Dissolution Behavior and Biodurability of Ingested Engineered

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Dissolution Behavior And Biodurability Of Ingested Engineered Nanomaterials In The Gastrointestinal Environment Ikjot Singh Sohal, Young Kwan Cho, Kevin S O'Fallon, Peter Gaines, Philip Demokritou, and Dhimiter Bello ACS Nano, Just Accepted Manuscript • DOI: 10.1021/acsnano.8b02978 • Publication Date (Web): 18 Jul 2018 Downloaded from http://pubs.acs.org on July 19, 2018

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Dissolution Behavior And Biodurability Of Ingested Engineered Nanomaterials In The Gastrointestinal Environment Ikjot Singh Sohal1*, Young Kwan Cho2, Kevin S. O’Fallon3, Peter Gaines4, Philip Demokritou5, and Dhimiter Bello1,5,6* 1

Biomedical Engineering & Biotechnology Program, University of Massachusetts Lowell, Lowell, MA 01854, USA

2

Department of Chemistry, Kennedy College of Sciences, University of Massachusetts Lowell, Lowell, MA 01854, USA 3

4

Natick Soldier Research, Development and Engineering Center, Natick, MA 01760, USA

Department of Biological Sciences, University of Massachusetts Lowell, Lowell, MA 01854, USA 5

Harvard T.H. Chan School of Public Health, Department of Environmental Health and the Harvard Center for Nanotechnology and Nanotoxicology; Boston, MA 02115, USA

6

Department of Biomedical and Nutritional Sciences, Zuckerberg College of Health Sciences, University of Massachusetts Lowell, Lowell, MA 01854 1 ACS Paragon Plus Environment

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*Correspondence to: [email protected]; [email protected] Department of Biomedical and Nutritional Sciences 883 Broadway Street, Dugan 110-S Lowell, MA 01854 978.934.3343 [email protected]

ABSTRACT Engineered nanomaterials (ENM) are extensively used as food additives in numerous food products and at present, little is known about the fate of ingested ENM (iENM) in the gastrointestinal (GI) environment. Here, we investigated the dissolution behavior, biodurability and persistence of 4 major iENM (TiO2, SiO2, ZnO and two Fe2O3) in individual simulated GI fluids (saliva, gastric and intestinal) and a physiologically relevant digestion cascade (saliva gastric intestinal) in the fasted state over physiologically relevant time frames. TiO2 was found to be the most biodurable and persistent iENM in simulated GI fluids with a maximum of only 0.42% (4 µM Ti4+ ion release) dissolution in cascade digestion, followed by iron oxides, of which the rod-like morphology was more biodurable and persistent (0.7% maximum dissolution, 8.7 µM Fe3+) than the acicular one (2.27% maximum dissolution, 16.7 µM Fe3+) in the cascade digestion, respectively. SiO2 and ZnO were less biodurable than Fe2O3, with 65.5% (416 µM Si4+) and 100% (1718.1 µM Zn2+) dissolution in the gastric phase, respectively. In the intestinal phase, however, Si4+ ions re-precipitated, possibly due to sudden pH changes while ZnO remained completely dissolved. These observations were also confirmed using high resolution 2 ACS Paragon Plus Environment

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particle size and concentration, and electron microscopy, time dependent analysis. In terms of decreasing biodurability and persistence in the simulated GI environment, the tested nanomaterials can be ranked as follows: TiO2 >> rod-like Fe2O3 > acicular Fe2O3 >> SiO2 > ZnO, which is in agreement with limited animal biokinetics data. Chronic uptake of these iENM as particles or ions by the GI tract, especially in the presence of a food matrix and authentic digestive media, and associated implications for human health, warrants further investigation.

KEYWORDS: engineered nanomaterials, food, ingested, gastrointestinal, biodurability, dissolution

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Engineered nanomaterials (ENM) are being used extensively in the food industry to fulfill a number of roles, including as food additives, nutritional supplements, and for food packaging. The underlying idea behind the above-mentioned ENM applications is to maintain and/or enhance the texture, flavor, color, consistency, quality, nutrient bioavailability, or even consumer’s perception of food.

1

We will refer to these ingested engineered nanomaterials as

iENM. Some of these iENM are 100% in the nanoscale (e.g. SiO2 E551), whereas others contain only a sub-fraction, which may vary by product type, manufacturer or process. The term iENM in this paper is used to indicate the nanoscale fraction in the nanomaterial food additives, unless otherwise specified. A good example of an iENM used widely in foods as a whiting agent is pigmented TiO2, which has an average size of 200-400 nm, with rod-like Fe2O3 (≤ 0.7%) > acicular Fe2O3 (≤ 2.27%) > SiO2 (≤ 65.5%) > ZnO (100%). Titania is used as an additive in several food products such as candies,

2

whereas iron oxides are used as food/color

additives in soft and hard candy, mints, chewing gums, and fish and crustacean paste.

46,47

In

addition, nano silica is present in several food products such as pancake mix, lasagna sauce mix and burrito seasoning mix at concentrations of > rod-like Fe2O3 > acicular Fe2O3 >> SiO2 > ZnO, which is in agreement with limited animal data. It remains to be seen how biodurability and persistence or lack thereof for a particular iENM affects the overall gut health chronically, and how authentic digestive media and the presence of food matrix would impact the dissolution behavior and biodurability of these iENM in the human GI tract.

Materials and methods Acquisition of food-grade nanomaterials Following an extensive literature review,

14

nanomaterials were acquired from the respective

vendors/manufacturers. Certificate of analysis listing the nanomaterials as food-grade was 29 ACS Paragon Plus Environment

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requested for each acquired nanomaterial separately. Eleven nanomaterials, which were certified as food-grade by their respective manufacturers, were acquired (Supplementary material, Table S6). Along with the documentation provided by the respective manufacturers that the nanomaterials are added to food products, titania, silicas and iron oxides also had a designated Enumber, which are codes for substances that can be used as food additives for use within the European Union and Switzerland. Based on the presence of nanoparticles in these materials and their current use in food products, 5 nanomaterials were selected for further investigation – TiO2 A200, SiO2 AEROSIL-200F, ZnO AZO66USP, Fe2O3 SICOVIT R30 (rod-shaped), and Fe2O3 R2130 (acicular-shaped). For brevity, we will refer to them as TiO2 (TiO2 A200), SiO2 (SiO2 AEROSIL-200F), ZnO (ZnO AZO66USP), Fe2O3 S (Fe2O3 SICOVIT R30) and Fe2O3 R (Fe2O3 R2130).

Chemicals The following chemicals were obtained from Sigma-Aldrich (St Louis, MO, USA): urea (ACS reagent, 99-100.5%), D-(+)-glucose (BioXtra, ≥99.5%), D-glucuronic acid (≥98%), D-(+)glucosamine hydrochloride (≥99%, crystalline), potassium chloride (ACS reagent, 99-100.5%), potassium thiocyanate (ACS reagent, ≥99%), potassium phosphate monobasic (anhydrous, freeflowing, Redi-Dri™, ACS reagent, ≥99%), sodium sulfate (ACS reagent, ≥99.0%, anhydrous, granular), sodium chloride (BioXtra, ≥99.5%), sodium bicarbonate (BioXtra, 99.5-100.5%), ammonium chloride (ACS reagent, ≥99.5%), calcium chloride dihydrate (BioXtra, ≥99.0%), sodium phosphate monobasic monohydrate (ACS reagent,

≥98%), magnesium chloride

hexahydrate (BioXtra, ≥99.0%), mucin from porcine stomach (Type III, bound sialic acid 0.51.5 %, partially purified powder), uric acid (≥99%, crystalline), α-amylase from bacillus species


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(powder, ≥400 units/mg protein), bovine serum albumin (lyophilized powder, Microbiologically tested, ≥96%), pepsin from porcine gastric mucosa (powder, ≥250 units/mg solid), pancreatin from porcine pancreas (8 × USP specifications), lipase from Candida Rugosa (Type VII, ≥700 unit/mg solid), bovine bile (dried, unfractionated), sodium hydroxide (ACS reagent, ≥97.0%, pellets), hydrochloric acid (ACS reagent, 37%), and pH 2.0, 4.0 and 7.0 reference buffers.

Dry state characterization of iENM The 5 selected iENM were extensively characterized using multiple independent and complementary techniques as follows: (i) Elemental and water-soluble metal analysis by SFICP-MS (sector field inductively coupled plasma mass spectrometry); (ii) Size and morphology characterization by TEM (transmission electron microscopy); (iii) Crystallinity by XRD (X-ray diffraction); (iv) Surface chemistry by FTIR (Fourier-transform infrared spectroscopy) and XPS (X-ray photoelectron spectroscopy); (v) Surface area by BET (Brunauer-Emmett-Teller, N2 sorption method); and (vi) total organic content by OC/EC analysis (organic carbon/elemental carbon) by thermo gravimetric analysis. Elemental analysis and water-soluble fraction of metals by SF-ICP-MS, OC/EC analysis, surface area measurements by BET, XRD, and XPS were conducted as described previously. 50,51 For TEM analysis, a dilute nanoparticle suspension in DI water at ~ 100µg/mL was vortexed briefly and ~50µL were transferred onto a 200-mesh copper grid (Electron Microscopy Sciences, EMS200-Cu), which was left in open air to air dry prior to imaging under a transmission electron microscope (Philips EM400T). FTIR spectroscopy analysis was conducted using an FTIR spectrometer (Bruker Tensor 27). Five mm diameter KBr micropellets were prepared for all


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nanomaterials (NM) at ~ 1% w/w iENM. FTIR spectra were acquired in transmission mode at a resolution of 2 cm-1.

Preparation of simulated digestive fluids The composition of each digestive fluid is summarized in Table S5 (Supplementary material). 52

For each dissolution experiment, 50 ml of organic and inorganic solution of each digestive

fluid were prepared 24 hr before the experiment and stirred overnight at room temperature. Approximately 1-2 hr before the experiment, the organic and inorganic solutions for the respective digestive fluid were mixed in a ratio of 1:1 (v/v). While the mixture was being stirred, the enzymes were weighed and added to the digestive fluid (Table S5) and the solution was stirred again for 30-40 min. The pH of the digestive fluids was then adjusted to the values indicated in Table S5 by using a pH meter calibrated with standard buffers at pH 2.0 (for gastric fluid) or pH 7.0 standard buffer (for saliva, duodenal and bile fluids). Digestive fluids adjusted to the correct pH were then used for dissolution experiments.

Dissolution in digestive fluids The schematic of the dissolution process is summarized in Figure VI. For all dissolution tests, a DS-126 dissolution tester (Erweka GmbH) USP Apparatus 2 (paddle method), retrofitted with 100 mL glass vessels was used. For silica iENM nanoparticles, Teflon-coated vessels had to be used to eliminate artifacts from Si leaching from glass walls. The nanoparticle suspensions in digestive fluids were stirred and maintained at physiological temperatures, and fractions were collected throughout incubations or between the steps to study size, size distribution, morphology, charge, pH and release of ions over time in a specific or a mixture of digestive fluids. We worked with 10-50 ml of digestive fluids to represent the physiological levels secreted 32 ACS Paragon Plus Environment

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Figure VI. Schematic of the dissolution procedure. The NP dispersion in DI water were prepared based on standard dispersion protocol 55 and characterized. For independent dissolution (

), NP dispersions were directly added to each digestive fluid and for cascade dissolution ( ), NP dispersions were sequentially added to saliva, gastric and intestinal fluid. Total and

filtrate fraction were collected at several time points ( denoted by “

) and analyzed for various parameters,

”. All the dissolutions were performed in fasted state.

per meal. 53,54 Before preparing suspensions of nanomaterials in digestive fluids, they were well dispersed in DI water using standardized dispersion protocols.

55-57

The DI water suspensions

were sonicated at DSEcr (critical delivered sonication energy) of the respective nanomaterial and confirmed for low polydispersity and no presence of agglomerates. The dissolution kinetics were 33 ACS Paragon Plus Environment

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studied in each digestive fluid independently (independent dissolution) as well as in a GI tractrelevant cascade (cascade dissolution). Based on an estimated daily intake range between 1.8 mg/kg bw for silica and 5.4 mg/kg bw for titania, we chose the initial iENM dose to be ~2 mg in each digestive fluid (see Supplementary material, Table S4). For dissolution in independent digestive fluids, a 1 mg/ml suspension of nanomaterial in DI water was sonicated and transferred to simulated saliva/gastric/intestinal fluid (1:10 dilution, 100µg/mL), preheated to 37° C in a glass vessel in the dissolution tester. For cascade dissolution experiments, the sonicated nanomaterial suspension was transferred to simulated saliva (1:10 dilution, 100µg/mL) preheated to 37° C followed by sequential dilution in preheated simulated gastric fluid (1:2 v/v saliva:gastric, 35.71 µg/mL final) after 15 min. After 6 hr in gastric fluid, the suspension was transferred into the intestinal phase, which involved further dilution in simulated duodenal and bile fluid in a saliva:gastric:duodenal:bile ratio of 1:2:2:1 by volume (18.18 µg/mL final). The intestinal phase was continued for 6 hr. The individual medium and cascade digestions in this initial investigation were performed in the fasted state. Fractions from each digestion medium were collected and analyzed at several time points for size and size distribution using Zetasizer Nano S90 (Malvern Instruments Inc., Westborough, MA, USA) and qNano (Izon Science Ltd., Christchurch, New Zealand), for morphology using Philips EM400T transmission electron microscope (TEM), for pH using a pH meter (Accumet® 925), and for total metals (nanoparticles + ions) and selective ion release using SF-ICP-MS. For dissolved ion analysis, 1mL of the suspension at each time point was filtered through a Whatman® Anotop® 25 plus 0.02µm syringe filter (GE Healthcare Bio-Sciences, Pittsburgh, PA, USA) into an externally threaded 1.8mL capacity cryovial and the filtrate volume


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was recorded. The absence of particles from the filtrate was confirmed using DLS and TRPS (tunable resistive pulse sensing) analysis (Izon Science), on a qNano instrument. 58

Changes in size distribution and particle concentration of iENM dispersions Size distribution and number concentration of iENM dispersions was tracked over time using TRPS (at discrete time points) and DLS (at all time points). Standard carboxylated polystyrene calibration particles (provided by the manufacturer) were used in simulated saliva and intestinal fluid dissolution experiments, whereas, 200 nm NIST monodisperse polystyrene particles (Alfa Aesar™), which were more stable at low pH conditions, were used to determine size distribution and particle concentration in simulated gastric fluid. In simulated saliva fluid, TRPS measurements were recorded at the beginning (1-5 min) and end (60 min) of the dissolution. In simulated gastric and intestinal fluid, the measurements were recorded at 2 min, 2 hr and 8 hr. To avoid artifacts in size distribution induced by possible pH changes during sample dilution for TRPS measurements, a pH 2.0 buffer was used to dilute nanoparticle suspensions in gastric fluid, and a 1X PBS (pH 7.0) to dilute nanoparticle suspensions in saliva and intestinal fluid.

Changes in ion release and agglomeration state of iENM dispersions Nanoparticle suspensions in individual digestive media and cascade digestion were characterized at all time points for Z-average (average agglomerate size) and PdI (polydispersity index) with a Zetasizer Nano S90 (Malvern Instruments Inc., Westborough, MA, USA) at 25 °C. Two to three measurements were made for each sample.


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Statistical analysis All experiments were conducted in triplicates. Ion release kinetics for each nanomaterial were fit to constant, linear or polynomial regression equations with 90% confidence intervals based on lower residual sum of squares and higher R2 values. The intercept, slope and coefficient of the regression equations, where applicable, were tested for statistical significance using unpaired two-tail t-test. Total and specific size range particle concentrations at different timepoints were also compared using unpaired two-tail t-test. Results are presented as mean ± SD. P-values < 0.05 were considered significant.

Supporting information Supplementary material: Dry state characterization of iENM; Table S1. Summary of major PCM properties of five tested iENM. Table S2. Summary of major toxicologically relevant elements and their concentrations (total and water-soluble) in the five food-grade nanomaterials tested in the study. Table S3. Summary of major elements present and their concentrations in various food-grade nanomaterials. Determination of initial nanomaterial dose for dissolution experiments (calculation); Table S4. Estimated single exposure for each nanomaterial, taking into account the nanoscale fraction; Table S5. Composition of simulated digestive fluids of the “fasted” in vitro digestion model (amounts based on 100 ml of fluid); Table S6. List of acquired model food-grade nanomaterials. Note that not all materials are nanoscale; Figure S1 – Representative TEM images of TiO2 A200 (A), SiO2 AEROSIL-200F (B), ZnO AZO66USP (C), Fe2O3 SICOVIT R30 (D), and Fe2O3 R2130 (E). Bar – 100 nm. Figure S2 – XRD patterns of food-grade nanomaterials used in the study. XRD pattern for SiO2 Aerosil-200F was not determined due to its amorphous nature; Figure S3 – Total particle concentration of different nanomaterials in simulated saliva fluid at 1 min and 60 min as measured by TRPS. First time point (0 min) represents the total particle concentration of blank saliva fluid; Figure S4 – Total particle concentration of different nanomaterials in simulated gastric fluid at 2 min, 2 hr (120 min) and 8 hr (480 min) as measured by TRPS. First time point (0 min) represents the total particle concentration of blank gastric fluid; Figure S5 – Total particle concentration of different nanomaterials in simulated intestinal fluid at 2 min, 2 hr (120 min) and 8 hr (480 min) as measured by TRPS. First time point (0 min) represents the total particle concentration of blank intestinal fluid; Figure S6 – Evaluation of changes in


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morphology or agglomeration state of various nanomaterials in simulated saliva fluid. TiO2 A200 (A), SiO2 AEROSIL-200F (B), ZnO AZO66USP (C), Fe2O3 SICOVIT-R30 (D), and Fe2O3 R2130 (E). The scale bar is 500 nm unless specified; Figure S7 – Evaluation of changes in morphology or agglomeration state of various nanomaterials in simulated gastric fluid. TiO2 A200 (A), SiO2 AEROSIL-200F (B), ZnO AZO66USP (C), Fe2O3 SICOVIT-R30 (D), and Fe2O3 R2130 (E). The scale bar is 500 nm; Figure S8 – Evaluation of changes in morphology or agglomeration state of various nanomaterials in simulated intestinal fluid. TiO2 A200 (A), SiO2 AEROSIL-200F (B), ZnO AZO66USP (C), Fe2O3 SICOVIT-R30 (D), and Fe2O3 R2130 (E). The scale bar is 500 nm. (PDF, 1,661 KB)


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Declarations The opinions or assertions contained herein are the private views of the author(s) and are not to be construed as official or as reflecting the views of the U.S. Army or the Department of Defense.

Ethics approval and consent to participate Not applicable

Consent for publication Not applicable

Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests The authors declare that they have no competing financial interests.

Funding This study was funded in part by the US Army Natick Soldier Systems Center, Natick Soldier Research, Development and Engineering Center (NSRDEC), Cooperative Agreement, W911QY14 and W911QY-14-2-0001; Advanced materials and processes for improving soldier protection and survivability, CLIN Project C5.


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Author’s contributions IS and DB designed the study. IS and YC collected the data and conducted the initial data analysis. IS compiled the results and prepared the draft manuscript. DB oversaw data analysis, data interpretation and co-wrote manuscript. K O’F, PG and PD contributed to the study design, interpretation, and provided important intellectual contribution to the manuscript. All authors read and approved the final manuscript.

Acknowledgements Not applicable

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