The Impact of Nanoparticle Protein Corona on Cytotoxicity, Immunotoxicity and Target Drug Delivery

Corbo, Claudia; Molinaro, Roberto; Parodi, Alessandro; Furman, Naama E. Toledano; Salvatore, Francesco; Tasciotti, Ennio

doi:10.2217/nnm.15.188

Cited by 514 publications

(419 citation statements)

References 162 publications

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“…46,47 The accumulation of iron NPs in organs of the reticuloendothelium system (eg, the spleen), for instance, can induce adverse health effects by disturbing immune homeostasis, 48 and the formation of protein coronas could modulate the immune response. 49 A recent comparison between current regulatory testing requirements and the accumulating knowledge on immunotoxic effects of NMPs showed that specific immunotoxic effects associated with NMPs, such as complement activation-related pseudo-allergy (CARPA), myelosuppression, inflammasome activation, and hypersensitivity, are not readily detected by using current testing guidelines. 45 Our first objective was to investigate whether specific toxicity could be related to certain structural types of NMPs.…”

Section: Discussionmentioning

confidence: 99%

Nanomedicinal products: a survey on specific toxicity and side effects

Brand¹,

Noorlander²,

Giannakou³

et al. 2017

IJN

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Due to their specific properties and pharmacokinetics, nanomedicinal products (NMPs) may present different toxicity and side effects compared to non-nanoformulated, conventional medicines. To facilitate the safety assessment of NMPs, we aimed to gain insight into toxic effects specific for NMPs by systematically analyzing the available toxicity data on approved NMPs in the European Union. In addition, by comparing five sets of products with the same active pharmaceutical ingredient (API) in a conventional formulation versus a nanoformulation, we aimed to identify any side effects specific for the nano aspect of NMPs. The objective was to investigate whether specific toxicity could be related to certain structural types of NMPs and whether a nanoformulation of an API altered the nature of side effects of the product in humans compared to a conventional formulation. The survey of toxicity data did not reveal nanospecific toxicity that could be related to certain types of structures of NMPs, other than those reported previously in relation to accumulation of iron nanoparticles (NPs). However, given the limited data for some of the product groups or toxicological end points in the analysis, conclusions with regard to (a lack of) potential nanomedicine-specific effects need to be considered carefully. Results from the comparison of side effects of five sets of drugs (mainly liposomes and/or cytostatics) confirmed the induction of pseudo-allergic responses associated with specific NMPs in the literature, in addition to the side effects common to both nanoformulations and regular formulations, eg, with liposomal doxorubicin, and possibly liposomal daunorubicin. Based on the available data, immunotoxicological effects of certain NMPs cannot be excluded, and we conclude that this end point requires further attention.

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Section: Discussionmentioning

confidence: 99%

Nanomedicinal products: a survey on specific toxicity and side effects

Brand¹,

Noorlander²,

Giannakou³

et al. 2017

IJN

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“…Although this matter was not discussed in this mini-review, formation of protein corona could change nanomaterial stability, bio-identity, targeting capability, cellular uptake, dissolution characteristics, and thereby their biodistribution and toxicity in vivo. [87][88][89][90] Thus, presence of protein corona is an important factor, in addition to the nanomaterials' physicochemical properties, that needs to be considered for safety assessment of ENMs in biomedicine and has been comprehensively discussed before. 88,89 For safety analysis of ENMs, it is essential to first identify their in vivo biodistribution and target organs after administration.…”

Section: Discussionmentioning

confidence: 99%

“…[87][88][89][90] Thus, presence of protein corona is an important factor, in addition to the nanomaterials' physicochemical properties, that needs to be considered for safety assessment of ENMs in biomedicine and has been comprehensively discussed before. 88,89 For safety analysis of ENMs, it is essential to first identify their in vivo biodistribution and target organs after administration. As mentioned earlier, RES, including liver and the immune system, is frequently targeted by various ENMs after administration, especially intravenous injection.…”

Section: Discussionmentioning

confidence: 99%

Facilitating Translational Nanomedicine via Predictive Safety Assessment

et al. 2017

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Extensive research on engineered nanomaterials (ENMs) has led to the development of numerous nano-based formulations for theranostic purposes. Although some nano-based drug delivery systems already exist on the market, growing numbers of newly designed ENMs exhibit improved physicochemical properties and are being assessed in preclinical stages. While these ENMs are designed to improve the efficacy of current nanobased therapeutic or imaging systems, it is necessary to thoroughly determine their safety profiles for successful clinical applications. As such, our aim in this mini-review is to discuss the current knowledge on predictive safety and structure-activity relationship (SAR) analysis of major ENMs at the developing stage, as well as the necessity of additional long-term toxicological analysis that would help to facilitate their transition into clinical practices. We focus on how the interaction of these nanomaterials with cells would trigger signaling pathways as molecular initiating events that lead to adverse outcomes. These mechanistic understandings would help to design safer ENMs with improved therapeutic efficacy in clinical settings.During the past decades, engineered nanomaterials (ENMs) have been widely used in biomedical applications, such as nanomedicine, bioimaging, and tissue engineering, because of their unique biophysicochemical properties.1,2 With regard to nanomedicine applications, ENMs could be formulated as drug carriers that deliver the therapeutic reagents within the human body and increase their bioavailability and blood circulation half-life.2 Moreover, these nanocarriers could be functionalized to deliver the drug specifically to the desired target tissues (e.g., tumors) and release the payload sustainably over long periods, thereby eliminating the necessity of multiple drug administration and reducing its cytotoxic side effects toward healthy cells.2 In addition to their implementation in drug delivery, ENMs could be used for diagnostic and imaging purposes that would help to monitor the disease and administer the treatment more accurately. 2Past research in nanomedicine has led to the design of various nanomaterial-based therapeutic and diagnostic systems that are being investigated in experimental stages (e.g., in vitro and in vivo) and clinical trials or are commercially available to the corresponding patients (Table 1). Most commercialized nanomaterial-based therapeutic reagents use lipids, proteins, and polymers that could self-assemble and biodegrade with few side effects.3 Because of high biocompatibility of lipids, several commercial liposome-drug formulations have been developed, mostly relying on polyethylene glycol (PEG)-conjugated lipids, such as DOXIL, AmBisome, Epaxal, and Inflexal V, and are under clinical trials focusing on various types of disease treatments. 4,5 Polymer-based nanoparticles (NPs) also present low toxicity, but their surface functionalization may affect their safety. The most commonly used materials include PEG, ploy(lactic-co-glycolic) acid (PLGA...

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“…44 Notably, the PC can affect particle clearance by immune cells, 8 thereby affecting their biodistribution properties. To obtain an overview of what could happen in the context of in vivo cancer therapy when therapeutic NPs are systemically injected, we studied their uptake by macrophages, which are responsible for particle clearance, and their internalization by cancer cells, which is essential for pharmacological efficacy.…”

Section: Cellular Uptake Of Liposomes Before and After Pc Formationmentioning

confidence: 99%

“…4 Most research studying the biomolecular corona has focused on protein composition characterization: 5,6 therefore, the biomolecular corona is generally called the "protein corona" (PC). 7,8 This natural coating provides NPs with a new biological identity and significantly affects their fate, pharmacokinetics, and cellular interactions.…”

Section: Introductionmentioning

confidence: 99%

<div>Effects of the protein corona on liposome–liposome and liposome–cell interactions</div>

Corbo

Molinaro

Taraballi³

et al. 2016

IJN

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A thorough understanding of interactions occurring at the interface between nanocarriers and biological systems is crucial to predict and interpret their biodistribution, targeting, and efficacy, and thus design more effective drug delivery systems. Upon intravenous injection, nanoparticles are coated by a protein corona (PC). This confers a new biological identity on the particles that largely determines their biological fate. Liposomes have great pharmaceutical versatility, so, as proof of concept, their PC has recently been implicated in the mechanism and efficiency of their internalization into the cell. In an attempt to better understand the interactions between nanocarriers and biological systems, we analyzed the plasma proteins adsorbed on the surface of multicomponent liposomes. Specifically, we analyzed the physical properties and ultrastructure of liposome/PC complexes and the aggregation process that occurs when liposomes are dispersed in plasma. The results of combined confocal microscopy and flow cytometry experiments demonstrated that the PC favors liposome internalization by both macrophages and tumor cells. This work provides insights into the effects of the PC on liposomes’ physical properties and, consequently, liposome–liposome and liposome–cell interactions.

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The Impact of Nanoparticle Protein Corona on Cytotoxicity, Immunotoxicity and Target Drug Delivery

Cited by 514 publications

References 162 publications

Nanomedicinal products: a survey on specific toxicity and side effects

Nanomedicinal products: a survey on specific toxicity and side effects

Facilitating Translational Nanomedicine via Predictive Safety Assessment

<div>Effects of the protein corona on liposome–liposome and liposome–cell interactions</div>

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The Impact of Nanoparticle Protein Corona on Cytotoxicity, Immunotoxicity and Target Drug Delivery

Cited by 514 publications

References 162 publications

Nanomedicinal products: a survey on specific toxicity and side effects

Nanomedicinal products: a survey on specific toxicity and side effects

Facilitating Translational Nanomedicine via Predictive Safety Assessment

<div>Effects of the protein corona on liposome&ndash;liposome and liposome&ndash;cell interactions</div>

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<div>Effects of the protein corona on liposome–liposome and liposome–cell interactions</div>