Complement activation in vitro and reactogenicity of low-molecular weight dextran-coated SPIONs in the pig CARPA model: Correlation with physicochemical features and clinical information

Fülöp, Tamás; Nemes, Réka; Mészáros, Tamás; Urbanics, Rudolf; Kok, Robbert J.; Jackman, Joshua A.; Cho, Nam‐Joon; Storm, Gert; Szebeni, János

doi:10.1016/j.jconrel.2017.11.043

Cited by 40 publications

(24 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to the above clinical data attesting to concordance between NP-induced HSRs in pigs and humans, we reported the coincidence of HSRs in pigs with historic data on HSRs in man in the case of low-molecular weight dextran-coated superparamagnetic iron oxide nanoparticles, Sinerem and Resovist [118].…”

Section: Concordant Symptoms Of Pseudoallergy In Pigs and Humanssupporting

confidence: 70%

Human Clinical Relevance of the Porcine Model of Pseudoallergic Infusion Reactions

Szebeni

Bawa

2020

Biomedicines

Self Cite

View full text Add to dashboard Cite

Pigs provide a highly sensitive animal model for pseudoallergic infusion reactions, which are mild-to-severe hypersensitivity reactions (HSRs) that arise following intravenous administration of certain nanoparticulate drugs (nanomedicines) and other macromolecular structures. This model has been used in research for three decades and was also proposed by regulatory bodies for preclinical assessment of the risk of HSRs in the clinical stages of nano-drug development. However, there are views challenging the human relevance of the model and its utility in preclinical safety evaluation of nanomedicines. The argument challenging the model refers to the “global response” of pulmonary intravascular macrophages (PIM cells) in the lung of pigs, preventing the distinction of reactogenic from non-reactogenic particles, therefore overestimating the risk of HSRs relative to its occurrence in the normal human population. The goal of this review is to present the large body of experimental and clinical evidence negating the “global response” claim, while also showing the concordance of symptoms caused by different reactogenic nanoparticles in pigs and hypersensitive man. Contrary to the model’s demotion, we propose that the above features, together with the high reproducibility of quantifiable physiological endpoints, validate the porcine “complement activation-related pseudoallergy” (CARPA) model for safety evaluations. However, it needs to be kept in mind that the model is a disease model in the context of hypersensitivity to certain nanomedicines. Rather than toxicity screening, its main purpose is specific identification of HSR hazard, also enabling studies on the mechanism and mitigation of potentially serious HSRs.

show abstract

Section: Concordant Symptoms Of Pseudoallergy In Pigs and Humanssupporting

confidence: 70%

Human Clinical Relevance of the Porcine Model of Pseudoallergic Infusion Reactions

Szebeni

Bawa

2020

Biomedicines

Self Cite

View full text Add to dashboard Cite

show abstract

“…We also established a significant impact of NP size and thus surface geometry (curvature) on C activation, most likely related to the flatness of particle surfaces on which C proteins are deposited. Although we did not investigate, size-dependent aggregate formation 36 may also play a role in C activation by PS-NPs, a possibility that requires further attention.…”

Section: Discussionmentioning

confidence: 97%

Involvement of complement activation in the pulmonary vasoactivity of polystyrene nanoparticles in pigs: unique surface properties underlying alternative pathway activation and instant opsonization

Mészáros¹,

Kozma²,

Shimizu³

et al. 2018

IJN

Self Cite

View full text Add to dashboard Cite

BackgroundIt has been proposed that many hypersensitivity reactions to nanopharmaceuticals represent complement (C)-activation-related pseudoallergy (CARPA), and that pigs provide a sensitive animal model to study the phenomenon. However, a recent study suggested that pulmonary hypertension, the pivotal symptom of porcine CARPA, is not mediated by C in cases of polystyrene nanoparticle (PS-NP)-induced reactions.GoalsTo characterize PS-NPs and reexamine the contribution of CARPA to their pulmonary reactivity in pigs.Study designC activation by 200, 500, and 750 nm (diameter) PS-NPs and their opsonization were measured in human and pig sera, respectively, and correlated with hemodynamic effects of the same NPs in pigs in vivo.MethodsPhysicochemical characterization of PS-NPs included size, ζ-potential, cryo-transmission electron microscopy, and hydrophobicity analyses. C activation in human serum was measured by ELISA and opsonization of PS-NPs in pig serum by Western blot and flow cytometry. Pulmonary vasoactivity of PS-NPs was quantified in the porcine CARPA model.ResultsPS-NPs are monodisperse, highly hydrophobic spheres with strong negative surface charge. In human serum, they caused size-dependent, significant rises in C3a, Bb, and sC5b-9, but not C4d. Exposure to pig serum led within minutes to deposition of C5b-9 and opsonic iC3b on the NPs, and opsonic iC3b fragments (C3dg, C3d) also appeared in serum. PS-NPs caused major hemodynamic changes in pigs, primarily pulmonary hypertension, on the same time scale (minutes) as iC3b fragmentation and opsonization proceeded. There was significant correlation between C activation by different PS-NPs in human serum and pulmonary hypertension in pigs.ConclusionPS-NPs have extreme surface properties with no relevance to clinically used nanomedicines. They can activate C via the alternative pathway, entailing instantaneous opsonization of NPs in pig serum. Therefore, rather than being solely C-independent reactivity, the mechanism of PS-NP-induced hypersensitivity in pigs may involve C activation. These data are consistent with the “double-hit” concept of nanoparticle-induced hypersensitivity reactions involving both CARPA and C-independent pseudoallergy.

show abstract

“…We also tested the blocking performance of BSA coatings on silica nanoparticles to inhibit nanoparticle-induced complement activation, which is an acute immune response that can occur in human serum (Fig. 5c) [46][47][48][49] . Using an enzyme-linked immunosorbent assay (ELISA), we measured the degree of protection which BSA coatings conferred against nanoparticle-induced complement activation, as judged by the amount of SC5b-9 protein biomarker in solution ( Fig.…”

Section: Surface Coating Application Performancementioning

confidence: 99%

Quantitative assessment of bovine serum albumin proteins for blocking applications

Junren

Ferhan

Jackman³

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Bovine serum albumin (BSA) is one of the most widely used protein reagents in the scientific community, especially for surface passivation ("blocking") applications in various bioassays. Numerous BSA protein options are commercially available, however, there is scarce information about which ones are preferable for blocking applications.Herein, we conducted biophysical and bioassay measurements to quantitatively compare the conformational, adsorption, and blocking properties of BSA protein reagents that were obtained through six purification methods. Depending on the method, there were significant differences in the conformational and adsorption properties of BSA proteins, mainly due to the presence of fatty acid stabilizers. In turn, we discovered that fatty acidfree BSA proteins exhibit superior blocking performance to fatty acid-stabilized BSA proteins in surface-and nanoparticle-based bioassays. We critically discuss mechanistic factors behind these performance variations and our findings offer a practical framework to guide BSA selection for blocking applications.A common element of bioassays is the need to minimize nonspecific binding of biomolecules in order to maximize assay specificity and sensitivity 1, 2 . To meet this objective, a wide range of reagents, ranging from crude materials such as milk proteins to synthetic nanomaterials such as finely tuned polymers, have been developed to coat target surfaces and to minimize nonspecific binding events-a function that is commonly referred to as

show abstract

Complement activation in vitro and reactogenicity of low-molecular weight dextran-coated SPIONs in the pig CARPA model: Correlation with physicochemical features and clinical information

Cited by 40 publications

References 43 publications

Human Clinical Relevance of the Porcine Model of Pseudoallergic Infusion Reactions

Human Clinical Relevance of the Porcine Model of Pseudoallergic Infusion Reactions

Involvement of complement activation in the pulmonary vasoactivity of polystyrene nanoparticles in pigs: unique surface properties underlying alternative pathway activation and instant opsonization

Quantitative assessment of bovine serum albumin proteins for blocking applications

Contact Info

Product

Resources

About