Artificial oxygen carriers based on perfluorodecalin-filled poly(<i>n</i>-butyl-cyanoacrylate) nanocapsules

Stephan, Claudia Christine; Schlawne, Carolin; Graß, Stefan; Waack, Indra Naemi; Ferenz, Katja Bettina; Bachmann, Michael; Barnert, Sabine; Schubert, Rolf; Bastmeyer, Martin; Groot, Herbert de; Mayer, Christian

doi:10.3109/02652048.2013.843600

Cited by 18 publications

(12 citation statements)

References 31 publications

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“…Transient systemic hypotension after infusion of PFC-based artificial oxygen carriers has been described long ago for PFC-based emulsion systems [ 24 , 25 ] and latterly also for capsule-based PFC-containing systems [ 26 ]. This undesirable side effect has been attributed to the action of the emulsifier without [ 27 , 28 ] or in combination with the PFC [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Safety of poly (ethylene glycol)-coated perfluorodecalin-filled poly (lactide-co-glycolide) microcapsules following intravenous administration of high amounts in rats

Ferenz

Waack

Laudien

et al. 2014

Results in Pharma Sciences

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The host response against foreign materials designates the biocompatibility of intravenously administered microcapsules and thus, widely affects their potential for subsequent clinical use as artificial oxygen/drug carriers. Therefore, body distribution and systemic parameters, as well as markers of inflammation and indicators of organ damage were carefully evaluated after administration of short-chained poly (vinyl alcohol, (PVA)) solution or poly (ethylene glycol (PEG))-shielded perfluorodecalin-filled poly (d,l-lactide-co-glycolide, PFD-filled PLGA) microcapsules into Wistar rats. Whereas PVA infusion was well tolerated, all animals survived the selected dose of 1247 mg microcapsules/kg body weight but showed marked toxicity (increased enzyme activities, rising pro-inflammatory cytokines and complement factors) and developed a mild metabolic acidosis. The observed hypotension emerging immediately after start of capsule infusion was transient and mean arterial blood pressure restored to baseline within 70 min. Microcapsules accumulated in spleen and liver (but not in other organs) and partly occluded hepatic microcirculation reducing sinusoidal perfusion rate by about 20%.Intravenous infusion of high amounts of PFD-filled PLGA microcapsules was tolerated temporarily but associated with severe side effects such as hypotension and organ damage. Short-chained PVA displays excellent biocompatibility and thus, can be utilized as emulsifier for the preparation of drug carriers designed for intravenous use.

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Section: Discussionmentioning

confidence: 99%

Safety of poly (ethylene glycol)-coated perfluorodecalin-filled poly (lactide-co-glycolide) microcapsules following intravenous administration of high amounts in rats

Ferenz

Waack

Laudien

et al. 2014

Results in Pharma Sciences

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“…Other alternatives to pulmonary oxygenation have been explored over the past years. Perfluorocarbon-based O 2 carriers have been tested using several routes of administration, including intravenous [ 21 ], transintestinal [ 22 ], and transpleural [ 23 ], as well as for liquid ventilation [ 24 ]. Nevertheless, none of these agents has been approved for clinical use due to storage, production, and clinical evaluation complications [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Exploring alternative routes for oxygen administration

Dyson

Zacchetti

Donati

et al. 2016

ICMx

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BackgroundHypoxemia may compromise cell metabolism and organ function. Supplemental oxygen (O2) at high concentrations may prove ineffective, and issues relating to hyperoxia, barotrauma, mechanical ventilation, and extracorporeal oxygenation are well documented. Old reports suggest the potential safety and efficacy of alternative routes for O2 administration, such as intravenous or intestinal. We re-explored these routes in rat models of hypoxemia.MethodsHypoxemia was induced in spontaneously breathing, anesthetized rats by breathing a hypoxic gas mix (FiO2 0.1). Pilot studies infusing pure O2 gas caused early death, likely due to pulmonary embolism. Instead, rats (n = 6/group) were given intravenous O2 via a continuous infusion of pre-oxygenated Hartmann’s solution (10 ml/kg/h) for 3 h with normal Ringer’s lactate used in control animals. In separate experiments (n = 8/group), bowel intraluminal oxygenation was assessed with pure O2 administered through a cannula placed into the jejunal lumen at a dose of a 15 ml/kg bolus followed by a continuous infusion of 50 ml/kg/h; no treatment was given to controls. Echocardiography, arterial blood gas analysis, mean arterial pressure, muscle and liver tPO2, muscle microvascular perfused vessel density, and urine output were measured.ResultsAdministration of oxygenated Hartmann’s solution (PO2 of solution at end-experiment = 87.5 ± 1.7 kPa) was safe but did not increase either systemic or tissue oxygenation. Similarly, the administration of bowel O2 was safe but did not improve neither systemic nor liver oxygenation.ConclusionsIn this rat model of hypoxemia, the intravenous infusion of gaseous O2 was unfeasible as it induced early mortality. Although safe, both intravenous infusion of oxygenated Hartmann’s solution and bowel O2 administration were unable to improve arterial or tissue oxygenation.

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“…An alternative option to guarantee a stable formulation without Ostwald ripening and the disadvantage of prolonged excretion time is the encapsulation of PFC with polymers, for example poly(lactide-co-glycolide) (Ferenz et al 2013, 2014) or poly( n -butyl-cyanoacrylate) (Stephan et al 2014; Laudien et al 2015). Potential areas of application for nanocapsules with a polymer-based shell are controlled drug delivery (Singh and Nalwa 2011; Byagari et al 2014; Huang et al 2013; Jiang et al 2013) and artificial oxygen carriers (Stephan et al 2014; Laudien et al 2015; Xiong et al 2013). The thin capsule wall provides compatibility with the aqueous medium blood and allows easy release or absorption of respiratory gases (Stephan et al 2014).…”

Section: Main Textmentioning

confidence: 99%

“…Potential areas of application for nanocapsules with a polymer-based shell are controlled drug delivery (Singh and Nalwa 2011; Byagari et al 2014; Huang et al 2013; Jiang et al 2013) and artificial oxygen carriers (Stephan et al 2014; Laudien et al 2015; Xiong et al 2013). The thin capsule wall provides compatibility with the aqueous medium blood and allows easy release or absorption of respiratory gases (Stephan et al 2014). Our recent toxicity studies showed insufficient biocompatibility of poly( n -butyl-cyanoacrylate) (Laudien et al 2015) (see “Reasons for failure of PFC-based preparations in clinical trials”).…”

Section: Main Textmentioning

confidence: 99%

“…Over 90% of the dissolved oxygen is released into the tissue, three times more compared to the oxygen extraction rate of an erythrocyte (Keipert et al 1996). This is the reason for the primary use of PFCs as "artificial blood" in different formulations and technologies (Dinkelmann and Northoff 2002; Stephan et al 2014; Bauer et al 2010; Spahn 1999; Ferenz 2019a). Furthermore, they are already used for liquid ventilation in newborns (Fuhrman et al 1991) and for vitreoretinal surgery (Mertens et al 2000).…”

Section: Introductionmentioning

confidence: 99%

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Perfluorocarbons for the treatment of decompression illness: how to bridge the gap between theory and practice

Mayer

Ferenz

2019

Eur J Appl Physiol

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Decompression illness (DCI) is a complex clinical syndrome caused by supersaturation of respiratory gases in blood and tissues after abrupt reduction in ambient pressure. The resulting formation of gas bubbles combined with pulmonary barotrauma leads to venous and arterial gas embolism. Severity of DCI depends on the degree of direct tissue damage caused by growing bubbles or indirect cell injury by impaired oxygen transport, coagulopathy, endothelial dysfunction, and subsequent inflammatory processes. The standard therapy of DCI requires expensive and not ubiquitously accessible hyperbaric chambers, so there is an ongoing search for alternatives. In theory, perfluorocarbons (PFC) are ideal non-recompressive therapeutics, characterized by high solubility of gases. A dual mechanism allows capturing of excess nitrogen and delivery of additional oxygen. Since the 1980s, numerous animal studies have proven significant benefits concerning survival and reduction in DCI symptoms by intravenous application of emulsion-based PFC preparations. However, limited shelf-life, extended organ retention and severe side effects have prevented approval for human usage by regulatory authorities. These negative characteristics are mainly due to emulsifiers, which provide compatibility of PFC to the aqueous medium blood. The encapsulation of PFC with amphiphilic biopolymers, such as albumin, offers a new option to achieve the required biocompatibility avoiding toxic emulsifiers. Recent studies with PFC nanocapsules, which can also be used as artificial oxygen carriers, show promising results. This review summarizes the current state of research concerning DCI pathology and the therapeutic use of PFC including the new generation of non-emulsified formulations based on nanocapsules.

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Artificial oxygen carriers based on perfluorodecalin-filled poly(n-butyl-cyanoacrylate) nanocapsules

Cited by 18 publications

References 31 publications

Safety of poly (ethylene glycol)-coated perfluorodecalin-filled poly (lactide-co-glycolide) microcapsules following intravenous administration of high amounts in rats

Safety of poly (ethylene glycol)-coated perfluorodecalin-filled poly (lactide-co-glycolide) microcapsules following intravenous administration of high amounts in rats

Exploring alternative routes for oxygen administration

Perfluorocarbons for the treatment of decompression illness: how to bridge the gap between theory and practice

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