The
current effort demonstrates that lutetium oxyorthosilicate
doped with 1–10% cerium (Lu2SiO5:Ce,
LSO:Ce) radioluminescent particles can be coated with a single dye
or multiple dyes and generate an effective energy transfer between
the core and dye(s) when excited via X-rays. LSO:Ce particles were
surface modified with an alkyne modified naphthalimide (6-piperidin-1-yl-2-prop-2-yn-1-yl-1H-benzo[de]isoquinoline-1,3-(2H)-dione, AlNap) and alkyne modified rhodamine B (N-(6-diethylamino)-9-{2-[(prop-2-yn-1-yloxy)carbonyl]phenyl}-3H-xanthen-3-ylidene)-N-ethylethanaminium,
AlRhod) derivatives to tune the X-ray excited optical luminescence
from blue to green to red using Förster Resonance Energy Transfer
(FRET). As X-rays penetrate tissue much more effectively than UV/visible
light, the fluorophore modified phosphors may have applications as
bioimaging agents. To that end, the phosphors were incubated with
rat cortical neurons and imaged after 24 h. The LSO:Ce surface modified
with AlNap was able to be successfully imaged in vitro with a low-output X-ray tube. To use the LSO:Ce fluorophore modified
particles as imaging agents, they must not induce cytotoxicity. Neither
LSO:Ce nor LSO:Ce modified with AlNap showed any cytotoxicity toward
normal human dermal fibroblast cells or mouse cortical neurons, respectively.
Optogenetics, the genetic incorporation of light-sensitive proteins such as Channelrhodopsin-2 (ChR2) into target mammalian neurons, has enabled activation, silencing, and receptor subtype specific neuromodulation with high spatiotemporal resolution. However, the essential components of the ontogenetic system require invasive procedures with very few non-invasive alternatives preventing its use as a translational tool. The implantation of light emitting fibers deep within brain structures is both technically demanding and causes tissue scarring in target brain regions. To overcome these limitations, while maintaining the highly-tuned components of optogenetics we have developed a novel noninvasive alternative. Our approach replaces fibers with light-emitting radioluminescent particles (RLPs) that can be activated non-invasively with X-ray exposure. Here, we report successful noninvasive delivery of RLPs to target brain regions using MRI-guided focused ultrasound (FUS) blood brain barrier opening. In addition, FUS BBBO can be used to deliver viral vectors for light sensitive channel expression. Combined, these components can provide a completely non-invasive optogenetic system.
Nanoparticle-based delivery systems have become a popular method for targeting tumors and impermeable tissue with drugs for treatment and imaging markers for biodetection. Nanomaterials are beneficial for medical treatment because they can be modified to have increased stability and carrying capacity, and their size and surface modifications allow them to reach otherwise impenetrable tissue. Nanoparticles have become particularly popular in medical imaging since they can be produced as scintillators that emit visible light which can be used in PET detectors, or they could be made with paramagnetic materials for magnetic resonance imaging. Localized or systemic injection can be used for delivery of nanoparticles; however, systemic injection without appropriate surface modifications is subjected to uptake by the mononuclear phagocytic system which clears particles from the circulation rapidly limiting their accumulation at target tissue and reducing efficacy. Here we demonstrate the biodistribution of Yttrium oxyorthosilicate nanoparticles doped with Cerium after localized injection to the cerebral cortex.
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