Silver nanoparticles biokinetics study by mathematical modelling of - PowerPoint PPT Presentation

NATIONAL RESEARCH CENTER “KURCHATOV INSTITUTE” Silver nanoparticles biokinetics study by mathematical modelling of the their transport in living organism Viacheslav A. Demin 1,2 , I.V. Gmoshinsky 3 , V.F. Demin 1 , A.A. Antsiferova 1 , P.K. Kashkarov 1,2,4 1 National Research Centre “ Kurchatov Institute”, Moscow , Russia 2 Moscow Institute of Physics and Technologies, Moscow Region, Russia 3 RAS Scientific Research Institute of Nutrition, Moscow, Russia 4 Lomonosov Moscow State University, Moscow, Russia

NATIONAL RESEARCH CENTER “KURCHATOV INSTITUTE” Nanotoxicity and Nanopharmaceutics Research: Aims and Problems  Nanomaterials (NMs) and, more specifically, Nanoparticles (NPs) potentially have new, emergent properties and unknown impact on living organisms.  Most of nanotoxicity research is implemented on cells cultures in vitro.  The experimental investigation of NPs impact on living beings is expensive and limited in literature.  Alternative: to investigate the Adsorbtion, Distribution, Metabolism and Excretion (ADME) of NPs by mathematical modelling of their transport in living organisms due to building of NPs impact prognostic scenarios based on limited experimental data.

NATIONAL RESEARCH CENTER “KURCHATOV INSTITUTE” The purpose of current study  The development and application of mathematical “chamber” model for adsorption, distribution and excretion of non-metabolizable NMs in the laboratory rat’s organism on the example of silver NPs. ARGOVIT-S  Silver NPs: (Biologically active food supplement; Russian production) – Ag NPs in PVP stabilizing shell with Average Diameter of 35  15 nm DLS measurements Number of NP, % Size, nm

NATIONAL RESEARCH CENTER “KURCHATOV INSTITUTE” Experiment on rats with Ag NP acute insertion through the gastrointestinal tract Activation by Insertion of neutrons in nuclear radioactively labelled Ag NPs reactor IR-8 Ag NPs through a colloids (Kurchatov Institute): stomach pump into Ag  110m Ag the rats’ GIT Organs and  -radiation bioliquids removal at measurements of 24, 48 and 72 hours radioactively labelled after NPs insertion Ag NPs in organs and bioliquids  Ag NPs content determination

NATIONAL RESEARCH CENTER “KURCHATOV INSTITUTE” Experimental results and specifications to the model Organ / tissue / Time after NP insertion, hours Specifications bioliquid* (simplifications) to the 24 48 72 model: GIT+feces (in total) >98 >98 >99 GIT (calculated value 65 6,2 0,2  Only those organs [Pinna K. et al, should be accounted J.Nutr., 2001]) for, the content of Ag Bone-muscular 0,36 ± 0,17 <0,6 0,23 ± 0,09 NPs in which is not carcass less than 20% of Liver 0,60 ± 0,18 0,8 ± 0,3 0,18 ± 0,10 blood NPs content Kidneys 0,014 ± 0,002 0,029 ± 0,008 0,007 ± 0,003 during the whole Blood experiment. 0,13 ± 0,05 0,20 ± 0,05 0,05 ± 0,02 Lungs 0,009 ± 0,003 0,016 ± 0,003 0,006 ± 0,003 Chambers for the model: Heart 0,0042 ± 0,0016 0,0060 ± 0,0015 0,0032 ± 0,0007 Pancreas  Gastrointestinal tract 0,0079 ± 0,0015 0,012 ± 0,005 0,0039 ± 0,0013  Blood Spleen 0,05 ± 0,02 0,06 ± 0,03 0,010 ± 0,004  Bone-muscular carcass Gonads 0,016 ± 0,003 0,033 ± 0,007 0,010 ± 0,004  Liver Brain  Spleen 0,0029 ± 0,0010 0,0123 ± 0,0023 0,0053 ± 0,0017 Urine (increasing 0,012 ± 0,002 0,032 ± 0,009 0,05 ± 0,04 total) * Values are in % of inserted dose of Ag NPs

NATIONAL RESEARCH CENTER “KURCHATOV INSTITUTE” Chamber Model Scheme k t,ex k t,b k b,t k b,r k r,b k b,m k m,b k b,l k l,b k b,s k s,b

NATIONAL RESEARCH CENTER “KURCHATOV INSTITUTE” Chamber Model System of Differential Equations  dM     M M , , M M M M , , , t k M k M k M , are where  t m l s b r t b , t b t , b t ex , t dt  the NPs mass or percentage dM     m k M k M , contents in the GIT, bone-  m b , m b m , b dt muscular carcass, liver, spleen,  dM blood and rest organs.     l k M k M , l b , l b l , b  dt According to the assumptions   dM made above about the chambers    s k M k M ,  s b , s b s , b dt that should be accounted for, we  can suppose that  dM      b k M k M k M k M k b,r  0.  t b , t m b , m l b , l s b , s dt Consequently, M r  0, and we         k k k k ) M k M k M ,  can neglect by the 2 terms of the b t , b m , b l , b s , b r b , r b r , b  last but one of equation and by dM     r k M k M , the last equation as a whole.  r b , r b r , b dt   This system of 5 ODE cannot be solved analytically, so the numerical methods should be used, along with a fitting of the biokinetics parameters set such that solutions would approximate the experimental data minimizing some optimization (e.g. the error least square) functional.

NATIONAL RESEARCH CENTER “KURCHATOV INSTITUTE” Chamber Model Solutions Results of biokinetics parameters fit:  k k   1/ 200 1/ 4.5  t b , b t ,     k k 1/ 60 1/ 45   m b , b m ,      k k    1 1/ 90 1/ 45 hour l b , b l ,     k k 1/ 90 1/ 27     s b , b s ,     1/15 0 k 0     t ex , The model does not satisfactorily approximate the GIT biokinetcs  The physiological timing of NPs excretion from GIT shall be accounted for in the case of acute NPs insertion: digestion process lasts from 18 to 25 0 50 100 150 hours, so hours  ( ) k     ( ) t ex , k ( ) t k ( ) t .  t ex , t ex ,  t 20    1 exp    5 

NATIONAL RESEARCH CENTER “KURCHATOV INSTITUTE” Chamber Model Solutions New results of biokinetics parameters fit:  k k    1/ 300 1/ 4 t b , b t ,     k k 1/ 50 1/ 55   m b , b m ,     k k     1 ( hour ) 1/ 50 1/ 30 l b , b l ,     k k   1/ 20 1/ 200   s b , b s ,      0 1/10 0 ( )   k   t ex ,  ( ) k   ( )   t ex , k ( ) t k ( ) t .  t ex , t ex ,  t 20    1 exp    5  0 50 100 150 The corrected model does satisfactorily hours approximate the GIT and other organs biokinetcs.

NATIONAL RESEARCH CENTER “KURCHATOV INSTITUTE” Chamber Model Prediction Capabilities 1. Stationary values of Ag NPs content in organs of rats reached under a sub- chronic nutrition can be evaluated. Percent of everyday NPs dose 100  k / k   M   417  b t , t b , t       k / k M 5       b m , m b , m k m        t b ,  M k / k m ng day [ / ]* 9 ( ng ) 10   l b l , l b ,   k k   t ex , b t , M 0.4  k / k      s b s , s b ,       0.1 5 M     1   b 0.01 where m is an everyday NPs dose in nanogramms. 10 -3 0 50 100 150 200 hours 2. Maximum (peak) dose evaluation of k k k    b o , b o , b o , M M ( t ) M 0,011 M , Ag NPs content in organ (indexed “o”) o ,max b o ,max b ,max 0 k k k o b , o b , o b , of rat, reached under the acute nutrition can be done.

NATIONAL RESEARCH CENTER “KURCHATOV INSTITUTE” Chamber Model Prediction Capabilities According to the most of literature sources [ Hussain S.M., et al., Toxicol. In vitro. 2005; Arora S., et al., Toxicol. Appl. Pharmacol. 2009; Haase A., et al., Toxicol. Sci. 2012; etc. ] any effects on cells cultures were observed at the Ag NPs concentration  3  g/g. Sub-chronic nutrition of Ag NPs Acute nutrition of Ag NPs 100 100 Stationary Ag NPs Content, Peak Ag NPs Content, 10 10  g/g of organ  g/g of organ 1 1 0.1 0.1 Liver Liver Spleen 0.01 Spleen 0.01 3  g/g 3  g/g 1E-3 1E-3 0.01 0.1 1 10 100 0.01 0.1 1 10 100 Daily dose,  g/g of body Single dose,  g/g of body Possible toxicity-emerging daily dose (for Possible toxicity-emerging daily dose (for liver): 10.6  g/g of body liver): 5.3  g/g of body These results qualitatively correspond to the experiments on rats and mices with Ag NPs: [ Kim Y.S., et al., Part. Fibre Toxicol. 2010; Shumakova A.A. , et al., Voprosy pitaniia 2011]