Search

The blood-brain barrier (BBB) is located at the interface between the vascular system and the brain parenchyma, and is responsible for communication with systemic circulation and peripheral tissues. During life, the BBB can be subjected to a wide range of perturbations or stresses that may be endogenous or exogenous, pathological or therapeutic, or intended or unintended. The risk factors for many diseases of the brain are multifactorial and involve perturbations that may occur simultaneously (e.g., two-hit model for Alzheimer's disease) and result in different outcomes. Therefore, it is important to understand the influence of individual perturbations on BBB function in isolation. Here we review the effects of eight perturbations: mechanical forces, temperature, electromagnetic radiation, hypoxia, endogenous factors, exogenous factors, chemical factors, and pathogens. While some perturbations may result in acute or chronic BBB disruption, many are also exploited for diagnostic or therapeutic purposes. The resultant outcome on BBB function depends on the dose (or magnitude) and duration of the perturbation. Homeostasis may be restored by self-repair, for example, via processes such as proliferation of affected cells or angiogenesis to create new vasculature. Transient or sustained BBB dysfunction may result in acute or pathological symptoms, for example, microhemorrhages or hypoperfusion. In more extreme cases, perturbations may lead to cytotoxicity and cell death, for example, through exposure to cytotoxic plaques. [ABSTRACT FROM AUTHOR]

Nanomedicine often failed clinically to show therapeutic efficacy due to reduced particle circulation and enhanced capture by the reticuloendothelial system (RES), including the liver. Developing novel immunomodulatory surface coating can prevent macrophage capture and increase the particle circulation of the nanomedicine, resulting in higher therapeutic efficiency. Herein, we demonstrate the development of immunomodulatory small molecule (RZA15) with triazole functionality using copper-catalyzed click chemistry to conjugate onto spherical polystyrene nanoparticles using amide coupling reactions, achieving higher blood circulation and lesser macrophage uptake of the nanoconjugates. In this work, we evaluated the effectiveness of RZA15 coating for the enhanced circulation of polystyrene nanoparticles of 100 nm size, which is commonly utilized for various drug delivery applications, and compared with poly(ethylene)glycol (PEG) coatings. Several polystyrene nanoconjugate formulations were analyzed in vitro in normal and macrophage cells for cell viability and cellular uptake studies. In vitro studies demonstrated lesser macrophage uptake of the nanoconjugates following RZA15 coating. Finally, in vivo, blood-circulation, pharmacokinetics, and biodistribution studies were performed in the C57BL/6J mouse model that endorsed the substantial role of RZA15 in preventing liver and spleen capture and results in extended circulation. Coating immunomodulatory small molecules to nanoparticles can severely enhance the potential therapeutic effects of nanomedicine at lower doses., (© 2024 IOP Publishing Ltd.)