Unique Coexistence of Two Resistive Switching Modes in a Memristor Device Enables Multifunctional Neuromorphic Computing Properties.

We report on hybrid memristor devices consisting of germanium dioxide nanoparticles (GeO2 NP) embedded within a poly(methyl methacrylate) (PMMA) thin film. Besides exhibiting forming-free resistive switching and an uncommon "ON" state in pristine conditions, the hybrid (nanocomposite) devices demonstrate a unique form of mixed-mode switching. The observed stopping voltage-dependent switching enables state-of-the-art bifunctional synaptic behavior with short-term (volatile/temporal) and long-term (nonvolatile/nontemporal) modes that are switchable depending on the stopping voltage applied. The short-term memory mode device is demonstrated to further emulate important synaptic functions such as short-term potentiation (STP), short-term depression (STD), paired-pulse facilitation (PPF), post-tetanic potentiation (PTP), spike-voltage-dependent plasticity (SVDP), spike-duration-dependent plasticity (SDDP), and, more importantly, the "learning-forgetting-rehearsal" behavior. The long-term memory mode gives additional long-term potentiation (LTP) and long-term depression (LTD) characteristics for long-term plasticity applications. The work shows a unique coexistence of the two resistive switching modes, providing greater flexibility in device design for future adaptive and reconfigurable neuromorphic computing systems at the hardware level.

Towards Effective Targeted Alpha Therapy for Neuroendocrine Tumours: A Review.

This review article explores the evolving landscape of Molecular Radiotherapy (MRT), emphasizing Peptide Receptor Radionuclide Therapy (PRRT) for neuroendocrine tumours (NETs). The primary focus is on the transition from ß-emitting radiopharmaceuticals to α-emitting agents in PRRT, offering a critical analysis of the radiobiological basis, clinical applications, and ongoing developments in Targeted Alpha Therapy (TAT). Through an extensive literature review, the article delves into the mechanisms and effectiveness of PRRT in targeting somatostatin subtype 2 receptors, highlighting both its successes and limitations. The discussion extends to the emerging paradigm of TAT, underlining its higher potency and specificity with α-particle emissions, which promise enhanced therapeutic efficacy and reduced toxicity. The review critically evaluates preclinical and clinical data, emphasizing the need for standardised dosimetry and a deeper understanding of the dose-response relationship in TAT. The review concludes by underscoring the significant potential of TAT in treating SSTR2-overexpressing cancers, especially in patients refractory to ß-PRRT, while also acknowledging the current challenges and the necessity for further research to optimize treatment protocols.

Quantum Dot Imaging Agents: Haematopoietic Cell Interactions and Biocompatibility.

Quantum dots (QDs) are semi-conducting nanoparticles that have been developed for a range of biological and non-biological functions. They can be tuned to multiple different emission wavelengths and can have significant benefits over other fluorescent systems. Many studies have utilised QDs with a cadmium-based core; however, these QDs have since been shown to have poor biological compatibility. Therefore, other QDs, such as indium phosphide QDs, have been developed. These QDs retain excellent fluorescent intensity and tunability but are thought to have elevated biological compatibility. Herein we discuss the applicability of a range of QDs to the cardiovascular system. Key disease states such as myocardial infarction and stroke are associated with cardiovascular disease (CVD), and there is an opportunity to improve clinical imaging to aide clinical outcomes for these disease states. QDs offer potential clinical benefits given their ability to perform multiple functions, such as carry an imaging agent, a therapy, and a targeting motif. Two key cell types associated with CVD are platelets and immune cells. Both cell types play key roles in establishing an inflammatory environment within CVD, and as such aid the formation of pathological thrombi. However, it is unclear at present how and with which cell types QDs interact, and if they potentially drive unwanted changes or activation of these cell types. Therefore, although QDs show great promise for boosting imaging capability, further work needs to be completed to fully understand their biological compatibility.

Impact of Surface Ligand on the Biocompatibility of InP/ZnS Quantum Dots with Platelets.

InP/ZnS quantum dots (QDs) have received a large focus in recent years as a safer alternative to heavy metal-based QDs. Given their intrinsic fluorescent imaging capabilities, these QDs can be potentially relevant for in vivo platelet imaging. The InP/ZnS QDs are synthesized and their biocompatibility investigated through the use of different phase transfer agents. Analysis of platelet function indicates that platelet-QD interaction can occur at all concentrations and for all QD permutations tested. However, as the QD concentration increases, platelet aggregation is induced by QDs alone independent of natural platelet agonists. This study helps to define a range of concentrations and coatings (thioglycolic acid and penicillamine) that are biocompatible with platelet function. With this information, the platelet-QD interaction can be identified using multiple methods. Fluorescent lifetime imaging microscopy (FLIM) and confocal studies have shown QDs localize on the surface of the platelet toward the center while showing evidence of energy transfer within the QD population. It is believed that these findings are an important stepping point for the development of fluorescent probes for platelet imaging.

Inorganic Chemistry of the Tripodal Picolinate Ligand Tpaa with Gallium(III) and Radiolabeling with Gallium-68.

We report here the improved synthesis of the tripodal picolinate chelator Tpaa, with an overall yield of 41% over five steps, in comparison to the previously reported 6% yield. Tpaa was investigated for its coordination chemistry with Ga(III) and radiolabeling properties with gallium-68 (68Ga). The obtained crystal structure for [Ga(Tpaa)] shows that the three picolinate arms coordinate to the Ga(III) ion, fully occupying the octahedral coordination geometry. This is supported by 1H NMR which shows that the three arms are symmetrical when coordinated to Ga(III). Assessment of the thermodynamic stability through potentiometry gives log KGa-Tpaa = 21.32, with a single species being produced across the range of pH 3.5-7.5. Tpaa achieved >99% radiochemical conversion with 68Ga under mild conditions ([Tpaa] = 6.6 µM, pH 7.4, 37 °C) with a molar activity of 3.1 GBq µmol-1. The resulting complex, [68Ga][Ga(Tpaa)], showed improved stability over the previously reported [68Ga][Ga(Dpaa)(H2O)] in a serum challenge, with 32% of [68Ga][Ga(Tpaa)] remaining intact after 30 min of incubation with fetal bovine serum.

ATP-responsive Mn(II)-based T1 contrast agent for MRI.

A novel diacetylpyridylcarbohydrazide-DAPyCOHz-based manganese(II) chelate with dipicolylamine/zinc(II) (DPA/Zn2+) arms (MnLDPA-Zn2) was developed for adenosine triphosphate (ATP) responsive magnetic resonance imaging (MRI) T1 contrast applications. Compound 2 shows enhanced relaxivity (r1 = 11.52 mM-1 s-1) upon selective ATP binding over other phosphates.

Redox double-switch cancer theranostics through Pt(IV) functionalised manganese dioxide nanostructures.

Manganese dioxide (MnO2)-based nanostructures have emerged as promising tumour microenvironment (TME) responsive platforms. Herein, we used a one-pot reaction to prepare MnO2 nanostructures with Pt(IV) prodrugs as redox- (and thus TME-) responsive theranostics for cancer therapy, in which the Pt(IV) complexes act as prodrugs of cisplatin (Pt(II)), a clinical chemotherapeutic drug. The cytotoxicity of these MnO2-Pt(IV) probes was evaluated in two and three dimensional (2D and 3D) A549 cell models and found to be as effective as active drug cisplatin in 3D models. Moreover, MnO2-Pt(IV) nanoparticles exhibited strong off/ON magnetic resonance (MR) contrast in response to reducing agents, with the longitudinal relaxivity (r1) increasing 136-fold upon treatment with ascorbic acid. This off/ON MR switch was also observed in (2D and 3D) cells in vitro. In vivo MRI experiments revealed that the nanostructures induce a strong and long-lasting T1 signal enhancement upon intratumoral injection in A549 tumour-bearing mice. These results show the potential of MnO2-Pt(IV) NPs as redox responsive MR theranostics for cancer therapy.

Platelet zinc status regulates prostaglandin-induced signaling, altering thrombus formation.

BACKGROUND: Approximately 17.3% of the global population exhibits an element of zinc (Zn2+) deficiency. One symptom of Zn2+ deficiency is increased bleeding through impaired hemostasis. Platelets are crucial to hemostasis and are inhibited by endothelial-derived prostacyclin (prostaglandin I2 [PGI2]), which signals via adenylyl cyclase (AC) and cyclic adenosine monophosphate signaling. In other cell types, Zn2+ modulates cyclic adenosine monophosphate concentrations by changing AC and/or phosphodiesterase activity. OBJECTIVES: To investigate if Zn2+ can modulate platelet PGI2 signaling. METHODS: Platelet aggregation, spreading, and western blotting assays with Zn2+ chelators and cyclic nucleotide elevating agents were performed in washed platelets and platelet-rich plasma conditions. In vitro thrombus formation with various Zn2+ chelators and PGI2 was assessed in whole blood. RESULTS: Incubation of whole blood or washed platelets with Zn2+ chelators caused either embolization of preformed thrombi or reversal of platelet spreading, respectively. To understand this effect, we analyzed resting platelets and identified that incubation with Zn2+ chelators elevated pVASPser157, a marker of PGI2 signaling. In agreement that Zn2+ affects PGI2 signaling, addition of the AC inhibitor SQ22536 blocked Zn2+ chelation-induced platelet spreading reversal, while addition of Zn2+ blocked PGI2-mediated platelet reversal. Moreover, Zn2+ specifically blocked forskolin-mediated AC reversal of platelet spreading. Finally, PGI2 inhibition of platelet aggregation and in vitro thrombus formation was potentiated in the presence of low doses of Zn2+ chelators, increasing its effectiveness in inducing platelet inhibition. CONCLUSION: Zn2+ chelation potentiates platelet PGI2 signaling, elevating PGI2's ability to prevent effective platelet activation, aggregation, and thrombus formation.

Insights into the Effect of Magnetic Confinement on the Performance of Magnetic Nanocomposites in Magnetic Hyperthermia and Magnetic Resonance Imaging.

The combination of superparamagnetic iron oxide nanoparticles (SPIONs) and lipid matrices enables the integration of imaging, drug delivery, and therapy functionalities into smart theranostic nanocomposites. SPION confinement creates new interactions primarily among the embedded SPIONs and then between the nanocomposites and the surroundings. Understanding the parameters that rule these interactions in real interacting (nano)systems still represents a challenge, making it difficult to predict or even explain the final (magnetic) behavior of such systems. Herein, a systematic study focused on the performance of a magnetic nanocomposite as a magnetic resonance imaging (MRI) contrast agent and magnetic hyperthermia (MH) effector is presented. The effect of stabilizing agents and magnetic loading on the final physicochemical and, more importantly, functional properties (i.e., blocking temperature, specific absorption rate, relaxivity) was studied in detail.

Bn2DT3A, a Chelator for 68Ga Positron Emission Tomography: Hydroxide Coordination Increases Biological Stability of [68Ga][Ga(Bn2DT3A)(OH)].

The chelator Bn2DT3A was used to produce a novel 68Ga complex for positron emission tomography (PET). Unusually, this system is stabilized by a coordinated hydroxide in aqueous solutions above pH 5, which confers sufficient stability for it to be used for PET. Bn2DT3A complexes Ga3+ in a hexadentate manner, forming a mer-mer complex with log K([Ga(Bn2DT3A)]) = 18.25. Above pH 5, the hydroxide ion coordinates the Ga3+ ion following dissociation of a coordinated amine. Bn2DT3A radiolabeling displayed a pH-dependent speciation, with [68Ga][Ga(Bn2DT3A)(OH)]- being formed above pH 5 and efficiently radiolabeled at pH 7.4. Surprisingly, [68Ga][Ga(Bn2DT3A)(OH)]- was found to show an increased stability in vitro (for over 2 h in fetal bovine serum) compared to [68Ga][Ga(Bn2DT3A)]. The biodistribution of [68Ga][Ga(Bn2DT3A)(OH)]- in healthy rats showed rapid clearance and excretion via the kidneys, with no uptake seen in the lungs or bones.

Practical Considerations of Dissolved Oxygen Levels for Platelet Function under Hypoxia.

Investigating human platelet function in low-oxygen environments is important in multiple settings, including hypobaric hypoxia (e.g., high altitude), sea level hypoxia-related disease, and thrombus stability. These studies often involve drawing blood from which platelets are isolated and analysed at atmospheric conditions or re-exposed to low oxygen levels in hypoxia chambers before testing. However, it remains unknown how the in vitro handling of the samples itself changes their dissolved oxygen concentration, which might affect platelet function and experimental results. Here, we prepared healthy donor platelet-rich plasma and washed platelet (WP) suspensions and exposed them to 2% oxygen. We found that the use of hypoxia pre-equilibrated tubes, higher platelet concentrations (>2 × 108/mL versus 2 × 107/mL), smaller volumes (600 µL versus 3 mL), and presence of plasma reduced the time for samples to reach 2% oxygen. Notably, oxygen levels decreased below 2% in most suspensions, but also in WP maintained at atmospheric 21% oxygen. Additionally, platelet spreading on fibrinogen was decreased when using hypoxic fibrinogen-coated culture plates regardless of the oxygen percentage (2% or 21%) in which platelet incubation took place. Thus, sample handling and experimental conditions should be carefully monitored in platelet-hypoxia studies as they might compromise results interpretation and comparison across studies.

Smart magnetic resonance imaging-based theranostics for cancer.

Smart theranostics are dynamic platforms that integrate multiple functions, including at least imaging, therapy, and responsiveness, in a single agent. This review showcases a variety of responsive theranostic agents developed specifically for magnetic resonance imaging (MRI), due to the privileged position this non-invasive, non-ionising imaging modality continues to hold within the clinical imaging field. Different MRI smart theranostic designs have been devised in the search for more efficient cancer therapy, and improved diagnostic efficiency, through the increase of the local concentration of therapeutic effectors and MRI signal intensity in pathological tissues. This review explores novel small-molecule and nanosized MRI theranostic agents for cancer that exhibit responsiveness to endogenous (change in pH, redox environment, or enzymes) or exogenous (temperature, ultrasound, or light) stimuli. The challenges and obstacles in the design and in vivo application of responsive theranostics are also discussed to guide future research in this interdisciplinary field towards more controllable, efficient, and diagnostically relevant smart theranostics agents.

Scandium calix[n]arenes (n = 4, 6, 8): structural, cytotoxicity and ring opening polymerization studies.

Interaction of [Sc(OR)3] (R = iPr or triflate) with p-tert-butylcalix[n]arenes, where n = 4, 6, or 8, affords a number of intriguing structural motifs, which are relatively non-toxic (cytotoxicity evaluated against cell lines HCT116 and HT-29) and a number were capable of the ring opening polymerization (ROP) of cyclohexene oxide.

NIR-quantum dots in biomedical imaging and their future.

Fluorescence imaging has gathered interest over the recent years for its real-time response and high sensitivity. Developing probes for this modality has proven to be a challenge. Quantum dots (QDs) are colloidal nanoparticles that possess unique optical and electronic properties due to quantum confinement effects, whose excellent optical properties make them ideal for fluorescence imaging of biological systems. By selectively controlling the synthetic methodologies it is possible to obtain QDs that emit in the first (650-950 nm) and second (1000-1400 nm) near infra-red (NIR) windows, allowing for superior imaging properties. Despite the excellent optical properties and biocompatibility shown by some NIR QDs, there are still some challenges to overcome to enable there use in clinical applications. In this review, we discuss the latest advances in the application of NIR QDs in preclinical settings, together with the synthetic approaches and material developments that make NIR QDs promising for future biomedical applications.

A Single-Pot Template Reaction Towards a Manganese-Based T1 Contrast Agent.

Manganese-based contrast agents (MnCAs) have emerged as suitable alternatives to gadolinium-based contrast agents (GdCAs). However, due to their kinetic lability and laborious synthetic procedures, only a few MnCAs have found clinical MRI application. In this work, we have employed a highly innovative single-pot template synthetic strategy to develop a MnCA, MnLMe , and studied the most important physicochemical properties in vitro. MnLMe displays optimized r1 relaxivities at both medium (20 and 64 MHz) and high magnetic fields (300 and 400 MHz) and an enhanced r1b =21.1 mM-1 s-1 (20 MHz, 298 K, pH 7.4) upon binding to BSA (Ka =4.2×103  M-1 ). In vivo studies show that MnLMe is cleared intact into the bladder through renal excretion and has a prolonged blood half-life compared to the commercial GdCA Magnevist. MnLMe shows great promise as a novel MRI contrast agent.

A Single-Pot Template Reaction Towards a Manganese-Based T1 Contrast Agent.

Manganese-based contrast agents (MnCAs) have emerged as suitable alternatives to gadolinium-based contrast agents (GdCAs). However, due to their kinetic lability and laborious synthetic procedures, only a few MnCAs have found clinical MRI application. In this work, we have employed a highly innovative single-pot template synthetic strategy to develop a MnCA, MnLMe, and studied the most important physicochemical properties in vitro. MnLMe displays optimized r 1 relaxivities at both medium (20 and 64 MHz) and high magnetic fields (300 and 400 MHz) and an enhanced r 1 b=21.1 mM-1 s-1 (20 MHz, 298 K, pH 7.4) upon binding to BSA (K a=4.2×103 M-1). In vivo studies show that MnLMe is cleared intact into the bladder through renal excretion and has a prolonged blood half-life compared to the commercial GdCA Magnevist. MnLMe shows great promise as a novel MRI contrast agent.

Tunable NIR-II emitting silver chalcogenide quantum dots using thio/selenourea precursors: preparation of an MRI/NIR-II multimodal imaging agent.

Aqueous-stable, Cd- and Pb-free colloidal quantum dots with fluorescence properties in the second near-infrared region (NIR-II, 1000-1400) are highly desirable for non-invasive deep-tissue optical imaging and biosensing. The low band-gap semiconductor, silver chalcogenide, offers a non-toxic and stable alternative to existing Pd, As, Hg and Cd-based NIR-II colloidal quantum dots (QDs). We report facile access to NIR-II emission windows with Ag2X (X = S, Se) QDs using easy-to-prepare thio/selenourea precursors and their analogues. The aqueous phase transfer of these QDs with a high conservation of fluorescence quantum yield (retention up to ∼90%) and colloidal stability is demonstrated. A bimodal NIR-II/MRI contrast agent with a tunable fluorescence and high T1 relaxivity of 408 mM-1 s-1 per QD (size ∼ 2.2 nm) and 990 mM-1 s-1 per QD (size ∼ 4.2 nm) has been prepared by grafting 50 and 120 monoaqua Gd(iii) complexes respectively to two differently sized Ag2S QDs. The size of the nanocrystals is crucial for tuning the Gd payload and the relaxivity.

Synthesis of a porphyrin with histidine-like chelate: an efficient path towards molecular PDT/SPECT theranostics.

The goal of "personalised" medicine has seen a growing interest in the development of theranostic agents. Bifunctional, and targeted-trifunctional, theranostic water-soluble porphyrins with a histidine-like chelating group have been synthesised via copper-catalysed azide-alkyne cycloaddition (CuAAC) "click" chemistry in high yield and purity. They are capable of photodynamic treatment and [99mTc(CO)3]+ complexation for single-photon emission computed tomography (SPECT) imaging, with a radiochemical yield of >95%. The toxicity and phototoxicity were evaluated on HT-29 cells, DU145, and DU145-PSMA cell lines, with the targeted theranostic showing more potent phototoxicity towards DU145-PSMA expressing cells.

The use of yttrium in medical imaging and therapy: historical background and future perspectives.

Yttrium is a chemically versatile rare earth element that finds use in a range of applications including lasers and superconductors. In medicine, yttrium-based materials are used in medical lasers and biomedical implants. This is extended through the array of available yttrium isotopes to enable roles for 90Y complexes as radiopharmaceuticals and 86Y tracers for positron emission tomography (PET) imaging. The naturally abundant isotope 89Y is proving to be suitable for nuclear magnetic resonance investigations, where initial reports in the emerging field of hyperpolarised magnetic resonance imaging (MRI) are promising. In this review we explore the coordination and radiochemical properties of yttrium, and its role in drugs for radiotherapy, PET imaging agents and perspectives for applications in hyperpolarised MRI.

Metallostar Assemblies Based on Dithiocarbamates for Use as MRI Contrast Agents.

Two different octadentate gadolinium chelates based on DO3A and DOTAGA chelates (hydration number q = 1) have been used to prepare a series of bi-, tri-, and tetrametallic d-f mixed-metal complexes. The piperazine-based dithiocarbamate linker ensures that rotation of the gadolinium chelates is restricted, leading to enhanced relaxivity (r1) values, which increase with the overall mass and number of gadolinium units. The r1 value (at 10 MHz, 25 °C) per gadolinium unit rises from 5.0 mM-1 s-1 for the Gd-DO3A-NH2 monogadolinium chelate to 9.2 mM-1 s-1 in a trigadolinium complex with a ruthenium(III) core. Using a 1.5 T clinical scanner operating at 63.87 MHz (25 °C), an 86% increase in the relaxivity per gadolinium unit is observed for this multimetallic compound compared to clinically approved Dotarem. The gadolinium complexes based on the DOTAGA chelate also performed well at 63.87 MHz, with a relaxivity value of 9.5 mM-1 s-1 per gadolinium unit being observed for the trigadolinium d-f mixed-metal complex with a ruthenium(III) core. The versatility of dithiocarbamate coordination chemistry thus provides access to a wide range of d-f hybrids with potential for use as high-performance MRI contrast agents.