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SOURCES OF BIASES IN THE IN VITRO TESTING OF NANOMATERIALS: THE ROLE OF BIOMOLECULAR CORONA

ABSTRACT: The biological fate of nanomaterials (NMs) is driven by the specific interactions that biomolecules, naturally adhering onto their surface, engage with cell membrane receptors and intracellular organelles. The molecular composition of this layer, called biomolecular corona (BMC), depends on both the physical-chemical features of the NM and the biological media in which the NM is dispersed and cells grow. In this work, we demonstrate that the widespread use of 10% fetal bovine serum for in vitro assay is unable to recapitulate the complexity of an in vivo systemic administration, with NMs being transported by the blood. To this purpose, we undertook a comparative journey involving proteomics, lipidomics, high-throughput multiparametric in vitro screening, as well as single molecular feature analysis, to investigate the molecular details behind this in vivo/in vitro bias. Our work indirectly highlights the need to introduce novel, more physiological-like media, closer in composition to human plasma, to produce realistic in vitro screening data for NMs. We also aim to set the basis to reduce this in vitro-in vivo mismatch, which currently limits the formulation of NMs for clinical settings.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Plasma

SUBMITTER: Andrea Armirotti

LAB HEAD: Andrea Armirotti

PROVIDER: PXD046988 | Pride | 2024-05-31

REPOSITORIES: Pride

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			Action	DRS
	CB_14Mar2022_GNPsCorona_Test1_DIA_Medium1hRep1.raw	Raw
	CB_14Mar2022_GNPsCorona_Test1_DIA_Medium1hRep2.raw	Raw
	CB_14Mar2022_GNPsCorona_Test1_DIA_Medium1hRep3.raw	Raw
	CB_14Mar2022_GNPsCorona_Test1_DIA_Medium1hRep4.raw	Raw
	CB_14Mar2022_GNPsCorona_Test1_DIA_Medium1hRep5.raw	Raw

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Project description:Fang2010 - Genome-scale metabolic network of Mycobacterium tuberculosis (iNJ661m) This model is described in the article: Development and analysis of an in vivo-compatible metabolic network of Mycobacterium tuberculosis. Fang X, Wallqvist A, Reifman J. BMC Syst Biol 2010; 4: 160 Abstract: BACKGROUND: During infection, Mycobacterium tuberculosis confronts a generally hostile and nutrient-poor in vivo host environment. Existing models and analyses of M. tuberculosis metabolic networks are able to reproduce experimentally measured cellular growth rates and identify genes required for growth in a range of different in vitro media. However, these models, under in vitro conditions, do not provide an adequate description of the metabolic processes required by the pathogen to infect and persist in a host. RESULTS: To better account for the metabolic activity of M. tuberculosis in the host environment, we developed a set of procedures to systematically modify an existing in vitro metabolic network by enhancing the agreement between calculated and in vivo-measured gene essentiality data. After our modifications, the new in vivo network contained 663 genes, 838 metabolites, and 1,049 reactions and had a significantly increased sensitivity (0.81) in predicted gene essentiality than the in vitro network (0.31). We verified the modifications generated from the purely computational analysis through a review of the literature and found, for example, that, as the analysis suggested, lipids are used as the main source for carbon metabolism and oxygen must be available for the pathogen under in vivo conditions. Moreover, we used the developed in vivo network to predict the effects of double-gene deletions on M. tuberculosis growth in the host environment, explore metabolic adaptations to life in an acidic environment, highlight the importance of different enzymes in the tricarboxylic acid-cycle under different limiting nutrient conditions, investigate the effects of inhibiting multiple reactions, and look at the importance of both aerobic and anaerobic cellular respiration during infection. CONCLUSIONS: The network modifications we implemented suggest a distinctive set of metabolic conditions and requirements faced by M. tuberculosis during host infection compared with in vitro growth. Likewise, the double-gene deletion calculations highlight the importance of specific metabolic pathways used by the pathogen in the host environment. The newly constructed network provides a quantitative model to study the metabolism and associated drug targets of M. tuberculosis under in vivo conditions. This model is hosted on BioModels Database and identified by: MODEL1507180018. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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SOURCES OF BIASES IN THE IN VITRO TESTING OF NANOMATERIALS: THE ROLE OF BIOMOLECULAR CORONA

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