Biophysically inspired model for functionalized nanocarrier adhesion to cell surface: roles of protein expression and mechanical factors

Abstract

In order to achieve selective targeting of affinity–ligand coated nanoparticles to the target tissue, it is essential to understand the key mechanisms that govern their capture by the target cell. Next-generation pharmacokinetic (PK) models that systematically account for proteomic and mechanical factors can accelerate the design, validation and translation of targeted nanocarriers (NCs) in the clinic. Towards this objective, we have developed a computational model to delineate the roles played by target protein expression and mechanical factors of the target cell membrane in determining the avidity of functionalized NCs to live cells. Model results show quantitative agreement with in vivo experiments when specific and non-specific contributions to NC binding are taken into account. The specific contributions are accounted for through extensive simulations of multivalent receptor–ligand interactions, membrane mechanics and entropic factors such as membrane undulations and receptor translation. The computed NC avidity is strongly dependent on ligand density, receptor expression, bending mechanics of the target cell membrane, as well as entropic factors associated with the membrane and the receptor motion. Our computational model can predict the in vivo targeting levels of the intracellular adhesion molecule-1 (ICAM1)-coated NCs targeted to the lung, heart, kidney, liver and spleen of mouse, when the contributions due to endothelial capture are accounted for. The effect of other cells (such as monocytes, etc.) do not improve the model predictions at steady state. We demonstrate the predictive utility of our model by predicting partitioning coefficients of functionalized NCs in mice and human tissues and report the statistical accuracy of our model predictions under different scenarios.

Multivalent Binding of a Ligand-Coated Particle: Role of Shape, Size, and Ligand Heterogeneity

“…We adopt the coarse grained approach developed in earlier works [38,48,78,79] to study the interaction of a ligand-coated NC with cell surface receptors. A snapshot of our mesoscale model is shown in Figs.…”

“…At the mesoscale (characteristic length ∼ 100 nm) , experimental studies have largely focused on the biodistribution of functionalized NPs, targeted to various cellular adhesion molecules both in vitro and in vivo, for use as targeted drug delivery systems [29][30][31][32][33][34][35][36]. A number of theoretical and computational models [37][38][39][40][41][42][43][44][45][46][47][48][49][50] have been developed to address the question of adhesion and super-selective targeting of functionalized NCs and their uptake into the target cell [51][52][53][54][55][56]. At the molecular scale (characteristic length < 20 nm), all atom molecular dynamics simulations have been extensively used to unravel the molecular mechanisms governing receptor-ligand interactions [57][58][59][60][61] and the interaction of gold and silver nanoparticles with the surface of a cell [62][63][64][65].…”

“…This would require a different class of models in which we retain the molecular nature of the receptor-ligand interactions. In the past, researchers have treated NC adhesion either as a continuum [37,43,44] or as semi-continuum [38,48] to quantify the specific adhesion of functionalized particles with rigid and flexible substrates. A main ingredient, namely entropy loss of receptors facilitating multivalent binding, is absent in such continuum models, which we address using our approach.…”

Biophysics of membrane curvature remodeling at molecular and mesoscopic lengthscales

“…Moreover, several of the CRPs feedback to the cytoskeletal pathways via direct or indirect recruitment of adaptors regulating actin assembly/disassembly [2]. Future work can focus on the effect of the cytoskeletal interactions, in particular, the roles of membrane, and frame tensions in regulating cellular processes and some promising headway in this direction has been reported in recent studies [125, 138, 201]. Another intriguing possibility suggested by the results we have discussed is that the recruitment of CRPs can be dependent on the membrane tension, which in turn is influenced by the cytoskeletal or cortical tension.…”

Effect of wall-mediated hydrodynamic fluctuations on the kinetics of a Brownian nanoparticle

“…For particlesurface or surface-surface interactions mediated by the action of receptors and ligands, the adhesion can compete with rotational mobility of particles, intervening tether dynamics [5][6][7], and size or shape-dependent margination effects [8,9]. In cell adhesion, cell membrane curvature undulations regulate protein mobility [10][11][12][13] and thereby influence fluctuating membrane-mediated transient adhesive kinetics. In biomedical applications such as vascular targeted drug delivery involving advanced functional materials, engineering the reaction rate constant of functionalized nanoparticle binding to the target tissue such as the endothelium is essential to the characterization of the targeting efficacy [14].…”