Simulation Based Analysis of Nanocarrier Internalization: Exciting Challenges with a New Computational Tool - Intracellular Delivery: Fundamentals and Applications - page 128

this example. Of course, a number of uptake (endocytic) routes can be considered
and explored. In our specific case, we only consider the following three routes:
FPM/NAE (fluid phase macropinocytosis, which we lumped together with nonspe-
cific adsorptive endocytosis), RME (receptor-mediated endocytosis) and LRME
(lipid-rafts mediated endocytosis) (Prokop and Davidson 2008 ; Doherty and
McMahon 2009 ) as the most predominant mechanisms. We also consider a molecular
motor in our scheme, as cellular motor proteins are responsible for moving struc-
tural elements to specific cellular locations and trafficking of endocytic and exo-
cytic vesicles (Holzbaur and Goldman 2010 ; Robert et al. 2010 ). We set the
exocytosis rate by one order of magnitude less of the endocytosis rate as found
experimentally by (Jin et al. 2009 ). Note, sorting and recycling is not properly
delineated as it may occur from different endosomal stages (early endosomes,
endosomal compartment and recycling endosome; Grant and Donaldson 2009 ).
Motor proteins may be considered as a recycling vehicle at this simplified stage.
There is very limited literature on simulation of endocytosis (see Wattis et al. 2008 ,
on LDL uptake by hepatocytes).
We consider multiple entry mechanisms simultaneously as there are several
means of internalization that operate concurrently at the cell surface. Various data
suggests that the cellular internalization of nanoparticles occurs through a multifac-
eted internalization mechanism primarily involving caveolae, yet clathrin-coated
vesicles and macropinosomes are also involved to a lesser degree. Various cells
may use alternative entry mechanisms to a different degree (Kumari et al. 2010 ).
Endocytosis also samples the extracellular milieu and serves to regulate various
processes initiated at the cell surface. These include nutrient uptake, signaling from
cell-surface receptors, and many other processes essential for cell and tissue func-
tion, emphasizing why the knowledge and extent of use different routes is of prime
importance. The ability to understand and predict the cellular uptake (and exocyto-
sis) of nanoparticles quantitatively should find utility in designing nano-systems
with controlled toxicity, efficacy and functionality.

2 Model Design

2.1 Simplified Scheme of the Model

Model design usually starts from the qualitative description of the biological
processes and the involved components. In this case, we try to develop a preliminary
model of the drug delivery related endocytosis and exocytosis. Modeling is limited
by the fact that we do not have experimental data for the identification and valida-
tion of the model. Rather we use the model to gain a better understanding of the
simultaneous trafficking and recycling processes. In addition, a preliminary model
can help to plan the appropriate set of possible measurements that supports the
identification and validation. Afterwards, with the knowledge gained from the