(318b) Design of Functionalized Deformable Hydrogel Nanocarriers through Brownian Dynamics of Entangled Star-Polymers

Targeting nanocarriers (NCs) loaded with drugs that are probed to precise locations in the body may improve the treatment and detection of many diseases. We focus on a new class of biocompatible nanogel-based NC consisting of lysozyme rich core with dextran brushes, which has the capability to host small-molecule drugs to larger silver nanoparticles,¹ important for a range of biotechnological and biomedical applications involving antimicrobial properties and therapeutic delivery. In the above-described nanogels, the lysozyme constitutes a defined central rigid core and dextran brushes constitute a fluid and soft corona. The overall size of the gel is determined by the molecular weight of the dextran and can be tuned in the range of 100-500 nm diameter. Softness of the gel is controlled by the degree of cross-linking interactions. While the carrier construct has been physically characterized and realized as a promising vehicle for drug delivery in vivo in mice models, its optimization for targeting specific tissues is far from clinical translation. In particular, there is a need for precise control of the specificity and selectivity of binding of the nanogels to the target (inflamed or diseased) tissue of interest under varying physiological and hydrodynamic conditions in the vasculature. How precisely the internal hydrodynamics of gel relaxation is coupled to the external hemodynamics to determine nanogel deformability, multivalent adhesion, and drug release kinetics is not obvious, and little mechanistic insight is available in the literature. For example, mixing of dextran brushes increases entropy, whereas entanglement opposes the motion and causes entropic penalty. The shear stress near the endothelial surface drives the system away from equilibrium. We have constructed a coarse-grained model of the cross-linked lysozyme-core/dextran-shell nanogels by mimicking their synthesis reactions and physical properties. We also include stochastic forces and hydrodynamic shear forces to model the internal dynamics of these deformable carriers under physiologically relevant conditions. Brownian dynamics simulations are carried out to understand their equilibrium properties and response to shear. We also include hydrodynamic interactions² between pairs of nanogels consistent with periodic boundary conditions. Depending on inter-particle positions, radii and viscosity of solvent, this long-range interaction depicts the diffusivities of pair particles approaching each other. They do not change the equilibrium and their effects are particularly important in the transient temporal response of the nanogel.

Static and dynamic properties (including structure factors, radius of gyration, and deformation anisotropy) are computed as a function of entanglement, while deformation under shear is expressed in terms of normal stress difference and shear stresses. We also focus on extending this method to resolve the effect of inhomogeneity in density distribution on measured stresses. Other physiological considerations included in the model are incorporation of boundary effects to include the effect of the endothelium³ and of the haematocrit.^4,5 We investigate effects of these properties on carrier deformation and relaxation.

The computational approaches described above serve as powerful tools to fine-tune nanocarrier design by considering both the physiological and hydrodynamic environments. Development of such models is essential to gain useful insights that can be translated into the optimal design of nanogel drug carriers for targeted drug delivery. Ongoing future work will focus on bridging the various modeling methods such as drug loading and release, direct numerical simulation of the continuum transport equations, molecular dynamics of antigen-antibody interactions and nanocarrier uptake into cells through internalization.

We acknowledge support from NIH through grant NIH 1R01EB006818-05.

Reference

1. M. Carme Coll Ferrer et. al., “A facile route to synthesize nanogels doped with silver nanoparticles”, J Nanopart Res (2013) 15:1323.
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J. Biomech. 19, 799 (1986).
4. A. W. Tilles and E. C. Eckstein, “The near-wall excess of platelet-sized particles in blood flow: Its dependence on hematocrit and wall shear rate”, 
 Microvasc. Res. 33, 211 
(1987).
5. C. Yeh and E. C. Eckstein, “Transient lateral transport of platelet-sized particles in flowing blood suspensions”,Biophys. J. 66, 1706 (1994).