的缺乏是明显的，与递送载体（SIM或HA-SIM-NP）无关。在游离药物条件下（SIM，3.33 μ M和33.33 nM），细胞骨架的剂量依赖性破坏、代谢活性的降低和组织工程化（TE）构建体的组织松弛是明显的。然而，当SIM通过HA-SIM-NP递送时，这些变化中的大多数得到改善。值得注意的是，与SIM相比，HA-SIM-NP中MMP 2、MMP 9和肌生成素的均匀表达概述了增强的再生反应。总之，这些结果概述了经由HA-SIM-NP的他汀类药物递送作为抑制有害的肌毒性副作用的有效递送机制。
Statins are currently the most prescribed hypercholesterolemia-lowering drugs worldwide, with estimated usage approaching one-sixth of the population. However, statins are known to cause pleiotropic skeletal myopathies in 1.5% to 10% of patients and the mechanisms by which statins induce this response, are not fully understood. In this study, a 3D collagen-based tissue-engineered skeletal muscle construct is utilised as a screening platform to test the efficacy and toxicity of a new delivery system. A hyaluronic acid derived nanoparticle loaded with simvastatin (HA-SIM-NPs) is designed and the effect of free simvastatin and HA-SIM-NPs on cellular, molecular and tissue response is investigated. Morphological ablation of myotubes and lack of de novo myotube formation (regeneration) was evident at the highest concentrations (333.33 mu M), independent of delivery vehicle (SIM or HA-SIM-NP). A dose-dependent disruption of the cytoskeleton, reductions in metabolic activity and tissue engineered (TE) construct tissue relaxation was evident in the free drug condition (SIM, 3.33 mu M and 33.33 nM). However, most of these changes were ameliorated when SIM was delivered via HA-SIM-NPs. Significantly, homogeneous expressions of MMP2, MMP9, and myogenin in HA-SIM-NPs outlined enhanced regenerative responses compared to SIM. Together, these results outline statin delivery via HA-SIM-NP as an effective delivery mechanism to inhibit deleterious myotoxic side-effects.