Liposome-induced complement activation and related cardiopulmonary distress in pigs: factors promoting reactogenicity of Doxil and AmBisome

Szebeni, János; Bedőcs, Péter; Rozsnyay, Zoltán; Weiszhár, Zsóka; Urbanics, Rudolf; Rosivall, László; Cohen, Rivka; Garbuzenko, Olga B.; Báthori, György; Tóth, Miklós; Bünger, Rolf; Barenholz, Yechezkel

doi:10.1016/j.nano.2011.06.003

Cited by 192 publications

(168 citation statements)

References 38 publications

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“…It was also established that vesicle structural factors of liposomes (e.g. phospholipid composition, vesicle size and surface charge) could modulate complement activation and CARPA (Szebeni et al 2000, Szebeni et al 2012.…”

Section: Introductionmentioning

confidence: 99%

Complement activation-related pseudoallergy in dogs following intravenous administration of a liposomal formulation of meglumine antimoniate

et al. 2013

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Pesq. Vet. Bras. 33(8):1016Bras. 33(8): -1020Bras. 33(8): , agosto 2013Bras. 33(8): 1016 RESUMO.-[Pseudoalergia relacionada à ativação do complemento em cães após administração intravenosa de uma formulação lipossomal de antimoniato de meglumina.] O crescente uso das nanotecnologias nas terapias avançadas tem permitido a observação de reações adversas específicas relacionadas às nanoestruturas. A toxicidade de uma nova formulação lipossomal de antimoniato de meglumina após dose única foi avaliada em cães com leishmaniose visceral. The increasing use of nanotechnologies in advanced therapies has allowed the observation of specific adverse reactions related to nanostructures. The toxicity of a novel liposome formulation of meglumine antimoniate in dogs with visceral leishmaniasis after single dose has been investigated. Groups of 12 animals received by the intravenous route a single dose of liposomal meglumine antimoniate (group I [GI], 6.5 mg Sb/kg), empty liposomes (GII) or isotonic saline (GIII). Evaluation of hematological and biochemical parameters showed no significant changes 4 days after administration. No undesired effects were registered in the GIII. However, adverse reactions were observed in 67.7% of dogs from both groups that received liposomal formulations. The side effects began moments after bolus administration and disappeared during the first 15 minutes after treatment. Prostation, sialorrhea and defecation were the most frequent clinical signs, registered in 33.3% and 41.6 % of animals from the groups GI and GII, respectively. Tachypnea, mydriasis, miosis, vomiting and cyanosis were also registered in both groups. The adverse reactions observed in this study were attributed to the activation of the complement system by lipid vesicles in a phenomenon known as Complement Activation-Related Pseudoallergy (CARPA). The influence of the physical-chemical characteristics of liposomal formulation in the triggering of CARPA is discussed.

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Section: Introductionmentioning

confidence: 99%

Complement activation-related pseudoallergy in dogs following intravenous administration of a liposomal formulation of meglumine antimoniate

et al. 2013

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“…There is a hypothesis that complement activation related pseudoallergy (CARPA), observed in the clinical practice when PEGylated liposomes are administered intravenously, may be caused by sporadic aggregation or fusion of liposomes [6]. The results presented above may open the route to produce aggregates or fused vesicles in a controlled manner and test their role in pseudoallergic reactions.…”

Section: Discussionmentioning

confidence: 88%

“…However, new benefits may be accompanied by new risks: e. g., it turned out that liposomes can induce complement activation related pseudoallergy (CARPA), a new type of drug-induced acute immune toxicity [5]. It is suspected that one of its causes could be the presence of liposomal aggregates in the formulated product [6].…”

Section: Graphical Abstract Introductionmentioning

confidence: 99%

Aggregation of PEGylated liposomes driven by hydrophobic forces

Bozó

Mészáros

Mihály

et al. 2016

Colloids and Surfaces B: Biointerfaces

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2 Graphical Abstract 3 Highlights Kosmotropes induce the aggregation and fusion of PEG-liposomes.  The effect depends on both the kosmotrope and PEG concentration.  Aggregation is reversible under certain conditions.  Kosmotropes lead to a dehydration-related conformational change of the PEG polymer.  The likely driving force behind aggregation is the hydrophobic effect. 4 ABSTRACTPolyethylene glycol (PEG) is widely used to sterically stabilize liposomes and improve the pharmacokinetic profile of drugs, peptides and nanoparticles. Here we report that ammonium sulfate (AS) can evoke the aggregation of PEGylated vesicles in a concentration-dependent manner. Liposomes with 5 mol% PEG were colloidally stable at AS concentrations up to 0.7 mM, above which they precipitated and formed micron-size aggregates with irregular shape. While aggregation was reversible up to 0.9 M of AS, above 1 M fusion occurred, which irreversibly distorted the size distribution. Zeta potential of liposomes markedly increased from -71±2.5 mV to 2±0.5 mV upon raising the AS concentration from 0 to 0.1 M, but no considerable increase was seen during further AS addition, showing that the aggregation is independent of surface charge. There was no aggregation in the absence of the PEG chains, and increasing PEG molar % shifted the aggregation threshold to lower AS concentrations. Changes in the FTIR spectral features of PEGylated vesicles suggest that AS dehydrates PEG chains. Other kosmotropic salts also led to aggregation, while chaotropic salts did not, which indicates a general kosmotropic phenomenon. The driving force behind aggregation is likely to be the hydrophobic effect due to salting out the polymer similarly to what happens during protein purification or Hydrophobic Interaction Chromatography. Since liposome aggregation and fusion may result in difficulties during formulation and adverse reaction upon application, the phenomena detailed in this paper may have both technological and therapeutical consequences.

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“…As mentioned before this approach failed if using synthetic liposomal delivery systems which can cause immune activation to an extent that can be fatal for the patient (71,72). Creating a stable formulation that mimics the structure and function of exosomes is a complex task and has to be the result of careful consideration of previous trials and errors in the field of nanomedicine (73,74).…”

Section: Exosomes As Immune-tolerated Delivery Systemsmentioning

confidence: 99%

Exosomes: potential model for complement-stealth delivery systems

Milosevits

Szebeni

Krol

2015

European Journal of Nanomedicine

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Abstract:Exosomes are nature's nanocarriers that transport biological information in humans. Their structural properties, origin and functions are making them interesting objects for the diagnosis of diseases, such as cancer, and also, as innovative tools for drug delivery. The interaction of exosomes with the immune system has been one of the focal points of interest; nevertheless their "stealth" properties helping to avoid adverse immune reactions are still not fully understood. In this review, after giving an overview of recent findings on the role of exosomes in disease pathogenesis and physiological functions, we focused on their interaction with the immune system and possibilities for clinical applications. The potential of exosomes of creating stealth nanoparticles that are better tolerated by the immune system than the presently available synthetic drug delivery systems represent a promising new approach in nanomedicine.

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Liposome-induced complement activation and related cardiopulmonary distress in pigs: factors promoting reactogenicity of Doxil and AmBisome

Abstract: -induced complement activation and related cardiopulmonary distress in pigs: factors promoting reactogenicity of Doxil and AmBisome" (2011).

Cited by 192 publications

References 38 publications

Complement activation-related pseudoallergy in dogs following intravenous administration of a liposomal formulation of meglumine antimoniate

Complement activation-related pseudoallergy in dogs following intravenous administration of a liposomal formulation of meglumine antimoniate

Aggregation of PEGylated liposomes driven by hydrophobic forces

Exosomes: potential model for complement-stealth delivery systems

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