Assessment of tumor redox status through (S)-4-(3-[18F]fluoropropyl)-L-glutamic acid positron emission tomography imaging of system xc- activity

The cell's endogenous antioxidant system is vital to maintenance of redox homeostasis. Despite its central role in normal and pathophysiology, no non-invasive tools exist to measure this system in patients. The cystine/glutamate antiporter system xc- maintains the balance between intracellular reactive oxygen species and antioxidant production through the provision of cystine, a key precursor in glutathione biosynthesis. Here we show that tumor cell retention of a system xc--specific positron emission tomography radiotracer, (S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG), decreases in proportion to levels of oxidative stress following treatment with a range of redox-active compounds. The decrease in [18F]FSPG retention correlated with a depletion of intracellular cystine resulting from increased de novo glutathione biosynthesis, shown through [U-13C6, U-15N2]cystine isotopic tracing. In vivo, treatment with the chemotherapeutic doxorubicin decreased [18F]FSPG tumor uptake in a mouse model of ovarian cancer, coinciding with markers of oxidative stress but preceding tumor shrinkage and decreased glucose utilization. Having already been used in pilot clinical trials, [18F]FSPG PET could be rapidly translated to the clinic as an early redox indicator of tumor response to treatment

Semiconducting polymer nanoparticles as photoacoustic molecular imaging probes in living mice.

Photoacoustic imaging holds great promise for the visualization of physiology and pathology at the molecular level with deep tissue penetration and fine spatial resolution. To fully utilize this potential, photoacoustic molecular imaging probes have to be developed. Here, we introduce near-infrared light absorbing semiconducting polymer nanoparticles as a new class of contrast agents for photoacoustic molecular imaging. These nanoparticles can produce a stronger signal than the commonly used single-walled carbon nanotubes and gold nanorods on a per mass basis, permitting whole-body lymph-node photoacoustic mapping in living mice at a low systemic injection mass. Furthermore, the semiconducting polymer nanoparticles possess high structural flexibility, narrow photoacoustic spectral profiles and strong resistance to photodegradation and oxidation, enabling the development of the first near-infrared ratiometric photoacoustic probe for in vivo real-time imaging of reactive oxygen species--vital chemical mediators of many diseases. These results demonstrate semiconducting polymer nanoparticles to be an ideal nanoplatform for developing photoacoustic molecular probes

Axial Phenoxylation of Aluminum Phthalocyanines for Improved Cannabinoid Sensitivity in OTFT Sensors

Abstract Cannabis producers, consumers, and regulators need fast, accurate, point‐of‐use sensors to detect Δ9‐tetrahydrocannabinol (THC) and cannabidiol (CBD) from both liquid and vapor source samples, and phthalocyanine‐based organic thin‐film transistors (OTFTs) provide a cost‐effective solution. Chloro aluminum phthalocyanine (Cl‐AlPc) has emerged as a promising material due to its unique coordinating interactions with cannabinoids, allowing for superior sensitivity. This work explores the molecular engineering of AlPc to tune and enhance these interactions, where a series of novel phenxoylated R‐AlPcs are synthesized and integrated into OTFTs, which are then exposed to THC and CBD solution and vapor samples. While the R‐AlPc substituted molecules have a comparable baseline device performance to Cl‐AlPc, their new crystal structures and weakened intermolecular interactions increase sensitivity to THC. Grazing‐incidence wide‐angle X‐ray scattering (GIWAXS) and atomic force microscopy (AFM) are used to investigate this film restructuring, where a significant shift in the crystal structure, grain size, and film roughness is detected for the R‐AlPc molecules that do not occur with Cl‐AlPc. This significant crystal reorganization and film restructuring are the driving force behind the improved sensitivity to cannabinoids relative to Cl‐AlPc and demonstrate that analyte–semiconductor interactions can be enhanced through chemical modification to create more responsive OTFT sensors

A prodrug strategy for the <i>in vivo</i> imaging of aldehyde dehydrogenase activity

Therapy resistance is one of the biggest challenges facing clinical oncology. Despite a revolution in new anti-cancer drugs targeting multiple components of the tumour microenvironment, acquired or innate resistance frequently blunts the efficacy of these treatments. Non-invasive identification of drug-resistant tumours will enable modification of the patient treatment pathway through the selection of appropriate second-line treatments. Here, we have designed a prodrug radiotracer for the non-invasive imaging of aldehyde dehydrogenase 1A1 (ALDH1A1) activity. Elevated ALDH1A1 activity is a marker of drug-resistant cancer cells, modelled here with matched cisplatin-sensitive and -resistant human SKOV3 ovarian cancer cells. The aromatic aldehyde of our prodrug radiotracer was intracellularly liberated by esterase cleavage of the geminal diacetate and specifically trapped by ALDH through its conversion to the charged carboxylic acid. Through this mechanism of action, ALDH-specific retention of our prodrug radiotracer in the drug-resistant tumour cells was twice as high as the drug-sensitive cells. Acylal masking of the aldehyde afforded a modest protection from oxidation in the blood, which was substantially improved in carrier-added experiments. In vivo positron emission tomography imaging of tumour-bearing mice produced high tumour-to-background images and radiotracer uptake in high ALDH-expressing organs but was unable to differentiate between drug-sensitive and drug-resistant tumours. Alternative strategies to protect the labile aldehyde are currently under investigation

Poly(2‐vinylpyridine) as an Additive for Enhancing N‐Type Organic Thin‐Film Transistor Stability

Abstract N‐type organic semiconductors are particularly susceptible to degradation by ambient air. One such solution to this issue is to include additives in the inks these semiconductors would be cast from that would enhance device stability after film deposition. This method would reduce the number of processing steps needed to fabricate devices compared to other stabilization methods, such as encapsulation. In this study, the stabilization of n‐type performance of the semiconductor poly{[N,N′‐bis(2‐octyldodecyl)‐naphthalene‐1,4,5,8‐bis(dicarboximide)‐2,6‐diyl]‐alt‐5,5′‐(2,29‐bisthiophene)} (P(NDI2OD‐T2)) when it is blended with an increasing proportion by weight of poly(2‐vinylpyridine) (P2VP) is reported. The simple synthesis of P2VP also makes it an ideal candidate material for large‐scale applications. Concentrations as low as 0.1% P2VP incorporated into the P(NDI2OD‐T2) blends provided an immediate stabilization effect, and at 10% and 50%, longer‐term stability after one week is observed

Bioorthogonal cyclization-mediated in situ self-assembly of small-molecule probes for imaging caspase activity in vivo

Directed self-assembly of small molecules in living systems could enable a myriad of applications in biology and medicine, and already this has been used widely to synthesize supramolecules and nano/microstructures in solution and in living cells. However, controlling the self-assembly of synthetic small molecules in living animals is challenging because of the complex and dynamic in vivo physiological environment. Here we employ an optimized first-order bioorthogonal cyclization reaction to control the self-assembly of a fluorescent small molecule, and demonstrate its in vivo applicability by imaging caspase-3/7 activity in human tumour xenograft mouse models of chemotherapy. The fluorescent nanoparticles assembled in situ were imaged successfully in both apoptotic cells and tumour tissues using three-dimensional structured illumination microscopy. This strategy combines the advantages offered by small molecules with those of nanomaterials and should find widespread use for non-invasive imaging of enzyme activity in vivo

Caspase-responsive smart gadolinium-based contrast agent for magnetic resonance imaging of drug-induced apoptosis

Non-invasive detection of caspase-3/7 activity in vivo has provided invaluable predictive information regarding tumor therapeutic efficacy and anti-tumor drug selection. Although a number of caspase-3/7 targeted fluorescence and positron emission tomography (PET) imaging probes have been developed, there is still a lack of gadolinium (Gd)-based magnetic resonance imaging (MRI) probes that enable high spatial resolution detection of caspase-3/7 activity in vivo. Here we employ a self-assembly approach and develop a caspase-3/7 activatable Gd-based MRI probe for monitoring tumor apoptosis in mice. Upon reduction and caspase-3/7 activation, the caspase-sensitive nano-aggregation MR probe (C-SNAM: 1) undergoes biocompatible intramolecular cyclization and subsequent self-assembly into Gd-nanoparticles (GdNPs). This results in enhanced r(1) relaxivity—19.0 (post-activation) vs. 10.2 mM(−1) s(−1) (pre-activation) at 1 T in solution—and prolonged accumulation in chemotherapy-induced apoptotic cells and tumors that express active caspase-3/7. We demonstrate that C-SNAM reports caspase-3/7 activity by generating a significantly brighter T(1)-weighted MR signal compared to non-treated tumors following intravenous administration of C-SNAM, providing great potential for high-resolution imaging of tumor apoptosis in vivo

Combining Nuclear Medicine With Other Modalities: Future Prospect for Multimodality Imaging

This meeting report summarizes a consultants meeting that was held at International Atomic Energy Agency Headquarters, Vienna, in July 2022 to provide an update on the development of multimodality imaging by combining nuclear medicine imaging agents with other nonradioactive molecular probes and/or biomedical imaging techniques