Optimizing the Physical Properties of Vascular Targeted Carriers for Maximum Efficacy in Inflammatory Disease

Vascular-targeted carriers;Hydrogels;Hemodynamics;Chemical Engineering;Engineering;Chemical Engineering

Fish, MargaretThurber, Greg Michael ;

University of Michigan

关键词: Vascular-targeted carriers;    Hydrogels;    Hemodynamics;    Chemical Engineering;    Engineering;    Chemical Engineering;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/144180/fishmarg_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Vascular targeted carriers (VTCs) increase the specificity of drug delivery while also protecting drugs from degradation in the bloodstream, and therefore, have the potential to revolutionize many clinical treatments of common diseases. It has previously been shown that rigid microparticles (MPs) are significantly more efficient than rigid nanoparticles (NPs) at adhering to target vasculature from bulk blood flow; yet, despite this increased efficiency, MP VTCs have not been successfully developed for therapeutic applications, and are routinely passed over in favor of NP systems, which better evade capillary occlusion and promote tissue transport. Here, we investigate different physical properties of VTCs, including the interplay between particle modulus, size, and targeting ligand regime, to enhance the translational potential of MP VTC therapeutics and to optimize the overall design of VTCs for a range of clinical applications.We systematically varied the physiochemical properties of particle modulus via poly(ethylene glycol) crosslinking density, targeting ligand (varied density, composition), and size (50 nm polystyrene to 2 µm hydrogels) and evaluated the impact of each property on targeted adhesion. VTC designs were evaluated in vitro using parallel plate flow chamber assays with inflamed human umbilical vein endothelial cells enabling controlled hemodynamic shear with primary human blood. VTC designs were evaluated in vivo using real time imaging of acute mouse mesentery inflammation, and full biodistribution studies following acute lung injury. The methods developed and employed here represent accurately simulated physiological conditions to encourage translatability of trends into that expected in the body. We confirmed that MPs were significantly better in targeted adhesion than NPs for all experimental conditions, with anywhere from 50% to 5,450% increase versus NPs, depending on the hemodynamic conditions. We found that both VTC modulus and targeting ligand regime could be tailored in vitro and in vivo to optimize adhesion given known hemodynamics. More deformable particles performed better at low wall shear rate (WSR), while more rigid particles adhered better at high WSRs. At high WSR, an increased ligand surface density improved the adhesion of deformable particles 27-fold, but not sufficiently to match the adhesion of rigid counterparts. While local shear rate dictated the optimal particle modulus, the local cellular protein expression dictated the adhesion kinetics required for optimized rigid NP and hydrogel MP adhesion. We found that a 25%-75% mix of ligand, skewed to the receptor which is lesser expressed, was consistently the most efficient at providing NP VTC adhesion, producing up to 9-fold more adhesion. We found that the addition of targeting ligand to MPs did not significantly decrease the circulation in vivo. Targeted, deformable MPs showed maximal retention at the target site over time versus rigid particles of any size. Finally, we showed that hydrogel MPs can greatly increase the transport of 50 nm NPs to the vascular wall, up to 5,450% versus free 50 nm NPs. This work explores and explains trends that depend on both the physiological conditions and particle properties in vitro and in vivo. Overall, we emphasize the importance of particle size, modulus, targeting ligand regime, and the local targeted tissue environment in engineering maximally efficient VTCs. We present work from VTC formulation which concludes with applications in multiple in vivo models, to provide a big picture view of how multiple particle properties cooperate to affect targeted adhesion.