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Hyaluronan derived nanoparticle for simvastatin delivery: evaluation of simvastatin induced myotoxicity in tissue engineered skeletal muscle

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Abstract

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 μM), 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 μM 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.

Graphical abstract: Hyaluronan derived nanoparticle for simvastatin delivery: evaluation of simvastatin induced myotoxicity in tissue engineered skeletal muscle

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Publication details

The article was received on 25 Jun 2019, accepted on 31 Oct 2019 and first published on 01 Nov 2019


Article type: Paper
DOI: 10.1039/C9BM00986H
Biomater. Sci., 2019, Advance Article
  • Open access: Creative Commons BY-NC license
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    Hyaluronan derived nanoparticle for simvastatin delivery: evaluation of simvastatin induced myotoxicity in tissue engineered skeletal muscle

    J. M. Jones, D. J. Player, S. Samanta, V. K. Rangasami, J. Hilborn, M. P. Lewis, O. P. Oommen and V. Mudera, Biomater. Sci., 2019, Advance Article , DOI: 10.1039/C9BM00986H

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