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Team:NJU China/Modeling
From 2013.igem.org
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Introduction
Pharmacokinetic Modeling
Parameters
Mass balance equation of exosome
Results and conclusions
After drug administration, what happened within the body is quite complex and all the tissues are involved in the drug metabolism. In order to construct a pharmacokinetic model, we need to first make a few simplification of the body to make a pharmacokinetic model feasible.
Based on the multi-compartmental model, we divide the human body into central compartment (blood circulation) and peripheral compartment (body tissues). Since the exosome is administrated by intravenous injection, we assume that the concentration of exosome within the blood circulation reached its peak soon after injection and there is no variation within different parts of the blood circulation. Inspired by the pharmacokinetic model made by iGEM Slovenia 2012, we subdivide the peripheral compartment into liver (our target organ), kidney, lung, rapidly perfused tissues (such as skin, muscle) and slowly perfused tissues (such as spleen, heart). Each peripheral compartment has blood exchange with the central blood circulation, and during this process, certain percentage of exosome flow through a compartment will be absorbed. Apart from that, some of the exosome get into the kidney will be eliminated. Based on these simplifications, our multi-compartmental model is shown in the figure 1.
Introduction
Pharmacokinetics is the quantitative study of the drug absorption, distribution and metabolism within the body. It shows the fluctuation of the drug concentration within a certain part of the body along the time. For a new drug, we need to first experimentally obtain the pharmacokinetic parameters and then make the pharmacokinetic model to predict the concentration change after drug administration. Thus pharmacokinetic model plays a vital role in new drug development. Since our targeting-exosome is a brand new drug delivery system, we need to make a pharmacokinetic model to check if it can really target the specific site we want and predict the concentration change within that site.
Pharmacokinetic Modeling
After drug administration, what happened within the body is quite complex and all the tissues are involved in the drug metabolism. In order to construct a pharmacokinetic model, we need to first make a few simplification of the body to make a pharmacokinetic model feasible.
Based on the multi-compartmental model, we divide the human body into central compartment (blood circulation) and peripheral compartment (body tissues). Since the exosome is administrated by intravenous injection, we assume that the concentration of exosome within the blood circulation reached its peak soon after injection and there is no variation within different parts of the blood circulation. Inspired by the pharmacokinetic model made by iGEM Slovenia 2012, we subdivide the peripheral compartment into liver (our target organ), kidney, lung, rapidly perfused tissues (such as skin, muscle) and slowly perfused tissues (such as spleen, heart). Each peripheral compartment has blood exchange with the central blood circulation, and during this process, certain percentage of exosome flow through a compartment will be absorbed. Apart from that, some of the exosome get into the kidney will be eliminated. Based on these simplifications, our multi-compartmental model is shown in the figure 1.
Parameters
Mass balance equation of Exosome
A. The concentration change of the exosome within each compartment over time
a .The central compartment-blood circulation
The exosomes are removed from the blood through two main ways: distribution to other compartments and metabolism in the blood. Based on that, the mass balance equation of exosomes goes like follows:
b. The peripheral compartments
There are two main factors affect the concentration fluctuation in peripheral compartments: absorption from the blood and metabolism within the compartments.
For kidney, there is an additional factor, which is the elimination rate of the exosomes by kidney.
Thus the mass balance equations of the peripheral compartments are listed as below:
Liver:
Lung:
Kidney:
Rapidly perfused tissues:
Slowly perfused tissues:
Solving all the mass equations above, we can get the function which show the concentration change within each compartment along the time:
Blood circulation:
Liver:
Lung:
Kidney:
Rapidly perfused tissues:
Slowly perfused tissues:
B. Examine the relationship between the exosome concentration change over time and absorption percentage within liver.
C. Examine the relationship between the exosme concentration change over time and drug half-life within liver.
Lung:
Kidney:
Rapidly perfused tissues:
Slowly perfused tissues:
Solving all the mass equations above, we can get the function which show the concentration change within each compartment along the time:
Blood circulation:
Liver:
Lung:
Kidney:
Rapidly perfused tissues:
Slowly perfused tissues:
B. Examine the relationship between the exosome concentration change over time and absorption percentage within liver.
C. Examine the relationship between the exosme concentration change over time and drug half-life within liver.
Results and Conclusions
A.Exosome concentration change over time within each compartment
Figure.2 Exosome concentration change along the time in different compartments.
As we can see from the figure.2, the concentration of exosomes in the blood falls down along the time while the concentration of exosomes in the peripheral compartment goes up first then falls down. Comparing the concentration change of exosomes over time in the liver(our target organ) with other tissues, we can easily see that the peak concentration of exosomes in liver is much higher than that of non-target tissues. Thus we can assure that the after add the liver targeting protein to the exosome (the percentage of exosomes get into the liver increases), the concentration of exosomes in the liver greatly outnumber that in other tissues.
B.The relationship between the exosome concentration change over time and absorption percentage in liver.
Figure.3 exosome concentration change over time with different absorption percentage in liver
The difference of exosome distribution between liver and other tissues lie in that the absorption percentage of exosomes in liver is much higher than that in other tissues. After plot concentration change over time and absorption percentage in 3D(Figure.3),we can see that as the absorption percentage increases, the peak of drug concentration also goes up. To achieve higher concentration in liver, we can make outside modification to exosomes to direct more exosomes into the liver.
C.The relationship between the exosome concentration change over time and drug half-life.
Figure.4 exosome concentration change over time with different exosome halflife in liver
Encapsulate the siRNA into exosomes can great increase the half-life of the siRNA, and via outside modification we can change the half-life of the exosome. As we can see from Figure.4 , after the drug half-life increases, the concentration falls more slowly so that the drug can function more time in the target tissue.
Reference:
1. Ishida T, Harashima H, Kiwada H. Liposome clearance[J]. Bioscience reports, 2002, 22: 197-224.
2. Dams ETM, Laverman P, Oyen W JG, et al. Accelerated blood clearance and altered biodistribution of repeated injections of sterically stabilized liposomes[J]. Journal of Pharmacology and Experimental Therapeutics, 2000, 292(3): 1071-1079.
3. Gao S, Dagnaes-Hansen F, Nielsen EJB, et al. The effect of chemical modification and nanoparticle formulation on stability and biodistribution of siRNA in mice[J]. Molecular Therapy, 2009, 17(7): 1225-1233.
4. Morrissey DV, Lockridge JA, Shaw L, et al. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs[J]. Nature biotechnology, 2005, 23(8): 1002-1007.
Figure.2 Exosome concentration change along the time in different compartments.
As we can see from the figure.2, the concentration of exosomes in the blood falls down along the time while the concentration of exosomes in the peripheral compartment goes up first then falls down. Comparing the concentration change of exosomes over time in the liver(our target organ) with other tissues, we can easily see that the peak concentration of exosomes in liver is much higher than that of non-target tissues. Thus we can assure that the after add the liver targeting protein to the exosome (the percentage of exosomes get into the liver increases), the concentration of exosomes in the liver greatly outnumber that in other tissues.
B.The relationship between the exosome concentration change over time and absorption percentage in liver.
Figure.3 exosome concentration change over time with different absorption percentage in liver
The difference of exosome distribution between liver and other tissues lie in that the absorption percentage of exosomes in liver is much higher than that in other tissues. After plot concentration change over time and absorption percentage in 3D(Figure.3),we can see that as the absorption percentage increases, the peak of drug concentration also goes up. To achieve higher concentration in liver, we can make outside modification to exosomes to direct more exosomes into the liver.
C.The relationship between the exosome concentration change over time and drug half-life.
Figure.4 exosome concentration change over time with different exosome halflife in liver
Encapsulate the siRNA into exosomes can great increase the half-life of the siRNA, and via outside modification we can change the half-life of the exosome. As we can see from Figure.4 , after the drug half-life increases, the concentration falls more slowly so that the drug can function more time in the target tissue.
Reference:
1. Ishida T, Harashima H, Kiwada H. Liposome clearance[J]. Bioscience reports, 2002, 22: 197-224.
2. Dams ETM, Laverman P, Oyen W JG, et al. Accelerated blood clearance and altered biodistribution of repeated injections of sterically stabilized liposomes[J]. Journal of Pharmacology and Experimental Therapeutics, 2000, 292(3): 1071-1079.
3. Gao S, Dagnaes-Hansen F, Nielsen EJB, et al. The effect of chemical modification and nanoparticle formulation on stability and biodistribution of siRNA in mice[J]. Molecular Therapy, 2009, 17(7): 1225-1233.
4. Morrissey DV, Lockridge JA, Shaw L, et al. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs[J]. Nature biotechnology, 2005, 23(8): 1002-1007.
