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.
Phthalocyanines (Pcs) are a class of photosensitizers (PSs) with a strong tendency to aggregate in aqueous solutions, which has a negative influence on their photosensitizing ability for photodynamic therapy. Four new axially disubstituted, non-aggregated silicon phthalocyanines (SiPcs), containing azide or alkyne functional groups have been synthesized and characterized. The method of synthesis is based on the reaction of silicon phthalocyanine dichloride with variable length poly(ethylene glycol) (PEG) chains in the presence of NaH. All synthesized dyes are highly soluble in alcohols, THF, CH 2Cl2, acetone, DMF and other common polar organic solvents, with the PEGylated silicon phthalocyanines (SiPcs) also being soluble in water. Photophysical and electrochemical properties of the dyes have been investigated. The presence of alkyne or azide groups in the phthalocyanine dyes, coupled with their high aqueous solubility, make these compounds useful as building blocks in copper catalyzed Huigsen azide-alkyne cycloaddition reactions (i.e. click chemistry).
A fluorophore modified nanoparticle was developed that can only fluoresce when a specific environmental parameter interacts with the system. The model system consisted of an azide modified bovine serum albumin (azBSA) that had been covalently attached to an alkyne modified silicon phthalocyanine (alSiPc) derivative through a copper catalyzed azide/alkyne Huisgen cycloaddition (click reaction). The azBSA/alSiPc assembly was then clicked to a ca. 67 nm poly(propargyl acrylate) (PA) nanoparticle (PA/azBSA/alSiPc). The resulting particles did not exhibit any florescence when the alSiPc was excited. Incubating the particles at 37 °C for 30 min with a proteolytic enzyme (trypsin) degraded the linking BSA and resulted in the appearance of florescence that was attributed to a "free" silicon phthalocyanine. The PA/azBSA/alSiPc particles were incubated with human non-small cell lung cancer cells (A549) and the florescence of the initially quenched particles was achieved with cellular uptake.
Survivin belongs to the family of inhibitor of apoptosis proteins (IAP) and is present in most cancers while being below detection limits in most terminally differentiated adult tissues, making it an attractive protein to target for diagnostic and, potentially, therapeutic roles. Sub-100 nm poly(propargyl acrylate) (PA) particles were surface modified through the copper-catalyzed azide/alkyne cycloaddition of an azide-terminated survivin ligand derivative (azTM) originally proposed by Abbott Labs and speculated to bind directly to survivin (protein) at its dimer interface. Using affinity pull-down studies, it was determined that the PA/azTM nanoparticles selectively bind survivin and the particles can enhance apoptotic cell death in glioblastomas and other survivin over-expressing cell lines such as A549 and MCF7 relative to cells incubated with the original Abbott-derived small molecule inhibitor.
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