Multiscale modeling of protein membrane interactions for nanoparticle targeting in drug delivery

Abstract

Nanoparticle (NP)-based imaging and drug delivery systems for systemic (e.g., intravenous) therapeutic and diagnostic applications are inherently a complex integration of biology and engineering. A broad range of length and time scales are essential to hydrodynamic and microscopic molecular interactions mediating NP (drug nanocarriers, imaging agents) motion in blood flow, cell binding/uptake, and tissue accumulation. A computational model of timedependent tissue delivery, providing in silico prediction of organ-specific accumulation of NPs, can be leveraged in NP design and clinical applications. In this article, we provide the current state-of-the-art and future outlook for the development of predictive models for NP transport, targeting, and distribution through the integration of new computational schemes rooted in statistical mechanics and transport. The resulting multiscale model will comprehensively incorporate: (i) hydrodynamic interactions in the vascular scales relevant to NP margination; (ii)

Quantifying and controlling bond multivalency for advanced nanoparticle targeting to cells

“…Purely experimental investigations inherently require large amounts of time and energy, and results are almost universally confounded by differences in numerous variables. Finally, multiscale modeling approaches that consider transport effects, hydrodynamics, bond formation dynamics, and molecular scale interactions will ultimately be required to optimize disparate parameters and produce the best targeted NPs [ 59 ], as well as achieve advanced phenomena such as superselectivity. Notably, the predictive power of simulation modeling will improve the likelihood that favorable parameter regimes are discovered and optimized.…”

Elucidating the rheological implications of adding particles in blood

“…This would allow for a faster design of suitable DCPs, reduce the need to perform numerous trials in animals, and alleviate all constraining factors associated with it, and/or minimize the error when conclusions of laboratory studies drawn on animals are extended to humans. Given the multitude of length and time scales involved, it is necessary to employ a multiscale modeling approach (Eckmann et al 2020 ).…”

Physiologically Based Multiphysics Pharmacokinetic Model for Determining the Temporal Biodistribution of Targeted Nanoparticles

“…By considering hydrodynamic parameters of the vascular system, and cell-binding/uptake parameters into a variety of organ tissues (as determined in previous studies such as [16]), a model that is governed by multiple time scales can be created, providing a more physiologically relevant determination of NP biodistribution with temporal resolution. This paper describes three variations of a multiscale pharmacokinetic model: 1) a steady-state model that facilitates the translation of the multivalent free energy of adhesion into a biodistribution; 2) two different compartmental models (models A and B) that are physiologically based and can predict temporal biodistribution; and 3) a compartmental model that incorporates the vascular branching network and can include multiphysics effects such as hydrodynamic interactions, NP size-dependent effects of flow and adhesion, with temporal resolution [6, 7]. We describe the steady-state or continuous temporal biodistribution of ICAM-1 targeted NP for a murine model in each case.…”

“…Eq (6) describes the change in concentration of NP bound to the endothelial cell surface receptors over time, where K i up denotes the rate of uptake of NP into the organ tissue via transcytosis. Each tissue compartment is described by:…”

“…Existing PBPK models for small molecules or biologics ( [13], [14], [15]) use an empirically derived framework for parameterization, resulting in a model that cannot be universally applied with varying NP constructs and experimental settings ( [16], [17]). Additionally, multiphysics aspects, including physiological and hydrodynamic factors governing NP biodistribution and tissue targeting, involve mechanisms operating at multiple lengths and timescales NP-Endothelial Cell (EC) adhesion properties, and NP subcellular interactions that govern targeted uptake to fully describe the movement and accumulation of NP within the body [6]. In order to create a comprehensive multiscale model, NP behavior must be understood at the system, hydrodynamic, and cell adhesion scales.…”