Growth Factor Delivery Systems for the Treatment of Cardiovascular Diseases - Biointerfaces: Where Material Meets Biology - page 90

4.3.2.3 Hepatocyte Growth Factor
This factor induces the production of VEGF and PDGF, endothelial cell
activation and motility and is a chemoattractant agent for pericytes. 109 Also,
it has been demonstrated that, combined with IGF-1, it reduces arrhyth-
mogenesis in chronic heart disease. 110
HGF was encapsulated into the PLGA/PHBV [poly(3-hydroxybutyrate-co-3-
hydroxyvalerate] composite microsphere with a core-shell structure, with
sustained delivery of HGF maintaining its bioactivity for at least 40 days. 111
Ruvinov et al. used sulfated alginate to form electrostatically complexed HGF
bound within alginate matrices. Following in vivo injection into ischemic
myocardial tissue, 75% of the initially loaded HGF was lost from the in-
jection site and subsequent release was slow; after 5 days, only

d n 3 r 4 n g | 4

85% of the
HGF had been released. 112 HGFs have been electrostatically bound to the
collagen but the manufacturing process reduced significantly HGF bioactiv-
ity. 113 A gelatin-based system to deliver HGF was capable of maintaining its
bioactivity, increasing capillary density and enhancing blood flow into a
hindlimb ischemic area in mice. 114 Recently, a clinical trial was open that aims
to evaluate HGF as an early marker of myocardial injury and prognostic factor
in patients with acute coronary syndrome 115 (clinicaltrials.gov-NCT01233336).

B

4.3.3 Other Proteins
Investigating the fundamental molecular mechanisms underlying CM
growth and survival in response to stress allow researchers to identify new
molecules with a potential use in protein therapy for MI.

.

4.3.3.1 Neuregulin-1b
Nrg1b regulates tissue organization during development through endo-
cardial, endothelial, and cardiomyocyte interactions, as well as maintains
cardiac function throughout life. After injury recombinant Nrg-1b improved
cardiac systolic function via alterations in myocardial structure in dogs 21
and primates. 116
Patients with systolic heart failure were treated for 10 days with Nrg-1b and
after 90 days magnetic resonance imaging showed an improvement in cardiac
structure and function at least at one dose studied. The analysis of acute
hemodynamic effects demonstrated that there is a vasodilator effect along with
an acute increase in cardiac output. Besides the nausea experienced by the
treated patients, the dosing program used in these trials is the most important
issuetotuneup. 117 DDS with Nrg-1b would help to avoid the administration of
protein that usually is prolonged (multi-hour), daily and for multiple days.

4.3.3.2 Yes-associated Protein-1
Yap-1 is a known important regulator of cardiomyocyte proliferation and
embryonic heart development. 118 However, recently it has been elucidated