Pre-clinical assessment of a water-in-fluorocarbon emulsion for the treatment of pulmonary vascular diseases

Abstract

Hypoxic pulmonary vasoconstriction (HPV) is a well-characterized vascular response to low oxygen pressures and is involved in life-threatening conditions such as high-altitude pulmonary edema (HAPE) and pulmonary arterial hypertension (PAH). While the efficacy of oral therapies can be affected by drug metabolism, or dose-limiting systemic toxicity, inhaled treatment via pressured metered dose inhalers (pMDI) may be an effective, nontoxic, practical alternative. We hypothesized that a stable water-in-perfluorooctyl bromide (PFOB) emulsion that provides solubility in common pMDI propellants, engineered for intrapulmonary delivery of pulmonary vasodilators, reverses HPV during acute hypoxia (HX). Male Sprague Dawley rats received two 10-min bouts of HX (13% O 2 ) with 20 min of room air and drug application between exposures. Treatment groups: intrapulmonary delivery (PUL) of (1) saline; (2) ambrisentan in saline (0.1 mg/kg); (3) empty emulsion; (4) emulsion encapsulating ambrisentan or sodium nitrite (NaNO 2 ) (0.1 and 0.5 mg/kg each); and intravenous (5) ambrisentan (0.1 mg/kg) or (6) NaNO 2 (0.5 mg/kg). Neither PUL of saline or empty emulsion, nor infusions of drugs prevented pulmonary artery pressure (PAP) elevation (32.6 ± 3.2, 31.5 ± 1.2, 29.3 ± 1.8, and 30.2 ± 2.5 mmHg, respectively). In contrast, PUL of aqueous ambrisentan and both drug emulsions reduced PAP by 20–30% during HX, compared to controls. IL6 expression in bronchoalveolar lavage fluid and whole lung 24 h post-PUL did not differ among cohorts. We demonstrate proof-of-concept for delivering pulmonary vasodilators via aerosolized water-in-PFOB emulsion. This concept opens a potentially feasible and effective route of treating pulmonary vascular pathologies via pMDI.

Therapeutic oxygen delivery by perfluorocarbon-based colloids

“…Reverse, water-in-PFC nanoemulsions (Scheme 5a) are mainly aimed at delivering water-soluble drugs, in particular through the pulmonary route, as with metered-dose inhalers [17,20,[199][200][201][202][203][204][205]. A non-ionic, molecular F-alkyldimorpholinophosphate 15 (Table 2) produced, for example, stable, heat-sterilizable reverse emulsions of water-in-F-octylbromide in which a variety of drugs could be loaded [199,206].…”

“…Water-in-PFC reverse emulsions are effective systems for delivery of hydrophilic drugs through the pulmonary route [20,199,203]. Pulmonary delivery of vasodilators was achieved via aerosolization of drug-loaded water-in-F-octylbromide NEs in rats, providing a potential treatment of high-altitude pulmonary edema and pulmonary artery hypertension [205].…”