Postdoctoral Fellow Yale University, United States
Objectives: Glomerular disease constitutes one of the largest causes of chronic kidney disease, thus targeting the glomerular endothelium with novel therapies is of intense interest to the kidney disease community. Recent work from our laboratory has shown that polymeric nanoparticles functionalized with endothelial cell-targeting antibodies show enhanced binding to the human glomerular endothelium [1, 2] and may provide an effective therapeutic delivery system for glomerular disease. Our objective in this study was to use mathematical modeling to predict which nanoparticle characteristics (e.g. size, charge, density, antibody orientation and affinity) can be tuned to alter their delivery to the endothelium in glomeruli.
Methods: We developed a mathematical model that describes the transport of nanoparticles (with associated size, density and surface charge) within a glomerular capillary, that includes a plasma-with-hematocrit compartment, a free plasma compartment, and a wall compartment. Transport rates were estimated using physical equations, taking into account the variance of hematocrit and viscosity of the plasma along the length of the capillary. We then applied this ‘nanoparticle capillary’ model to an anatomically accurate mathematical model of the glomerular capillary network, previously developed by one of us [3, 4]. This model incorporates filtration of plasma through the glomerular capillary wall, hematocrit distribution at network nodes, and plasma protein concentration, as well as alterations in pressure and flow due to renal autoregulation.
Results: Our results indicate that nanoparticle size plays a significant role in nanoparticle margination to the wall within our simulated glomerular capillaries, whereas both size and density impact the nanoparticle unbinding from the wall under enhanced shear stress. Anatomical and physiological aspects of glomerular hemodynamics, including the heterogeneity of plasma viscosity and hematocrit throughout the glomerular capillary network, are significant factors that alter nanoparticle delivery to the wall as well as maintenance of nanoparticle binding to the endothelium. Our results indicate that reduction of the efficiency of renal autoregulation minimally impacts nanoparticle binding to the glomerular capillaries, while full amelioration of autoregulation significantly reduces nanoparticle binding to the wall.
Conclusions: Myriad factors impact the delivery of nanoparticles to the endothelium of the microvasculature. The glomerulus is a special case in which viscosity and hematocrit change along the length of the capillary network due to filtration, and numerous mechanisms of autoregulation alter the flow and shear stress in individual glomerular capillaries. Our results indicate that nanoparticles can be tuned to optimize their delivery in this environment, thereby providing a basis for design of novel therapies for glomerular disease.
Citations: 1. Tietjen, G.T., et al., Nanoparticle targeting to the endothelium during normothermic machine perfusion of human kidneys. Science translational medicine, 2017. 9(418): p. eaam6764.
2. Albert, C., et al., Monobody adapter for functional antibody display on nanoparticles for adaptable targeted delivery applications. Nature Communications, 2022. 13(1): p. 5998.
3. Richfield, O., R. Cortez, and L.G. Navar, Simulations of Glomerular Shear and Hoop Stresses in Diabetes, Hypertension, and Reduced Renal Mass using a Network Model of a Rat Glomerulus. Physiological Reports, 2020. 8(18): p. e14577.
4. Richfield, O., R. Cortez, and L.G. Navar, Simulations of Increased Glomerular Capillary Wall Strain in the 5/6-Nephrectomized Rat. Microcirculation, 2021. n/a(n/a): p. e12721.
