Nanoparticle-enhanced generation of gene-transfected mesenchymal stem cells for in vivo cardiac repair.

Transplantation of gene-transfected bone marrow-derived mesenchymal stem cells (BMMSCs) is a promising strategy for ischemic myocardium repair, but current therapeutic strategy suffers from high toxicity and inefficient gene transfection in primary BMMSCs. Here we designed and synthesized molecularly organic-inorganic hybrid hollow mesoporous organosilica nanoparticles (HMONs) based on nano-synthetic chemistry, which are featured with concurrent large pore size over 20 nm, small particulate size, hollow cavity and high dispersity for gene transfection in BMMSCs and subsequent in vivo cardiac repair. To efficiently create the therapeutic gene-transfected stem-cell lines, hepatocyte growth factor (HGF) gene was applied to transfect BMMSCs via biocompatible surface-engineered HMONs as a high-performance gene-delivery nanosystem. On the rat model of myocardial infarction, transplantation of HGF gene-transfected BMMSCs enables the largely decreased apoptotic cardiomyocytes, reduced infarct scar size, relieved interstitial fibrosis, and increased angiogenesis in myocardium. The resultant cardiac repair further promotes the significant improvement of heart function. Therefore, the fabricated organic-inorganic hybrid HMONs with large pore size represent a generalizable strategy and platform for gene transfection in BMMSCs and further regenerative medicine.

[1]  Zongxi Li,et al.  Engineered design of mesoporous silica nanoparticles to deliver doxorubicin and P-glycoprotein siRNA to overcome drug resistance in a cancer cell line. , 2010, ACS nano.

[2]  Shige Wang,et al.  Hollow mesoporous organosilica nanoparticles: a generic intelligent framework-hybridization approach for biomedicine. , 2014, Journal of the American Chemical Society.

[3]  Min Zhang,et al.  Co-delivery of doxorubicin and Bcl-2 siRNA by mesoporous silica nanoparticles enhances the efficacy of chemotherapy in multidrug-resistant cancer cells. , 2009, Small.

[4]  C. Bordignon.  Stem-cell therapies for blood diseases , 2006, Nature.

[5]  M. Maynadier,et al.  Biodegradable Ethylene‐Bis(Propyl)Disulfide‐Based Periodic Mesoporous Organosilica Nanorods and Nanospheres for Efficient In‐Vitro Drug Delivery , 2014, Advanced materials.

[6]  Lei Zhang,et al.  Mesenchymal stem cells over-expressing SDF-1 promote angiogenesis and improve heart function in experimental myocardial infarction in rats. , 2009, European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery.

[7]  Thomas J. Morgan,et al.  A gold nanoparticle pentapeptide: gene fusion to induce therapeutic gene expression in mesenchymal stem cells. , 2014, Journal of the American Chemical Society.

[8]  Thomas E Sharp,et al.  Bone-Derived Stem Cells Repair the Heart After Myocardial Infarction Through Transdifferentiation and Paracrine Signaling Mechanisms , 2013, Circulation research.

[9]  Richard T. Lee,et al.  Stem-cell therapy for cardiac disease , 2008, Nature.

[10]  Linlin Li,et al.  Facile and Scalable Synthesis of Tailored Silica “Nanorattle” Structures , 2009 .

[11]  Taeghwan Hyeon,et al.  Multifunctional mesoporous silica nanocomposite nanoparticles for theranostic applications. , 2011, Accounts of chemical research.

[12]  S. Arai,et al.  Aqueous colloidal mesoporous nanoparticles with ethenylene-bridged silsesquioxane frameworks. , 2011, Journal of the American Chemical Society.

[13]  W. Walther,et al.  Viral Vectors for Gene Transfer , 2012, Drugs.

[14]  Feng Chen,et al.  Hollow/rattle-type mesoporous nanostructures by a structural difference-based selective etching strategy. , 2010, ACS nano.

[15]  Joseph H. Gorman,et al.  Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition , 2014, Nature materials.

[16]  M. Penn,et al.  Genetic enhancement of stem cell engraftment, survival, and efficacy. , 2008, Circulation research.

[17]  L. Ye,et al.  Nanoparticle based delivery of hypoxia-regulated VEGF transgene system combined with myoblast engraftment for myocardial repair. , 2011, Biomaterials.

[18]  P. Libby,et al.  Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction. , 2000, The Journal of clinical investigation.

[19]  E. Marbán,et al.  Mixed results for bone marrow–derived cell therapy for ischemic heart disease. , 2012, JAMA.

[20]  T. Henry,et al.  Safety of a non-viral plasmid-encoding dual isoforms of hepatocyte growth factor in critical limb ischemia patients: a phase I study , 2011, Gene Therapy.

[21]  Jun Lin,et al.  Functionalized mesoporous silica materials for controlled drug delivery. , 2012, Chemical Society reviews.

[22]  J. Paeng,et al.  Intramyocardial transfer of hepatocyte growth factor as an adjunct to CABG: phase I clinical study , 2012, Gene Therapy.

[23]  T. Doyle,et al.  Hepatocyte Growth Factor or Vascular Endothelial Growth Factor Gene Transfer Maximizes Mesenchymal Stem Cell–Based Myocardial Salvage After Acute Myocardial Infarction , 2009, Circulation.

[24]  Taeghwan Hyeon,et al.  Uniform mesoporous dye-doped silica nanoparticles decorated with multiple magnetite nanocrystals for simultaneous enhanced magnetic resonance imaging, fluorescence imaging, and drug delivery. , 2010, Journal of the American Chemical Society.

[25]  Daniel W. Pack,et al.  Design and development of polymers for gene delivery , 2005, Nature Reviews Drug Discovery.

[26]  Xiao Xu,et al.  The application of cell‐based label‐free technology in drug discovery , 2008, Biotechnology journal.

[27]  Jeffrey M Karp,et al.  Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease. , 2012, Cell stem cell.

[28]  Yongsheng Li,et al.  Colloidal HPMO Nanoparticles: Silica‐Etching Chemistry Tailoring, Topological Transformation, and Nano‐Biomedical Applications , 2013, Advanced materials.

[29]  J. Hare,et al.  Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease. , 2011, Circulation research.

[30]  Benjamin M. Wu,et al.  Delivery of siRNA via cationic Sterosomes to enhance osteogenic differentiation of mesenchymal stem cells. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[31]  Joshua M Hare,et al.  Comparison of allogeneic vs autologous bone marrow–derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. , 2012, JAMA.

[32]  Jongkil Kim,et al.  Effective gene delivery into human stem cells with a cell-targeting Peptide-modified bioreducible polymer. , 2015, Small.

[33]  C. Hodgkinson,et al.  Genetic engineering of mesenchymal stem cells and its application in human disease therapy. , 2010, Human gene therapy.

[34]  Lonnie D Shea,et al.  Design of modular non-viral gene therapy vectors. , 2006, Biomaterials.

[35]  Zongxi Li,et al.  Mesoporous silica nanoparticles in biomedical applications. , 2012, Chemical Society reviews.

[36]  J. Karp,et al.  Mesenchymal stem cells: immune evasive, not immune privileged , 2014, Nature Biotechnology.

[37]  Chuanbin Mao,et al.  Virus-mimetic cytoplasm-cleavable magnetic/silica nanoclusters for enhanced gene delivery to mesenchymal stem cells. , 2013, Angewandte Chemie.

[38]  S. Ajroud‐Driss,et al.  Phase 1/2 open-label dose-escalation study of plasmid DNA expressing two isoforms of hepatocyte growth factor in patients with painful diabetic peripheral neuropathy. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[39]  Jianlin Shi,et al.  In Vivo Bio‐Safety Evaluations and Diagnostic/Therapeutic Applications of Chemically Designed Mesoporous Silica Nanoparticles , 2013, Advanced materials.

[40]  María Vallet-Regí,et al.  Mesoporous materials for drug delivery. , 2007, Angewandte Chemie.