Drug delivery using intravascular injection of targeted nanocarriers (NCs) is a potent application of nanotechnology to treat disease. Many aspects of targeted drug nanocarrier design and medical use such as optimization of carrier size, concentration, surface coverage with targeting molecule and drug cargo packaging are amenable to multiscale computational modeling. Simulation used to provide predictive values of appropriate characteristics for manufacture and clinical application can reduce the time, expense and other resources necessary for otherwise large scale experimentation. For instance, hydrodynamic and microscopic interactions mediating NC motion and cargo offloading occurring in bloodflow, endothelial cell binding and cell internalization are complex interplay of defineable mechanical and molecular events occuring at multiple length and time scales. We hypothesize that computational modeling and simulation of these critical hydrodynamic and molecular events can be accessed to optimize design parameters such that nanocarriers loaded with trackable cargoes and decorated with targeting molecules to endothelial determinants (e.g., ICAM-1 surface molecules) will: i) efficiently bid to endothelial cells, ii) enter endothelial endosomes and, iii) effectively unload their cargo in this compartment. We propose to develop and validate a multiscale computational modeling platform to optimize endothelial drug delivery, including dispersal of the delivered cargo within target cells. Our model includes sensitivity analysis~ it will be validated through synergistic animal and cell culture experiments of NC binding mechanics and intracellular cargo offloading efficiency. This will be accomplished via three specific aims:
Aim 1 : Multiscal modeling of hydrodynamic and microscopic interactions mediating NC motion in vascular targeted drug delivery involving three distinct scales: a macroscopic regime, a lubrication regime and an adhesion regime.
Aim 2 : Multiscale modeling of transport and controlled drug release from a targeted NC in blood flow. The computational model approaches in Aims 1 and 2 will be tuned using sensitivity analysis on important governing parameters.
Aim 3 : Experimentally quantify NC targeting kinetics (using prototype anti-ICAM and alternative surface molecules), carrier internalization and intracellular drug delivery using dextran hydrogel nanocarriers loaded with prototype model fluorescence-labeled cargoes. We will utilize physiologically relevant in vitro and in vivo systems forthese experiments. Validation of numerical simulation results (Aims 1 and 2) will be made by comparison of predictions with experimentally observed transport and release properties (Aim 3). Our team of Engineers, Materials Scientists, Pharmacologists and Vascular Biologists brings combined expertise in modeling and experimental approaches that are versatile. This will enable us to adapt protocols to specific applications for optimal engineering design and clinical translation of NC drug delivery for targeted disease treatment.

Public Health Relevance

Drugs can be packaged as deliverable cargo into nanocarrier particles designed to target diseased tissue directly via bloodstream delivery. We are developing a computational model to optimize vascular drug delivery, including dispersal of the delivered cargo within target cells. Our model will be validated through synergistic animal and cell culture experiments of nanocarrier binding mechanics and cargo offloading efficiency. This work will provide computationally quantitative and predictive methods to optimize targeted nanocarrier design for drug therapies used to treat many diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
2R01EB006818-05A1
Application #
8500720
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Tucker, Jessica
Project Start
2006-12-01
Project End
2017-03-31
Budget Start
2013-06-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$491,533
Indirect Cost
$184,325
Name
University of Pennsylvania
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Vitoshkin, Helena; Yu, Hsiu-Yu; Eckmann, David M et al. (2016) Nanoparticle stochastic motion in the inertial regime and hydrodynamic interactions close to a cylindrical wall. Phys Rev Fluids 1:
Clancy, Colleen E; An, Gary; Cannon, William R et al. (2016) Multiscale Modeling in the Clinic: Drug Design and Development. Ann Biomed Eng 44:2591-610
Myerson, Jacob W; Anselmo, Aaron C; Liu, Yaling et al. (2016) Non-affinity factors modulating vascular targeting of nano- and microcarriers. Adv Drug Deliv Rev 99:97-112
Ramakrishnan, N; Tourdot, Richard W; Eckmann, David M et al. (2016) Biophysically inspired model for functionalized nanocarrier adhesion to cell surface: roles of protein expression and mechanical factors. R Soc Open Sci 3:160260
Zhang, Yanhang; Barocas, Victor H; Berceli, Scott A et al. (2016) Multi-scale Modeling of the Cardiovascular System: Disease Development, Progression, and Clinical Intervention. Ann Biomed Eng 44:2642-60
Sarkar, Arijit; Eckmann, David M; Ayyaswamy, Portonovo S et al. (2015) Hydrodynamic interactions of deformable polymeric nanocarriers and the effect of crosslinking. Soft Matter 11:5955-69
Ramakrishnan, N; Radhakrishnan, Ravi (2015) Phenomenology based multiscale models as tools to understand cell membrane and organelle morphologies. Adv Planar Lipid Bilayers Liposomes 22:129-175
Yu, Hsiu-Yu; Eckmann, David M; Ayyaswamy, Portonovo S et al. (2015) Composite generalized Langevin equation for Brownian motion in different hydrodynamic and adhesion regimes. Phys Rev E Stat Nonlin Soft Matter Phys 91:052303
Caporizzo, Matthew Alexander; Roco, Charles M; Ferrer, Maria Carme Coll et al. (2015) Strain-rate Dependence of Elastic Modulus Reveals Silver Nanoparticle Induced Cytotoxicity. Nanobiomedicine (Rij) 2:
Ramakrishnan, N; Sunil Kumar, P B; Radhakrishnan, Ravi (2014) Mesoscale computational studies of membrane bilayer remodeling by curvature-inducing proteins. Phys Rep 543:1-60

Showing the most recent 10 out of 44 publications