Mitochondria-targeted cyclosporin A delivery system to treat myocardial ischemia reperfusion injury of rats

BackgroundCyclosporin A (CsA) is a promising therapeutic drug for myocardial ischemia reperfusion injury (MI/RI) because of its definite inhibition to the opening of mitochondrial permeability transition pore (mPTP). However, the application of cyclosporin A to treat MI/RI is limited due to its immunosuppressive effect to other normal organ and tissues. SS31 represents a novel mitochondria-targeted peptide which can guide drug to accumulate into mitochondria. In this paper, mitochondria-targeted nanoparticles (CsA@PLGA-PEG-SS31) were prepared to precisely deliver cyclosporin A into mitochondria of ischemic cardiomyocytes to treat MI/RI.ResultsCsA@PLGA-PEG-SS31 was prepared by nanoprecipitation. CsA@PLGA-PEG-SS31 showed small particle size (~ 50 nm) and positive charge due to the modification of SS31 on the surface of nanoparticles. CsA@PLGA-PEG-SS31 was stable for more than 30 days and displayed a biphasic drug release pattern. The in vitro results showed that the intracellular uptake of CsA@PLGA-PEG-SS31 was significantly enhanced in hypoxia reoxygenation (H/R) injured H9c2 cells. CsA@PLGA-PEG-SS31 delivered CsA into mitochondria of H/R injured H9c2 cells and subsequently increased the viability of H/R injured H9c2 cell through inhibiting the opening of mPTP and production of reactive oxygen species. In vivo results showed that CsA@PLGA-PEG-SS31 accumulated in ischemic myocardium of MI/RI rat heart. Apoptosis of cardiomyocyte was alleviated in MI/RI rats treated with CsA@PLGA-PEG-SS31, which resulted in the myocardial salvage and improvement of cardiac function. Besides, CsA@PLGA-PEG-SS31 protected myocardium from damage by reducing the recruitment of inflammatory cells and maintaining the integrity of mitochondrial function in MI/RI rats.ConclusionCsA@PLGA-PEG-SS31 exhibited significant cardioprotective effects against MI/RI in rats hearts through protecting mitochondrial integrity, decreasing apoptosis of cardiomyocytes and myocardial infract area. Thus, CsA@PLGA-PEG-SS31 offered a promising therapeutic method for patients with acute myocardial infarction.

[1]  B. He,et al.  YiXin-Shu, a ShengMai-San-based traditional Chinese medicine formula, attenuates myocardial ischemia/reperfusion injury by suppressing mitochondrial mediated apoptosis and upregulating liver-X-receptor α , 2016, Scientific Reports.

[2]  A. Halestrap,et al.  Inhibition of Ca2(+)-induced large-amplitude swelling of liver and heart mitochondria by cyclosporin is probably caused by the inhibitor binding to mitochondrial-matrix peptidyl-prolyl cis-trans isomerase and preventing it interacting with the adenine nucleotide translocase. , 1990, The Biochemical journal.

[3]  Jarno Salonen,et al.  In vitro and in vivo assessment of heart-homing porous silicon nanoparticles. , 2016, Biomaterials.

[4]  N. Mewton,et al.  Cyclosporine Protects the Heart during Aortic Valve Surgery , 2014, Anesthesiology.

[5]  N. Mewton,et al.  Cyclosporine before PCI in Patients with Acute Myocardial Infarction. , 2015, The New England journal of medicine.

[6]  Pierre Croisille,et al.  Effect of cyclosporine on reperfusion injury in acute myocardial infarction. , 2008, The New England journal of medicine.

[7]  H. Bøtker,et al.  Targeting reperfusion injury in patients with ST-segment elevation myocardial infarction: trials and tribulations , 2016, European heart journal.

[8]  H. Hayashi,et al.  Transient opening of mitochondrial permeability transition pore by reactive oxygen species protects myocardium from ischemia-reperfusion injury. , 2009, American journal of physiology. Heart and circulatory physiology.

[9]  Sandeep Kumar,et al.  Hybrid poly(lactic-co-glycolic acid) nanoparticles: design and delivery prospectives. , 2015, Drug discovery today.

[10]  L. Horwitz,et al.  Time course of coronary endothelial healing after injury due to ischemia and reperfusion. , 1994, Circulation.

[11]  Laura M Ensign,et al.  PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. , 2016, Advanced drug delivery reviews.

[12]  Tal Dvir,et al.  Nanoparticles targeting the infarcted heart. , 2011, Nano letters.

[13]  X. Zou,et al.  Triptolide induces apoptotic cell death of human cholangiocarcinoma cells through inhibition of myeloid cell leukemia-1 , 2014, BMC Cancer.

[14]  P. Évora,et al.  Ischemia/Reperfusion Injury Revisited: An Overview of the Latest Pharmacological Strategies , 2019, International journal of molecular sciences.

[15]  Christopher E. Nelson,et al.  Ex vivo red blood cell hemolysis assay for the evaluation of pH-responsive endosomolytic agents for cytosolic delivery of biomacromolecular drugs. , 2013, Journal of visualized experiments : JoVE.

[16]  M. Ghosh,et al.  The interrelationship between cerebral ischemic stroke and glioma: a comprehensive study of recent reports , 2019, Signal Transduction and Targeted Therapy.

[17]  中川 崇.  Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. , 2005 .

[18]  Jeffrey Robbins,et al.  Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death , 2005, Nature.

[19]  Mauro Ferrari,et al.  The physiology of cardiovascular disease and innovative liposomal platforms for therapy , 2013, International journal of nanomedicine.

[20]  Nicholas A Peppas,et al.  Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. , 2006, International journal of pharmaceutics.

[21]  A. Halestrap,et al.  Further evidence that cyclosporin A protects mitochondria from calcium overload by inhibiting a matrix peptidyl-prolyl cis-trans isomerase. Implications for the immunosuppressive and toxic effects of cyclosporin. , 1991, The Biochemical journal.

[22]  Richard T. Lee,et al.  Custom Design of the Cardiac Microenvironment With Biomaterials , 2005, Circulation research.

[23]  Xiaowei Niu,et al.  Weighted Gene Co-Expression Network Analysis Identifies Critical Genes in the Development of Heart Failure After Acute Myocardial Infarction , 2019, Front. Genet..

[24]  A. Qian,et al.  The Development of Functional Non-Viral Vectors for Gene Delivery , 2019, International journal of molecular sciences.

[25]  M. Crompton,et al.  Inhibition by cyclosporin A of a Ca2+-dependent pore in heart mitochondria activated by inorganic phosphate and oxidative stress. , 1988, The Biochemical journal.

[26]  D. Yellon,et al.  Ischaemic conditioning and reperfusion injury , 2016, Nature Reviews Cardiology.

[27]  L. B. Chen,et al.  Mitochondrial membrane potential monitored by JC-1 dye. , 1995, Methods in enzymology.

[28]  Kok-Gan Chan,et al.  Efficacy and Safety of Cyclosporine in Acute Myocardial Infarction: A Systematic Review and Meta-Analysis , 2018, Front. Pharmacol..

[29]  P. Oliveira,et al.  Pharmacological Targeting of the Mitochondrial Permeability Transition Pore for Cardioprotection , 2018 .

[30]  H. Szeto.  First‐in‐class cardiolipin‐protective compound as a therapeutic agent to restore mitochondrial bioenergetics , 2014, British journal of pharmacology.

[31]  H. Szeto.  Cell-permeable, mitochondrial-targeted, peptide antioxidants , 2006, The AAPS Journal.

[32]  Tetsuya Watanabe,et al.  Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death , 2005, Nature.

[33]  R. Guyton,et al.  Inhibition of myocardial apoptosis reduces infarct size and improves regional contractile dysfunction during reperfusion. , 2003, Cardiovascular research.

[34]  R. Kloner,et al.  An update on cardioprotection: a review of the latest adjunctive therapies to limit myocardial infarction size in clinical trials. , 2012, Journal of the American College of Cardiology.

[35]  S. Jha,et al.  Hydrogen Sulfide Mediates Cardioprotection Through Nrf2 Signaling , 2009, Circulation research.

[36]  P. Gillet,et al.  PLGA-Based Nanoparticles: a Safe and Suitable Delivery Platform for Osteoarticular Pathologies , 2015, Pharmaceutical Research.

[37]  N. Mewton,et al.  Cyclosporine A, a Potential Therapy of Ischemic Reperfusion Injury. A Common History for Heart and Brain , 2016, Cerebrovascular Diseases.

[38]  Jingkun Yan,et al.  Self-aggregated nanoparticles of carboxylic curdlan-deoxycholic acid conjugates as a carrier of doxorubicin. , 2015, International journal of biological macromolecules.

[39]  S. Javadov,et al.  Mitochondrial permeability transition in cardiac ischemia–reperfusion: whether cyclophilin D is a viable target for cardioprotection? , 2017, Cellular and Molecular Life Sciences.

[40]  R. Soares,et al.  Studies on the hemocompatibility of bacterial cellulose. , 2011, Journal of Biomedical Materials Research. Part A.

[41]  Jose H. Flores-Arredondo,et al.  A specifically designed nanoconstruct associates, internalizes, traffics in cardiovascular cells, and accumulates in failing myocardium: a new strategy for heart failure diagnostics and therapeutics , 2016, European journal of heart failure.

[42]  J. Gorman,et al.  Reduction of Ischemia/Reperfusion Injury With Bendavia, a Mitochondria-Targeting Cytoprotective Peptide , 2012, Journal of the American Heart Association.

[43]  Y. Korchev,et al.  Functional interaction between charged nanoparticles and cardiac tissue: a new paradigm for cardiac arrhythmia? , 2013, Nanomedicine.

[44]  Wenjian Yang,et al.  SS31 Ameliorates Sepsis-Induced Heart Injury by Inhibiting Oxidative Stress and Inflammation , 2019, Inflammation.

[45]  Mónica P. A. Ferreira,et al.  Drug-Loaded Multifunctional Nanoparticles Targeted to the Endocardial Layer of the Injured Heart Modulate Hypertrophic Signaling. , 2017, Small.