Oncometabolite Fingerprinting Using Fluorescent Single‐Walled Carbon Nanotubes

Abstract

These local changes in the levels of involved metabolites or products can indicate an ongoing process of a cancerous transformation, and even further contribute to its escalation, rendering them oncometabolites. [1][2][3][4][5][6][7][8][9] D-2-hydroxyglutarate (D2HG) is a product of the gain-of-function-mutated enzymes isocitrate dehydrogenase (IDH1/ IDH2), whereas the normal mitochondrial form plays a role in the tricarboxylic acid (TCA) cycle by producing α-ketoglutarate. [1,2,[4][5][6][7][8][9] Hence, an accumulation of D2HG in the mitochondria indicates a mutagenesis of isocitrate dehydrogenase (IDH) and interruption of the TCA cycle, implying that the cell is in a state of pseudo-hypoxia (resembling a state of low oxygen levels), and mainly relying on glycolysis for energy production (Scheme 1). [4] Normally, as a minor metabolic byproduct, D2HG levels are kept low as D-2-hydroxyglutarate dehydrogenase (D2HGDH) converts it to α-ketoglutarate. [1,10] However, D2HGDH does not prevent D2HG accumulation in the case of overproduction. [10] Moreover, a congenital loss of D2HGDH causes D2HG accumulation, which can lead to a severe brain damage in a rare condition called D-2-hydroxyglutarate aciduria. [1,10] The accumulation of D2HG was shown to inhibit a group of enzymes named a-ketoglutarate-dependent dioxygenases (aKGdd), resulting in the promotion of mutagenesis by epigenetic modification of DNA and histone hypermethylation. [1,4,5,7] Notably, IDH1-mutated tumors were shown to exhibit DNA hypermethylation in gliomas and leukemia, and also histone hypermethylation. [1,[5][6][7]9,11] Accumulation of 2-hydroxyglutarate (both D and L optical isomers) was found to suppress cell-proliferation regulation. [1,9] As a demonstration of D2HG cellular potency, it was shown that incubating hematopoietic stem cells with D2HG alters differentiation patterns and promotes immune resistance. [1,6] IDH mutations and D2HG accumulation were found in gliomas and glioblastomas, and D2HG accumulation is suspected to be sufficient for promoting the development of acute myeloid leukemia (AML). [1,6] Another possible oncogenic mechanism linked to D2HG abundance, is its ability to shift cellular redox equilibrium toward overproduction of reactive oxygen species (ROS), which are well-known oncogenic agents. [4] The same mechanism was also found to impair immune antitumor activity. [1,8] The production of oncometabolites is the direct result of mutagenesis in key cellular metabolic enzymes, appearing typically in cancers such as glioma, leukemia, and glioblastoma. Once accumulated, oncometabolites promote cancerous transformations by interfering with important cellular functions. Hence, the ability to sense and quantify oncometabolites is essential for cancer research and clinical diagnosis. Here, the authors present a near-infrared optical nanosensor for a known oncometabolite, D-2-hydroxyglutarate (D2HG), discovered in a screening of a library of fluorescent single-walled carbon nanotubes (SWCNTs) functionalized with ssDNA. The screening r...

Multicomponent System of Single‐Walled Carbon Nanotubes Functionalized with a Melanin‐Inspired Material for Optical Detection and Scavenging of Metals

“…[22,23] SWCNTs are graphene-based nanostructures, where different rolling orientations of graphene sheets give rise to a wide range of nanotube chiralities, [24,25] each of which has unique physical, chemical, and optical properties. [26][27][28][29] Semiconducting SWCNTs fluoresce in the near-infrared (NIR) range, which overlaps with the transparency window of biological samples, thus can be utilized for biotechnological and biomedical imaging and sensing applications, [23,[30][31][32][33][34][35][36][37] including sensing of small molecules, [38][39][40][41][42][43][44] reactive oxygen species, [45][46][47] microRNA, [48] lipids, [49] proteins, [50][51][52][53][54] enzymes, [55][56][57][58] volatiles, [59,60] and pathogens. [61,62] While previously, DNA functionalized fluorescent SWCNTs were utilized to detect arsenite within plants, [63] most SWCNT applications as metal sensors are based on oxidized (non-fluorescent) SWCNTs and do not exploit their optical properties.…”

Monitoring the Activity and Inhibition of Cholinesterase Enzymes using Single-Walled Carbon Nanotube Fluorescent Sensors

“…We chose a screening assay approach, based on previous successful demonstrations of SWCNT-sensors discovery, to find an optimal cholinesterase SWCNT-based sensor. In this approach, a library of DNA-SWCNTs are exposed to various analytes, establishing the specificity and sensitivity of these suspensions toward the selected analytes. ,,,, To this end, we measured the fluorescence response of a library of DNA-SWCNTs, including (GT) 15 -, (T) 30 -, (TAT) 4 -, (GTTT) 7 -, and (GC) 30 -SWCNT, to either AChE, its substrate acetylthiocholine (ATC), or their combination (Figure ). The rational was to identify a DNA-SWCNT suspension that would selectively respond to the byproducts of the hydrolytic reaction between AChE and ATC, but would be inactive to each of the initial reactants.…”

Single-Walled Carbon Nanotubes as Fluorescent Probes for Monitoring the Self-Assembly and Morphology of Peptide/Polymer Hybrid Hydrogels

“…SWCNTs are highly hydrophobic and must be individually suspended in water to reveal their characteristic fluorescence in the NIR spectral region . Several classes of dispersants are reported to suspend SWCNTs in water, e.g., surfactants, , single-stranded DNA, , amphiphilic polymers, − and also proteins, peptoids, and peptides. − Several studies showed that (Fmoc-)­conjugated amino acids and peptides are able to disperse SWCNTs in an aqueous environment, , and molecular dynamics simulation showed the hybridization of amino acid crystals with carbon nanotubes. , Further, SWCNTs have proven high biocompatibility in several in vivo applications, rendering them favorable for usage in implantable hydrogels. − …”