Nanotheranostics
Developing oxidative stress-responsive neuroprotective nanotheranostic agents for the image-guided treatment of radiotherapy-induced brain injury
By Maiti S, Teitz M, Velarde E and 9 others.
Abstract
Rationale
Radiotherapy-induced brain injury (RIBI) is a chronic side effect, that affects up to ~90% of brain tumor survivors treated with radiotherapy. Chronic oxidative stress and neuroinflammation are key drivers of RIBI. Here, we developed oxidative stress-responsive polymeric nanotheranostic agents and evaluated their ability to reduce neuroinflammation in a preclinical mouse model of RIBI.
Method
Two oxidative stress-responsive amphiphilic block copolymers possessing varied numbers of phenylboronic acid pinacol ester (BAPE) moieties to scavenge reactive oxygen species (ROS) were designed, synthesized, and characterized by proton and carbon-13 nuclear magnetic resonance spectroscopy. Polymer P2b was designed to have twice as many BAPE moieties as polymer P2a, for a structure-activity relationship study. The polymers were then formulated into nanoparticles and characterized using fluorescence spectroscopy, dynamic light-scattering, transmission and scanning electron microscopy, and fluorescence imaging. The ability of the agents to prevent the degradation of fluorescent R-phycoerythrin (RPE) protein under oxidative stress was also evaluated. Then, the cellular uptake and toxicity of the agents were evaluated in human umbilical vein endothelial cells (HUVECs). Next, the in vivo therapeutic efficacies of the agents were evaluated in four groups of eight-week-old female BALB/c mice. Mice from one group (Group 1) were not irradiated and were used as controls, while the right brain hemispheres of mice from the other three groups were stereotactically irradiated at 80 Gy (1.7 Gy/minute). At two weeks post-irradiation, mice were intravenously treated with either a fluorescently labelled nanoparticle or phosphate buffered saline (PBS), as follows: Group 2 (PBS); Group 3 (P2a); Group 4 (P2b); and the delivery of the nanoparticles to the irradiated brain lesion was monitored with fluorescence imaging. Next, all the mice were monitored with multi-parametric magnetic resonance imaging (mp-MRI) and immunohistochemistry (CD68, IBA1, and GFAP) at 1.5 months after nanoparticle administration.
