Effect of circadian rhythm modulated blood flow on nanoparticle based targeted drug delivery in virtual in vivo arterial geometries

Drug delivery using nanocarriers that are tethered with vasculature-targeting epitopes aims to maximize the therapeutic efficacy of the drug while minimizing the drug side effects. Circadian rhythm which is governed by the central nervous system has implications for targeted drug delivery due to sleep-wake cycle changes in blood flow dynamics. This paper presents an advanced fluid dynamics modeling method that is based on viscous incompressible shear-rate fluid (blood) coupled with an advection–diffusion equation to simulate the formation of concentration gradients in the blood stream, and buildup of the concentration of drug-carrying nanoparticles at the targeted site. The method is equipped with an experimentally calibrated nanoparticle-endothelial cell adhesion model that employs Robin boundary conditions to describe nanoparticle retention based on the probability of adhesion, a friction model accounting for surface roughness of endothelial cell layer, and a dispersion model based on Taylor-Aris expression for effective diffusion of nanocarriers in the boundary layer. The computational model is first experimentally validated and then tested on engineered bifurcating arterial systems where impedance boundary conditions are applied at the outflow to account for the downstream resistance at each outlet. It is then applied to a virtual geometric model of an in vivo arterial tree developed via MRI-based image processing techniques. These test cases highlight the potential of the proposed modeling method for investigating drug transport, adhesion, and retention at multiple sites in the virtual in vivo models under circadian rhythm modulated blood flow dynamics. Statement of significance This paper presents a novel mathematical method that integrate a nanoparticle-based drug delivery model with shear-rate dependent blood flow model for targeted drug delivery in the in vivo arterial networks. The framework is comprised of a unique combination of mechanics-based dispersion model, an asperity model for endothelium surface roughness, and a stochastic nanoparticle-endothelial cell adhesion model. Simulations of MRI based in vivo carotid artery system showcase the effects of vessel geometry on nanoparticle adhesion and retention at the target site. Vessel geometry and target site location impact nanoparticle adhesion; curved and bifurcating regions favor local accumulation of drug carrying nanoparticles. It is also shown that aligning drug administration with circadian rhythm and sleep cycle can enhance the efficacy of drug delivery processes. These simulations demonstrate the potential of the computational modeling method for exploring circadian rhythm modulated blood flow for targeted drug delivery while reducing the in vivo experimentation. • Nanoparticle-based drug delivery model is integrated with a shear-rate blood flow model. • Framework combines multiscale models for NP adhesion and retention at target sites. • Vessel geometry affects nanoparticle adhesion; curved regions favor drug adhesion. • Results show aligning drug delivery with circadian rhythm and sleep boosts efficacy.