Activation of complement by therapeutic liposomes and other lipid excipient-based therapeutic products: Prediction and prevention

Szebeni, János; Fm, Muggia; Gabizón, Alberto; Barenholz, Yechezkel

doi:10.1016/j.addr.2011.06.017

Cited by 367 publications

(302 citation statements)

References 82 publications

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“…This was attributed to complement activation-related pseudoallergy (CARPA), a hypersensitivity reaction to LIPs reported in pigs and some humans. 18 No features of allergy were observed in the present work, however. This phenomenon was negated through reduction of LIP size through sonication (a technique employed in this work), yet remains a concern for potential clinical use.…”

Section: Discussioncontrasting

confidence: 70%

Comparison of Intravenous Lipid Emulsion, Bicarbonate, and Tailored Liposomes in Rabbit Clomipramine Toxicity

Cave

Harvey

Shaw

et al. 2013

Academic Emergency Medicine

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Objectives: Liposome (LIP)-like lipid dispersions have emerged as useful detoxification vehicles in vitro. The authors compare resuscitation with tailored LIPs, 20% intravenous lipid emulsion (ILE), and sodium bicarbonate (BIC), in a rabbit model of clomipramine toxicity.Methods: Sedated, instrumented New Zealand white rabbits underwent clomipramine infusion at 3.2 mg/kg/min to 50% baseline mean arterial pressure (MAP) and then at 1.6 mg/kg/min for 30 minutes. BIC (3 mL/kg 8.4%), ILE (3 mL/kg 20%), or LIP (24 mg/kg) were infused as rescue treatments at toxicity and were repeated at 10 minutes (n = 5 in each group). remains a difficult therapeutic challenge. Mainstays of therapy include aggressive supportive care and sodium bicarbonate (BIC)-initiated systemic alkalinization. 1 More recently, intravenous lipid emulsion (ILE) preparations have been forwarded as adjuncts to standard management of TCA toxicity with successful reports of use in animal models 2 and human subjects. 3 Both pharmacokinetic and pharmacodynamic mechanisms have been forwarded to explain the beneficial effects of ILE. The widely held lipid sink theory is that lipid sequesters certain xenobiotics (such as TCAs) and reduces toxicity by decreasing the free serum concentration of the offending toxin. 4,5 Liposomes are spherical vesicles of phospholipids and effectively sequester amitriptyline and imipramine in vitro. 6,7 Specific advantages afforded by liposomes (LIPs) include increased surface area:volume ratios, the ability to modulate surface charge and internal pH, and the inherent lipid bilayer structure. To date, however, there are limited data on the antidotal efficacy of liposomal formulations in intact animal models.We examined the effect of LIPs in an established animal model of TCA toxicity. Specifically, in this study we compare resuscitation with bicarbonate (BIC), ILE, and LIPs in a previously studied rabbit model of clomipramineinduced shock. METHODS Study DesignThis was a laboratory study of clomipramine-induced cardiotoxicity in a rabbit model. The study was approved by the institutional ethics committee of the

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Section: Discussioncontrasting

confidence: 70%

Comparison of Intravenous Lipid Emulsion, Bicarbonate, and Tailored Liposomes in Rabbit Clomipramine Toxicity

Cave

Harvey

Shaw

et al. 2013

Academic Emergency Medicine

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“…10) This disappearance of subsequent doses via the production of anti-PEG IgM is referred to as the "accelerated blood clearance (ABC) phenomenon." [10][11][12][13] The ABC phenomenon has been identified as comprising two phases: the induction phase, in which the biological system is "primed" by the first administration of SL, leading to the induction of an anti-PEG IgM response against the SL, and the effectuation phase that follows the second, or subsequent, administration in which the SL are rapidly opsonized and cleared from the blood circulation by Kupffer cells via complement receptor-mediated endocytosis/ phagocytosis 14) via anti-PEG IgM-mediated activation of the complement system. 10) IgM has great potential to activate the complement system via classic pathway.…”

mentioning

confidence: 99%

Relationship between the Concentration of Anti-polyethylene Glycol (PEG) Immunoglobulin M (IgM) and the Intensity of the Accelerated Blood Clearance (ABC) Phenomenon against PEGylated Liposomes in Mice

Hashimoto

Shimizu

Lila

et al. 2015

Biological & Pharmaceutical Bulletin

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PEGylation, which is the surface modification of nanocarriers with polyethylene glycol (PEG), has increased the circulation time and reduced the immunogenic responses to nanocarriers. However, many reports have demonstrated that the intravenous injection of sterically stabilized PEGylated liposome (SL) causes an accelerated blood clearance (ABC) of subsequent doses via anti-PEG immunoglobulin M (IgM)-mediated complement activation. In the present study, the relationships between serum anti-PEG IgM concentration, the intensity of complement activation and the hepatic clearance of SL were quantitatively investigated for their role in the ABC phenomenon. Interestingly, with increasing serum anti-PEG IgM concentrations, the intensity of complement activation increased linearly, while the intensity of the hepatic clearance of SL was increased and then saturated. In addition, only 15-17% of anti-PEG IgM in blood circulation induced by SL at different doses was associated with a second dose SL. The present results indicate that it is the hepatic uptake of SL that is the limiting step in the ABC phenomenon, rather than the association of anti-PEG IgM to the SL and a subsequent complement activation.

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“…The size and shape of nanocarriers are very similar to those of pathogenic microorganisms, subcellular organelles, and cell debris. 34 The intravenous injection of PE was immediately recognized by the immune cells, and the immune cells migrated to the injected limb from the limb opposite to the injected limb. Subsequently, a large number of immune cells gathered around the injected PE and hindered its circulation from the injected limb to the opposite limb (from where the blood was taken).…”

Section: Discussionmentioning

confidence: 99%

Accelerated blood clearance phenomenon upon cross-administration of PEGylated nanocarriers in beagle dogs

Cheng¹,

Su²,

Pei³

et al. 2015

IJN

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The cross-administration of nanocarriers modified by poly(ethylene glycol) (PEG), named PEGylated nanocarriers, a type of combination therapy, is becoming an increasingly important method of long-term drug delivery, to decrease side effects, avoid multidrug resistance, and increase therapeutic efficacy. However, repeated injections of PEGylated nanocarriers induces the accelerated blood clearance (ABC) phenomenon, prevents long circulation, and can cause adverse effects owing to alterations in the biodistribution of the drug. Although the nature of the ABC phenomenon that is induced by repeated injections of PEGylated nanocarriers has already been studied in detail, there are few reports on the immune response elicited by the cross-administration of PEGylated nanocarriers. In this study, we investigated the ABC phenomenon induced by the intravenous cross-administration of various PEGylated nanocarriers, including PEGylated liposomes (PL), PEG micelles (PM), PEGylated solid lipid nanoparticles (PSLN), and PEGylated emulsions (PE), in beagle dogs. The results indicated that the magnitude of the immune response elicited by the cross-administration was in the following order (from the strongest to the weakest): PL, PE, PSLN, PM. It is specifically PEG in the brush structure that elicits a significant immune response, in both the induction phase and the effectuation phase. Furthermore, the present study suggests that there is a considerable difference between the effect of repeated injections and cross-administration, depending on the colloidal structure. This work is a preliminary investigation into the cross-administration of PEGylated nanocarriers, and our observations can have serious implications for the design of combination therapies that use PEGylated vectors.

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Activation of complement by therapeutic liposomes and other lipid excipient-based therapeutic products: Prediction and prevention

Cited by 367 publications

References 82 publications

Comparison of Intravenous Lipid Emulsion, Bicarbonate, and Tailored Liposomes in Rabbit Clomipramine Toxicity

Comparison of Intravenous Lipid Emulsion, Bicarbonate, and Tailored Liposomes in Rabbit Clomipramine Toxicity

Relationship between the Concentration of Anti-polyethylene Glycol (PEG) Immunoglobulin M (IgM) and the Intensity of the Accelerated Blood Clearance (ABC) Phenomenon against PEGylated Liposomes in Mice

Accelerated blood clearance phenomenon upon cross-administration of PEGylated nanocarriers in beagle dogs

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