Section: Non-viral gene therapy is a promising approach to treating myocardial ischemia where the supply of oxygen and nutrients are blocked due to blockage in the blood vessels. Vascular Endothelial Growth Factor (VEGF) can trigger new blood vessel formation. Thus, one of the gene therapy strategies for treating myocardial ischemia is to graft mesenchymal stem cells (MSCs) with VEGF transfected in damaged heart tissue not only because the expressed VEGF can induce the formation of new blood vessels to supply the required oxygen and nutrients but also because MSCs can differentiate into heart muscle cells and revive the damaged tissue. Our long-term goal is to integrate biomolecular recognition and nanotechnology to build target-specific non-viral nano-vectors that can deliver VEGF gene to heart for treating myocardial ischemia. The objective of this application is to mimic the structure of phage to assemble target-specific peptides selected by phage display and a VEGF gene-tethered superparamagnetic nanoparticle into a phage-like nanoparticle for VEGF gene delivery. The overall hypotheses of this project are that phage display selected peptides that can target MSCs can be integrated into the VEGF gene-tethered superparamagnetic nanoparticles with cell-specific peptide motif protruding from the surface by a self-assembly process and the resultant multi-functional phage-like nanoparticle will have desired cell-specificity and improved efficiency of VEGF gene transfer into MSCs.
Aim 1 is to select a peptide that can be specifically internalized into MSCs by using phage display technology.
Aim 2 is to integrate cell-targeting peptides into VEGF gene-tethered superparamagnetic nanoparticles to build phage-like nanoparticles with cell-specific peptide motifs protruding from the surface through self-assembly.
Aim 3 is to evaluate the stability, cytotoxicity, cell-specificity and transfection efficiency of the nanoparticles with and without an external magnetic field. Successful completion of this project will enable the development of a new gene therapy strategy for treating diseases that require VEGF expression to induce new blood vessel formation.

Public Health Relevance

Phage-Inspired Nanoparticles with Genetically Tunable Target-Specificity Project Narrative This project mimics how nature assembles proteins and DNA to build a cell-recognizing phage particle to fabricate a gene delivery nanoparticle that can carry and protect therapeutic DNA inside and bear multiple target-recognizing peptide motifs on the surface. Such nanoparticle can be used to deliver therapeutic gene to the desired cells and tissues in non-viral gene therapy. Accomplishment of this project will advance the fields of gene delivery and cancer treatment such as treating diseases that require new blood vessel formation and delivering therapeutic agents to the desired tumor cells and tissues to treat cancers.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL092526-01A2
Application #
7737268
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Danthi, Narasimhan
Project Start
2009-09-30
Project End
2011-08-31
Budget Start
2009-09-30
Budget End
2010-08-31
Support Year
1
Fiscal Year
2009
Total Cost
$401,096
Indirect Cost
Name
University of Oklahoma Norman
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
848348348
City
Norman
State
OK
Country
United States
Zip Code
73019
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Yang, Mingying; Zhou, Guanshan; Castano-Izquierdo, Harold et al. (2015) Biomineralization of Natural Collagenous Nanofibrous Membranes and Their Potential Use in Bone Tissue Engineering. J Biomed Nanotechnol 11:447-56
Polini, Alessandro; Wang, Jianglin; Bai, Hao et al. (2014) Stable biofunctionalization of hydroxyapatite (HA) surfaces by HA-binding/osteogenic modular peptides for inducing osteogenic differentiation of mesenchymal stem cells. Biomater Sci 2:1779-1786
Wang, Jianglin; Yang, Mingying; Zhu, Ye et al. (2014) Phage nanofibers induce vascularized osteogenesis in 3D printed bone scaffolds. Adv Mater 26:4961-4966
Cao, Binrui; Xu, Hong; Mao, Chuanbin (2014) Phage as a template to grow bone mineral nanocrystals. Methods Mol Biol 1108:123-35
Hao, Lijing; Yang, Hui; Du, Chang et al. (2014) Directing the fate of human and mouse mesenchymal stem cells by hydroxyl-methyl mixed self-assembled monolayers with varying wettability. J Mater Chem B 2:4794-4801
Yang, Mingying; Shuai, Yajun; Zhou, Guanshan et al. (2014) Tuning molecular weights of Bombyx mori (B. mori) silk sericin to modify its assembly structures and materials formation. ACS Appl Mater Interfaces 6:13782-9
Li, Xin; Mao, Chuanbin (2014) Using phage as a platform to select cancer cell-targeting peptides. Methods Mol Biol 1108:57-68
Rajala, Ammaji; Wang, Yuhong; Zhu, Ye et al. (2014) Nanoparticle-assisted targeted delivery of eye-specific genes to eyes significantly improves the vision of blind mice in vivo. Nano Lett 14:5257-63
Cao, Binrui; Yang, Mingying; Zhu, Ye et al. (2014) Stem cells loaded with nanoparticles as a drug carrier for in vivo breast cancer therapy. Adv Mater 26:4627-31

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