Original ArticleProlonged vasodilatory response to nanoencapsulated sildenafil in pulmonary hypertension
Graphical Abstract
Nanoencapsulation of sildenafil resulted in a prolonged vasodilatory effect in an animal model of pulmonary hypertension. The current approach represents a promising novel strategy to improve the inhalative therapy of this life-threatening disease.
Section snippets
Materials
The thromboxane A2 mimetic U46619 was supplied by Sigma-Aldrich (Steinheim, Germany). Sildenafil (free base) was obtained from bioKEMIX (Nienburg, Germany). Poly(lactide-co-glycolide) (PLGA), Resomer® RG502H was acquired from Boehringer Ingelheim (Ingelheim, Germany). Poly(vinyl sulfonate-co-vinyl alcohol)-graft-poly(lactide-co-glycolide) (P(VS-VA)-g-PLGA) was synthesized and characterized as described previously.27 All other chemicals and solvents were of analytical grade.
Preparation and characterization of sildenafil-loaded polymeric nanomedicines
Submicron particles
Results
After a stable steady state period of 20-30 min a continuous infusion of U46619 (1.2 ± 0.5 μg/kg · min) induced significant PH. When averaging all groups (n = 34), the PAP increased from 16.6 ± 0.3 at baseline to 24.6 ± 0.2 mmHg within 15-20 min (P < 0.001). Likewise, the PVRI escalated from 275 ± 3431 to 726 ± 26 dyne · s · m2/cm5. On the contrary, the SAP remained unchanged (108.3 ± 0.7 vs. 110.3 ± 1.0 mmHg (P = 0.100)). No substantial alterations in blood gases were observed as compared to baseline values (data not shown).
Discussion
PH patients manifest a significant mismatch of vasodilators and vasoconstrictors which leads to excessive pulmonary vasoconstriction.3, 4 Orally administered phosphodiesterase-5 inhibitors (e.g. sildenafil or tadalafil) resulted in significant pulmonary vasodilation and favorable effects on exercise capacity, however, this non-selective way of drug administration sparked side effects due to systemic drug availability.5, 10, 11, 12
On the contrary, inhalative therapy enables targeted drug
Acknowledgments
The authors are deeply saddened by the recent passing of Dr. Thomas Schmehl. He was our esteemed colleague and renowned researcher. His contributions to the field of pulmonary hypertension are invaluable.
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Cited by (0)
Sources of support for research: This study was supported by a grant from the “Universitätsklinikum Giessen und Marburg” (1/2012 GI). The funding source had no involvement in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.
Conflict of interest: The authors declare that there are no conflicts of interest.
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Deceased.