(232b) Kinetic Assembly of Macromolecular Therapeutics for the Potential Management of Atherosclerosis

Nano-sized assemblies are attractive for developing novel therapies as they are small enough (10 to 200 nm) to interact with cellular surfaces but large enough to transport and protect molecular actives upon administration.¹  Several technologies exist (i.e. ligand exchange with inorganic nanoparticles, self-assembly of polymeric amphiphiles, mini emulsions, and rapid solvent exchange techniques) for the fabrication of molecular nanoassemblies used in either diagnostic or therapeutic applications.  In particular, polymer amphiphiles assembled through kinetic (solvent exchange) rather than thermodynamic (self-assembly) means can provide a more colloidal stable nanoassembly that provides greater resistance to disruption in biological fluids.²

Amphiphilic macromolecules (AMs) synthetically prepared by our labs and derived from sugar backbones, have shown the capacity to manage atherosclerosis by competitively inhibiting the uptake of oxidized low-density lipoproteins (oxLDL) in both murine and human macrophages.³  Recently, we demonstrated that kinetic assemblies of these bioactive AMs, via Flash NanoPrecipitation, into organic nanoparticles (NPs) have superior physiological stability and bioactivity relative to analogous micellar assemblies which lose structural integrity in the presence of serum proteins.^2c  Since most oxLDL uptake occurs through class A and B scavenger receptors,⁴ we have chosen to investigate interactions between novel formulations of kinetically assembled NPs and macrophage scavenger receptors.  Here, we have considered the interaction of a series of distinct nanoparticles with scavenger receptor A (SR-A) through surface plasmon resonance measurements.  To verify these receptor-particle interactions, in vitro studies were carried out in human embryonic kidney cells engineered to express SR-A and the ability of the nanoparticle to inhibit modified LDL uptake was examined in human macrophages.  The physiochemical properties of the formulated NPs and how these attributes influence the inhibition of modified LDL uptake in macrophages will be discussed.  Furthermore, the use of Flash NanoPrecipitation to formulate NPs comprised of both bioactive AMs and small molecule actives at the NP core for the potential management of atherosclerosis will be highlighted.      

1.         Mailänder, V.; Landfester, K., Interaction of Nanoparticles with Cells. Biomacromolecules 2009, 10 (9), 2379-2400.

2.         (a) Ansell, S. M.; Johnstone, S. A.; Tardi, P. G.; Lo, L.; Xie, S.; Shu, Y.; Harasym, T. O.; Harasym, N. L.; Williams, L.; Bermudes, D.; Liboiron, B. D.; Saad, W.; Prud'homme, R. K.;                            Mayer, L. D., Modulating the Therapeutic Activity of Nanoparticle Delivered Paclitaxel by Manipulating the Hydrophobicity of Prodrug Conjugates. J. Med. Chem. 2008, 51 (11), 3288-3296; (b) Johnson, B. K.; Prud'homme, R. K., Flash NanoPrecipitation of organic actives and block copolymers using a confined impinging jets mixer. Aust. J. Chem. 2003, 56 (10), 1021-1024; (c) York, A. W.; Zablocki, K. R.; Lewis, D. R.; Gu, L.; Uhrich, K. E.; Prud'homme, R. K.; Moghe, P. V., Kinetically Assembled Nanoparticles of Bioactive Macromolecules Exhibit Enhanced Stability and Cell-Targeted Biological Efficacy. Adv. Mater. 2012, 24 (6), 733-739.

3.         (a) Iverson, N. M.; Sparks, S. M.; Demirdirek, B.; Uhrich, K. E.; Moghe, P. V., Controllable inhibition of cellular uptake of oxidized low-density lipoprotein: structure-function relationships for nanoscale amphiphilic polymers. Acta Biomater. 2010, 6 (8), 3081-3091; (b) Tian, L.; Yam, L.; Zhou, N.; Tat, H.; Uhrich, K. E., Amphiphilic Scorpion-like Macromolecules:Design, Synthesis, and Characterization. Macromolecules 2004, 37 (2), 538-543.

4.         Shashkin, P.; Dragulev, B.; Ley, K., Macrophage Differentiation to Foam Cells. Curr. Pharm. Des. 2005, 11, 3061-3072.