Bypassing adverse injection reactions to nanoparticles through shape modification and attachment to erythrocytes

Wibroe, Peter P.; Anselmo, Aaron C.; Nilsson, Per H.; Sarode, Apoorva; Gupta, Vivek; Urbanics, Rudolf; Szebeni, János; Hunter, A. Christy; Mitragotri, Samir; Mollnes, Tom Eirik; Moghimi, S. Moein

doi:10.1038/nnano.2017.47

Cited by 160 publications

(202 citation statements)

References 49 publications

(75 reference statements)

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“…Despite that evidence in pig models points to the role of complement in pseudoallergy, 9 recent data suggest that initial interaction of nanoparticles with lung macrophages could also play a role in the infusion-related reactions. 39 …”

Section: Discussionmentioning

confidence: 99%

Variability of Complement Response toward Preclinical and Clinical Nanocarriers in the General Population

Benasutti

Wang

et al. 2017

Bioconjugate Chem.

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Opsonization (coating) of nanoparticles with complement C3 component is an important mechanism that triggers immune clearance and downstream anaphylactic and proinflammatory responses. The variability of complement C3 binding to nanoparticles in the general population has not been studied. We examined complement C3 binding to dextran superparamagnetic iron oxide nanoparticles (superparamagnetic iron oxide nanoworms, SPIO NWs, 58 and 110 nm) and clinically approved nanoparticles (carboxymethyl dextran iron oxide ferumoxytol (Feraheme, 28 nm), highly PEGylated liposomal doxorubicin (LipoDox, 88 nm), and minimally PEGylated liposomal irinotecan (Onivyde, 120 nm)) in sera from healthy human individuals. SPIO NWs had the highest variation in C3 binding (n = 47) between subjects, with a 15−30 fold range in levels of C3. LipoDox (n = 12) and Feraheme (n = 18) had the lowest levels of variation between subjects (an approximately 1.5-fold range), whereas Onivyde (n = 18) had intermediate between-subject variation (2-fold range). There was no statistical diﬀerence between males and females and no correlation with age. There was a significant correlation in complement response between small and large SPIO NWs, which are similar structurally and chemically, but the correlations between SPIO NWs and other types of nanoparticles, and between LipoDox and Onivyde, were not significant. The calculated average number of C3 molecules bound per nanoparticle correlated with the hydrodynamic diameter but was decreased in LipoDox, likely due to the PEG coating. The conclusions of this study are (1) all nanoparticles show variability of C3 opsonization in the general population; (2) an individual’s response toward one nanoparticle cannot be reliably predicted based on another nanoparticle; and (3) the average number of C3 molecules per nanoparticle depends on size and surface coating. These results provide new strategies to improve nanomedicine safety.

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Section: Discussionmentioning

confidence: 99%

Variability of Complement Response toward Preclinical and Clinical Nanocarriers in the General Population

Benasutti

Wang

et al. 2017

Bioconjugate Chem.

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“…Similarly, Moghimi et al compared complement activation using spherical, prolate ellipsoidal (rods) and oblate ellipsoidal (disks) polystyrene NPs with equivalent surface area in pig and human blood. They found that all types of NPs induced complement activation (through measurements of C3bc, C3a, C5a, and sC5b-9) within the first 5 minutes of contact with blood, but rods and disks generate more profound complement activation than spheres at later timepoints [40]. Recently, Bigini et al demonstrated that spherical and star-like Au NPs show the same percentage of accumulation but a different localization in liver, and only star-like Au NPs could be able to accumulate in lung [41].…”

Section: Physicochemical Properties Of Nanoparticles Modulate Innamentioning

confidence: 99%

Effects of engineered nanoparticles on the innate immune system

Liu

Hardie

Zhang

et al. 2017

Seminars in Immunology

207

131

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Engineered nanoparticles (NPs) have broad applications in industry and nanomedicine. When NPs enter the body, interactions with the immune system are unavoidable. The innate immune system, a non-specific first line of defense against potential threats to the host, immediately interacts with introduced NPs and generates complicated immune responses. Depending on their physicochemical properties, NPs can interact with cells and proteins to stimulate or suppress the innate immune response, and similarly activate or avoid the complement system. NPs size, shape, hydrophobicity and surface modification are the main factors that influence the interactions between NPs and the innate immune system. In this review, we will focus on recent reports about the relationship between the physicochemical properties of NPs and their innate immune response, and their applications in immunotherapy.

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“…15 Previous studies used this model to examine cholesterol crystal-induced inflammasome activation, 16 or to study the effects of implantable sensors 17 and polycation-containing microspheres. 18 It has also been used to study polystyrene nanoparticles, 19 but this human whole blood model has not been previously used to evaluate the biological effects of IONPs.…”

mentioning

confidence: 99%

Iron oxide nanoparticles induce cytokine secretion in a complement-dependent manner in a human whole blood model

Wolf-Grosse¹,

Rokstad²,

Ali³

et al. 2017

IJN

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Iron oxide nanoparticles (IONPs) are promising nanomaterials for biomedical applications. However, their inflammatory potential has not been fully established. Here, we used a lepirudin anti-coagulated human whole blood model to evaluate the potential of 10 nm IONPs to activate the complement system and induce cytokine production. Reactive oxygen species and cell death were also assessed. The IONPs activated complement, as measured by C3a, C5a and sC5b-9, and induced the production of pro-inflammatory cytokines in a particle-dose dependent manner, with the strongest response at 10 µg/mL IONPs. Complement inhibitors at C3 (compstatin analog Cp40) and C5 (eculizumab) levels completely inhibited complement activation and secretion of inflammatory mediators induced by the IONPs. Additionally, blockade of complement receptors C3aR and C5aR1 significantly reduced the levels of various cytokines, indicating that the particle-induced secretion of inflammatory mediators is mainly C5a and C3a mediated. The IONPs did not induce cell death or reactive oxygen species, which further suggests that complement activation alone was responsible for most of the particle-induced cytokines. These data suggest that the lepirudin anti-coagulated human whole blood model is a valuable ex vivo system to study the inflammatory potential of IONPs. We conclude that IONPs induce complement-mediated cytokine secretion in human whole blood.

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Bypassing adverse injection reactions to nanoparticles through shape modification and attachment to erythrocytes

Cited by 160 publications

References 49 publications

Variability of Complement Response toward Preclinical and Clinical Nanocarriers in the General Population

Variability of Complement Response toward Preclinical and Clinical Nanocarriers in the General Population

Effects of engineered nanoparticles on the innate immune system

Iron oxide nanoparticles induce cytokine secretion in a complement-dependent manner in a human whole blood model

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