E. Although ventricular surgical procedures are widely practised, their clinical outcome remains unsatisfactory due to the limited regenerative ability of the matured heart [2]. The placement of an anti-fibrotic-eluting cardiac patch to prevent fibrotic scar development is a promising strategy to reverse LV remodelling. The current work presents the development of polymeric matrix that provides sustained release of CD-NP. Sustained release of CD-NP from three different initial release profiles of high, mediumand low up to 30 days was attained. Additionally, the bioactivity of released cenderitide was verified through the inhibition of HCF proliferation studies and the elevation of intracellular cGMP in HCF. Finally, the performance of CD-NP released from polymer films were compared to daily dose CD-NP in their inhibition of hypertrophic and hyperplasia HCF. Our results seemed to indicate that continuous delivery may be necessary for optimal inhibition of hypertrophic HCF. CD-NP is a relatively new therapeutic entity; the therapeutic window has not been fully established. From the literature, the CD-NP infusion range between 0.1?0 ng/kg/minute (for 1? days) and 10?0 ng/kg/day (for 5?0 days) via intravenous and subcutaneous infusions were reported to be effective; however there is no literature on an ideal therapeutic profile [20]. Hence when developing the films, we explored different release profiles while keeping in mind the MedChemExpress BTZ-043 effective concentrations reported. This led us to select 3 distinctly different initial release profiles. All three films achieved sustained CD-NP release for up to 30 days with two phase release profiles. We believe that the first phase release isCenderitide-Eluting 1315463 FilmFigure 6. Correlation between relative cell index (RCI) and CD-NP concentration. Correlation between RCI (primary y-axis) and peptide concentration (secondary y-axis) of (a) Daily infusion of CD-NP, (b) film 1, (c) film 2 and (d) film 3 over 5 days (x-axis). doi:10.1371/journal.pone.0068346.gattributed to the immediate dissolution of CD-NP found near or at the surface of the film. As we observed no significant film degradation from our degradation study, we believe that subsequent release over 30 days was due to diffusion controlled release of hydrophilic CD-NP diffusing out of hydrophobic polymer matrix. The slow degrading characteristics of PCL [31,32]and the diffusion release from PCL [33] had been reported in literature respectively. All films displayed sustained release over time in the range of 12?4 mg/mL (for 0? hours) and 1? mg/mL (for 1?0 days). Daily subcutaneous infusion of CD-NP at 10?30 ng/kg/day over period of 5 to 30 days had Indolactam V biological activity successful elevation of plasma and urine cGMP whilst improving cardiac load and minimizing arterial pressure [20]. Our film (1 cm 6 1 cm 6 0.004 cm) was able to achieve release of 1? ng/kg/day (between 1 to 30 days), suggesting that it could potentially be developed into cardiac patches, which are likely to be larger in volume for treatment purpose. Polymeric PCL was chosen as material for film development because it is biocompatibility, elastic mechanical properties and predictable biodegradability [31,32]. As a cardiac patch or ventricular restrain device, the slow degrading nature of PCL is advantageous because the temporal presence of it post MI could act as mechanical support preventing recurrent LV remodelling, whilst its eventual degradation precludes potential complications associated with non-degradable.E. Although ventricular surgical procedures are widely practised, their clinical outcome remains unsatisfactory due to the limited regenerative ability of the matured heart [2]. The placement of an anti-fibrotic-eluting cardiac patch to prevent fibrotic scar development is a promising strategy to reverse LV remodelling. The current work presents the development of polymeric matrix that provides sustained release of CD-NP. Sustained release of CD-NP from three different initial release profiles of high, mediumand low up to 30 days was attained. Additionally, the bioactivity of released cenderitide was verified through the inhibition of HCF proliferation studies and the elevation of intracellular cGMP in HCF. Finally, the performance of CD-NP released from polymer films were compared to daily dose CD-NP in their inhibition of hypertrophic and hyperplasia HCF. Our results seemed to indicate that continuous delivery may be necessary for optimal inhibition of hypertrophic HCF. CD-NP is a relatively new therapeutic entity; the therapeutic window has not been fully established. From the literature, the CD-NP infusion range between 0.1?0 ng/kg/minute (for 1? days) and 10?0 ng/kg/day (for 5?0 days) via intravenous and subcutaneous infusions were reported to be effective; however there is no literature on an ideal therapeutic profile [20]. Hence when developing the films, we explored different release profiles while keeping in mind the effective concentrations reported. This led us to select 3 distinctly different initial release profiles. All three films achieved sustained CD-NP release for up to 30 days with two phase release profiles. We believe that the first phase release isCenderitide-Eluting 1315463 FilmFigure 6. Correlation between relative cell index (RCI) and CD-NP concentration. Correlation between RCI (primary y-axis) and peptide concentration (secondary y-axis) of (a) Daily infusion of CD-NP, (b) film 1, (c) film 2 and (d) film 3 over 5 days (x-axis). doi:10.1371/journal.pone.0068346.gattributed to the immediate dissolution of CD-NP found near or at the surface of the film. As we observed no significant film degradation from our degradation study, we believe that subsequent release over 30 days was due to diffusion controlled release of hydrophilic CD-NP diffusing out of hydrophobic polymer matrix. The slow degrading characteristics of PCL [31,32]and the diffusion release from PCL [33] had been reported in literature respectively. All films displayed sustained release over time in the range of 12?4 mg/mL (for 0? hours) and 1? mg/mL (for 1?0 days). Daily subcutaneous infusion of CD-NP at 10?30 ng/kg/day over period of 5 to 30 days had successful elevation of plasma and urine cGMP whilst improving cardiac load and minimizing arterial pressure [20]. Our film (1 cm 6 1 cm 6 0.004 cm) was able to achieve release of 1? ng/kg/day (between 1 to 30 days), suggesting that it could potentially be developed into cardiac patches, which are likely to be larger in volume for treatment purpose. Polymeric PCL was chosen as material for film development because it is biocompatibility, elastic mechanical properties and predictable biodegradability [31,32]. As a cardiac patch or ventricular restrain device, the slow degrading nature of PCL is advantageous because the temporal presence of it post MI could act as mechanical support preventing recurrent LV remodelling, whilst its eventual degradation precludes potential complications associated with non-degradable.
