Local myocardial insulin-like growth factor 1 (IGF-1) delivery with biotinylated peptide nanofibers improves cell therapy for myocardial infarction

Abstract

Strategies for cardiac repair include injection of cells, but these approaches have been hampered by poor cell engraftment, survival, and differentiation. To address these shortcomings for the purpose of improving cardiac function after injury, we designed self-assembling peptide nanofibers for prolonged delivery of insulin-like growth factor 1 (IGF-1), a cardiomyocyte growth and differentiation factor, to the myocardium, using a ''biotin sandwich'' approach. Biotinylated IGF-1 was complexed with tetravalent streptavidin and then bound to biotinylated self-assembling peptides. This biotin sandwich strategy allowed binding of IGF-1 but did not prevent self-assembly of the peptides into nanofibers within the myocardium. IGF-1 that was bound to peptide nanofibers activated Akt, decreased activation of caspase-3, and increased expression of cardiac troponin I in cardiomyocytes. After injection into rat myocardium, biotinylated nanofibers provided sustained IGF-1 delivery for 28 days, and targeted delivery of IGF-1 in vivo increased activation of Akt in the myocardium. When combined with transplanted cardiomyocytes, IGF-1 delivery by biotinylated nanofibers decreased caspase-3 cleavage by 28% and increased the myocyte cross-sectional area by 25% compared with cells embedded within nanofibers alone or with untethered IGF-1. Finally, cell therapy with IGF-1 delivery by biotinylated nanofibers improved systolic function after experimental myocardial infarction, demonstrating how engineering the local cellular microenvironment can improve cell therapy.engineering ͉ maturation ͉ scaffold

Injectable Acellular Hydrogels for Cardiac Repair

“…In addition to GAG affinities, the natural affinity of streptavidin for biotin has been exploited to sustain the release of IGF-1 from injectable hydrogels [20]. Davis et al biotinylated self-assembling (SA) oligopeptides and IGF-1 to form a streptavidin-biotin complex upon mixing the biotinylated oligopeptides and IGF-1 with tetravalent streptavidin.…”

“…However, these approaches are limited by the invasive procedure in which they are applied, and clinical adoption has not occurred. In order to circumvent the invasive surgical placement of restraining devices early post-MI, our group and others have begun to explore the use of injectable materials, and specifically hydrogels, to limit infarct expansion and normalize the regional stress distribution [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35].…”

Heart regeneration after myocardial infarction using synthetic biomaterials

“…Concerning full synthetic biomaterials, self-assembling peptide RAD16-II has been used to create injectable hydrogels incorporating IGF (approximately 1 ng) in combination with CMC (1x10 6 ) [147] or CPC (1x10 5 ) [148] for cardiac repair. In both studies the administration of cell-seeded-IGF-hydrogels significantly improved the recovery of myocardial structure and function in rats one month after treatment.…”

Microenvironmental regulation of biomacromolecular therapies

“…Bioactive growth-factor-releasing matrices can also be used as a cell transplantation vehicle. For example, keratinocytes and EGF encapsulated into a fibrin matrix stimulated epidermal regeneration in skin wound-healing 90 , and hydrogels containing bone-forming cells, bFGF and BMP2 improved bone regeneration [91][92][93] . A more refined presentation of cell-adhesion cues in the materials using nanoscale and microscale patterning techniques [94][95][96] could provide an even greater level of control and improve the therapeutic efficiency of proteins both when host cells are recruited into the target tissue and when cells are transplanted.…”