Mechanisms of Pegylated Nanoparticle-Induced Transient Hypotension and Tachyphylaxis

Nanomedicines exert great potential in target therapeutics. Surface characteristics of nanoparticles play a crucial role in determination on how these nanoparticles interact with the biology system, and consequently the therapeutic efficacy, biological distribution/fate, and toxicity. Polyethylene glycol (PEG) is the most commonly used coating material, which is known to change the composition of the protein adsorption on the surface, or “protein corona”, in circulation. Covalent attachment of PEG chains on the surface of the nanoparticles, or PEGylation, is a widely used strategy to gain stealth effect for nanoparticles against the immune system. Intriguingly, a variety of nanotechnology-based drugs, such as PEGylated liposomes, have been shown to induce hypersensitivity reactions at first exposure in humans. This adverse effect is often described as complement activation-related pseudoallergy (CARPA), which is manifested as profound hypotension followed by tachyphylaxis. Although the hypotensive effect was proposed to be due to systemic vasodilation, there is lack of evidence to support this mechanism. Our preliminary data indicate that PEGylated magnetic nanoparticles (PEG-MNPs) induced profound hypotension, followed by tachyphylaxis in rat; the hypotensive effect was associated with reduced blood flow and increase in vascular resistance in vasculature of both the kidney and cremaster muscle, and therefore, cannot be explained as systemic vasodilation. With this rat model, we would like to test a hypothesis that complement assembly in the corona formation may be more vigorous on the surface of PEGylated particle than that without PEG, resulting in agglomeration in microvessels that transiently causes reduction in venous return and entrains hypotension; whereas consumption/depletion of complement components after the first exposure may mediate tachyphylaxis of the hypotensive effects. Specific Aims are proposed:Aim 1- to characterize nanoparticle-induced hemodynamic effectsAim 2- to characterize plasma proteins interacting with the PEGylated particlesAim 3- to determine the mechanism of tachyphylaxis of PEG-MNP-induced hypotension

Project ID:PC10907-1122
External Project ID:MOST109-2320-B182-017