Fluorescence imaging has gained increased attention over the past two decades as a viable means to detect a variety of cancers. Fluorescence imaging has the potential to provide physicians with high resolution images with enhanced contrast, which will allow them to be able to better diagnose and treat patients with cancer. Early detection and treatment are key to erradicating cancer in a patient, and fluorescence imaging has the ability to identify non-advanced, even pre-cancerous, tumors where imaging based on white light or radiation overlooked them. Several fluorescent dyes have been identified as possible fluorophores for enhanced fluorescence imaging, such as cyanine, squaraine, porphyrin, phthalocyanine, and borondipyrromethane dyes. These dyes have high fluorescence quantum yields, which provides a high target to background ratio; however, these dyes are often plagued by low water solubility. This low solubility can be ameliorated by conjugating or covalently attaching these dyes to polymeric crosslinked micelles, polymersomes, or polymer-core nanoparticles. These particle & dye systems then can become platforms on which secondary components can be attached to enhance the systems functionality. For example, dyes attached to these nanocarriers can target tumors through passive targeting; however, active targeting can be achieved by further modifying these nanocarriers with ligands that have a binding affinity for receptors overexpressed in tumor cells, cell surface receptors located on the tumor cell membrane, or endothelium. Fluorescence activation of the probes is another promising technology for the early detection of cancer. Activation requires that there be a change in fluorescence, whether it be an emission wavelength change or a fluorescence "on/off" signal when in the presence of some external stimuli. Activation increase the target to background ratio and enhances the contrast of the obtained image. This review serves to highlight the recent developments of (1) improved fluorescent dyes for the detection of cancer, with a specific focus on dyes that are being coupled to nanocarriers; (2) dye & nanocarrier systems that target, both actively and passively, tumors, and (3) fluorescence activation of these fluorophore systems for better image quality.

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.

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Optogenetics is widely used in neuroscience to control neural circuits. However, non-invasive methods for light delivery in brain are needed to avoid physical damage caused by current methods. One potential strategy could employ x-ray activation of radioluminescent particles (RPLs), enabling localized light generation within the brain. RPLs composed of inorganic scintillators can emit light at various wavelengths depending upon composition. Cerium doped lutetium oxyorthosilicate (LSO:Ce), an inorganic scintillator that emits blue light in response to x-ray or ultraviolet (UV) stimulation, could potentially be used to control neural circuits through activation of channelrhodopsin-2 (ChR2), a light-gated cation channel. Whether inorganic scintillators themselves negatively impact neuronal processes and synaptic function is unknown, and was investigated here using cellular, molecular, and electrophysiological approaches. As proof of principle, we applied UV stimulation to 4 μm LSO:Ce particles during whole-cell recording of CA1 pyramidal cells in acute hippocampal slices from mice that expressed ChR2 in glutamatergic neurons. We observed an increase in frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs), indicating activation of ChR2 and excitation of neurons. Importantly, LSO:Ce particles did not affect survival of primary mouse cortical neurons, even after 24 h of exposure. In extracellular dendritic field potential recordings, no change in the strength of basal glutamatergic transmission was observed during exposure to LSO:Ce microparticles. However, the amplitude of the fiber volley was slightly reduced with high stimulation. Additionally, there was a slight decrease in the frequency of sEPSCs in whole-cell voltage-clamp recordings from CA1 pyramidal cells, with no change in current amplitudes. The amplitude and frequency of spontaneous inhibitory postsynaptic currents were unchanged. Finally, long term potentiation (LTP), a synaptic modification believed to underlie learning and memory and a robust measure of synaptic integrity, was successfully induced, although the magnitude was slightly reduced. Together, these results show LSO:Ce particles are biocompatible even though there are modest effects on baseline synaptic function and long-term synaptic plasticity. Importantly, we show that light emitted from LSO:Ce particles is able to activate ChR2 and modify synaptic function. Therefore, LSO:Ce inorganic scintillators are potentially viable for use as a new light delivery system for optogenetics.