A porcine model of complement-mediated infusion reactions to drug carrier nanosystems and other medicines

Szebeni, János; Bedőcs, Péter; Csukás, Domokos; Rosivall, László; Bünger, Rolf; Urbanics, Rudolf

doi:10.1016/j.addr.2012.07.005

Cited by 114 publications

(139 citation statements)

References 52 publications

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“…In this context, the clinical significance of CARPA-genic reaction upon the intravenous administration of nanosystems lies not only in the severe, occasionally lethal cardiopulmonary distress but also in a heightened risk that the nano medicines become immunogenic, preventing their multiple applications [32]. In order to minimize such risks, the nanoparticles included in our analyses are currently entering the CARPA tests in the pig model [53]. The results of a pilot study involving the intravenous bolus administration of LP-NP1 confirmed the in vitro data, indicating a favorable safety profile and low immunogenicity of these nanoparticles.…”

Section: Io-np2mentioning

confidence: 99%

Nanoparticles for Intravascular Applications: Physicochemical Characterization and Cytotoxicity Testing

Matuszak

Baumgartner

Zaloga

et al. 2016

Nanomedicine (Lond.)

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Aim:We report the physicochemical analysis of nanosystems intended for cardiovascular applications and their toxicological characterization in static and dynamic cell culture conditions. Methods: Size, polydispersity and ζ-potential were determined in 10 nanoparticle systems including liposomes, lipid nanoparticles, polymeric and iron oxide nanoparticles. Nanoparticle effects on primary human endothelial cell viability were monitored using real-time cell analysis and live-cell microscopy in static conditions, and in a flow model of arterial bifurcations. Results & conclusions: The majority of tested nanosystems were well tolerated by endothelial cells up to the concentration of 100 μg/ml in static, and up to 400 μg/ml in dynamic conditions. Pilot experiments in a pig model showed that intravenous administration of liposomal nanoparticles did not evoke the hypersensitivity reaction. These findings are of importance for future clinical use of nanosystems intended for intravascular applications.

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Section: Io-np2mentioning

confidence: 99%

Nanoparticles for Intravascular Applications: Physicochemical Characterization and Cytotoxicity Testing

Matuszak

Baumgartner

Zaloga

et al. 2016

Nanomedicine (Lond.)

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“…33 In order to evaluate the risk of SPIONdex particles as a trigger of hypersensitivity, we performed the dedicated CARPA tests in a pig model. 41 It was previously shown that pigs are extremely sensitive to infused nanoformulations, including liposomal doxorubicin (Doxil ® ). Interestingly, independent of the physicochemical characteristics of the trigger particles (eg, material, size, charge), the pattern of induced cardiopulmonary responses is essentially the same.…”

mentioning

confidence: 99%

Non-immunogenic dextran-coated superparamagnetic iron oxide nanoparticles: a biocompatible, size-tunable contrast agent for magnetic resonance imaging

Unterweger

Janko

Schwarz

et al. 2017

IJN

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Iron oxide-based contrast agents have been in clinical use for magnetic resonance imaging (MRI) of lymph nodes, liver, intestines, and the cardiovascular system. Superparamagnetic iron oxide nanoparticles (SPIONs) have high potential as a contrast agent for MRI, but no intravenous iron oxide-containing agents are currently approved for clinical imaging. The aim of our work was to analyze the hemocompatibility and immuno-safety of a new type of dextran-coated SPIONs (SPIONdex) and to characterize these nanoparticles with ultra-high-field MRI. Key parameters related to nanoparticle hemocompatibility and immuno-safety were investigated in vitro and ex vivo. To address concerns associated with hypersensitivity reactions to injectable nanoparticulate agents, we analyzed complement activation-related pseudoallergy (CARPA) upon intravenous administration of SPIONdex in a pig model. Furthermore, the size-tunability of SPIONdex and the effects of size reduction on their biocompatibility were investigated. In vitro, SPIONdex did not induce hemolysis, complement or platelet activation, plasma coagulation, or leukocyte procoagulant activity, and had no relevant effect on endothelial cell viability or endothelial–monocytic cell interactions. Furthermore, SPIONdex did not induce CARPA even upon intravenous administration of 5 mg Fe/kg in pigs. Upon SPIONdex administration in mice, decreased liver signal intensity was observed after 15 minutes and was still detectable 24 h later. In addition, by changing synthesis parameters, a reduction in particle size <30 nm was achieved, without affecting their hemo- and biocompatibility. Our findings suggest that due to their excellent biocompatibility, safety upon intravenous administration and size-tunability, SPIONdex particles may represent a suitable candidate for a new-generation MRI contrast agent.

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“…It leads to tachyphylaxis when the stimulus is way under the effective sub-threshold level. The theory, illustrated in Figure 5, equally applies to mast cells and PIM cells (3). Future studies will hopefully reveal more details about the involvement of PIM cells in CARPA and the mechanism of tachyphylaxis.…”

Section: The Double Hit Theory Of Carpamentioning

confidence: 99%

“…One of our previous reviews (3) in this volume highlights the variation of cardiovascular symptoms in porcine CARPA, while the present review focuses solely on the likely role of a particular cell in the lung of pigs: pulmonary intravascular macrophages, or PIM cells. The goal is to summarize the information on PIM cells that point to their central role in CARPA.…”

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confidence: 99%

Pulmonary intravascular macrophages: prime suspects as cellular mediators of porcine CARPA

Csukás

Urbanics²,

Weber

et al. 2015

European Journal of Nanomedicine

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Pigs provide a highly sensitive and quantitative in vivo model for complement (C) activation-related pseudoallergy (CARPA), a hypersensitivity reaction caused by some state-of-art nanomedicines. In an effort to understand the mechanism of the pigs' unique sensitivity for CARPA, this review focuses on pulmonary intravascular macrophages (PIMs), which are abundantly present in the lung of pigs. These cells represent a macrophage subpopulation whose unique qualities explain the characteristic symptoms of CARPA in this species, most importantly the rapidly (within minutes) developing pulmonary vasoconstriction, leading to elevation of pulmonary arterial pressure. The unique qualities of PIM cells include the following; 1) they are strongly adhered to the capillary walls via desmosomelike intercellular adhesion plaques, which secure stable and lasting direct exposition of the bulk of these cells to the blood stream; 2) their ruffled surface engaged in intense phagocytic activity ensures efficient binding and phagocytosis of nanoparticles; 3) PIM cells express anaphylatoxin receptors, this way C activation can trigger these cells, 4) they also express pattern recognition molecules on their surface, whose engagement with certain coated nanoparticles may also activate these cells or act in synergy with anaphylatoxins and, finally 5) their high metabolic activity and capability for immediate secretion of vasoactive mediators upon stimulation explain the circulatory blockage and other robust physiological effects that their stimulation may cause. These qualities taken together with reports on liposome uptake by PIM cells during CARPA and the possible presence of these cells in human lung suggests that PIM cells may be a potential therapeutic target against CARPA.

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A porcine model of complement-mediated infusion reactions to drug carrier nanosystems and other medicines

Cited by 114 publications

References 52 publications

Nanoparticles for Intravascular Applications: Physicochemical Characterization and Cytotoxicity Testing

Nanoparticles for Intravascular Applications: Physicochemical Characterization and Cytotoxicity Testing

Non-immunogenic dextran-coated superparamagnetic iron oxide nanoparticles: a biocompatible, size-tunable contrast agent for magnetic resonance imaging

Pulmonary intravascular macrophages: prime suspects as cellular mediators of porcine CARPA

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