Original Article
Prolonged vasodilatory response to nanoencapsulated sildenafil in pulmonary hypertension

https://doi.org/10.1016/j.nano.2015.08.009Get rights and content

Abstract

Direct vasodilator delivery to the airways enables a selective therapy of pulmonary hypertension (PH). However, short-term effects of the applied medication require multiple daily inhalations. Controlled release formulations (polymeric nanomedicines) offer the potential of prolonging drug effects within the respiratory tract, thereby reducing the number of necessary inhalations. In the model of U46619-elicited PH, sildenafil and two sildenafil-loaded polymeric submicron particle formulations were evaluated for their pharmacodynamic and pharmacokinetic characteristics and acute tolerability. Lung-delivered sildenafil caused a selective dose-dependent decline of the pulmonary arterial pressure and vascular resistance. Compared to the transient pharmacodynamic effect observed for sildenafil, the same dose of nanoencapsulated sildenafil resulted in prolongation, but not augmentation, of the pulmonary vasodilatation. An extended pharmacokinetic profile was observed for nanoencapsulated sildenafil, and nanomedicines revealed no acute toxicity. The amplification of pulmonary vasodilatory response caused by nanoencapsulation of sildenafil offers an intriguing approach to ameliorate the therapy of PH.

From the Clinical Editor

Pulmonary hypertension usually results in right heart failure long term. Current medical therapy includes the use of potent vasodilators such as sildenafil. In this article, the authors investigated the use of nanoencapsulated formulation for sustained delivery via inhalation route. An extended pharmacokinetic profile was seen for this nanoformulation with little side effects. It is hoped that clinical application of this would come to fruition soon.

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.

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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.

    Deceased.

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