Unraveling the mechanistic complexity of Alzheimer's disease through systems biology.

Alzheimer's disease (AD) is a complex, multifactorial disease that has reached global epidemic proportions. The challenge remains to fully identify its underlying molecular mechanisms that will enable development of accurate diagnostic tools and therapeutics. Conventional experimental approaches that target individual or small sets of genes or proteins may overlook important parts of the regulatory network, which limits the opportunity of identifying multitarget interventions. Our perspective is that a more complete insight into potential treatment options for AD will only be made possible through studying the disease as a system. We propose an integrative systems biology approach that we argue has been largely untapped in AD research. We present key publications to demonstrate the value of this approach and discuss the potential to intensify research efforts in AD through transdisciplinary collaboration. We highlight challenges and opportunities for significant breakthroughs that could be made if a systems biology approach is fully exploited.

Oral nanotherapeutic formulation of insulin with reduced episodes of hypoglycaemia.

Injectable insulin is an extensively used medication with potential life-threatening hypoglycaemic events. Here we report on insulin-conjugated silver sulfide quantum dots coated with a chitosan/glucose polymer to produce a responsive oral insulin nanoformulation. This formulation is pH responsive, is insoluble in acidic environments and shows increased absorption in human duodenum explants and Caenorhabditis elegans at neutral pH. The formulation is sensitive to glucosidase enzymes to trigger insulin release. It is found that the formulation distributes to the liver in mice and rats after oral administration and promotes a dose-dependent reduction in blood glucose without promoting hypoglycaemia or weight gain in diabetic rodents. Non-diabetic baboons also show a dose-dependent reduction in blood glucose. No biochemical or haematological toxicity or adverse events were observed in mice, rats and non-human primates. The formulation demonstrates the potential to orally control blood glucose without hypoglycaemic episodes.

Online dynamical learning and sequence memory with neuromorphic nanowire networks.

Nanowire Networks (NWNs) belong to an emerging class of neuromorphic systems that exploit the unique physical properties of nanostructured materials. In addition to their neural network-like physical structure, NWNs also exhibit resistive memory switching in response to electrical inputs due to synapse-like changes in conductance at nanowire-nanowire cross-point junctions. Previous studies have demonstrated how the neuromorphic dynamics generated by NWNs can be harnessed for temporal learning tasks. This study extends these findings further by demonstrating online learning from spatiotemporal dynamical features using image classification and sequence memory recall tasks implemented on an NWN device. Applied to the MNIST handwritten digit classification task, online dynamical learning with the NWN device achieves an overall accuracy of 93.4%. Additionally, we find a correlation between the classification accuracy of individual digit classes and mutual information. The sequence memory task reveals how memory patterns embedded in the dynamical features enable online learning and recall of a spatiotemporal sequence pattern. Overall, these results provide proof-of-concept of online learning from spatiotemporal dynamics using NWNs and further elucidate how memory can enhance learning.

Neuromorphic learning, working memory, and metaplasticity in nanowire networks.

Nanowire networks (NWNs) mimic the brain's neurosynaptic connectivity and emergent dynamics. Consequently, NWNs may also emulate the synaptic processes that enable higher-order cognitive functions such as learning and memory. A quintessential cognitive task used to measure human working memory is the n-back task. In this study, task variations inspired by the n-back task are implemented in a NWN device, and external feedback is applied to emulate brain-like supervised and reinforcement learning. NWNs are found to retain information in working memory to at least n = 7 steps back, remarkably similar to the originally proposed "seven plus or minus two" rule for human subjects. Simulations elucidate how synapse-like NWN junction plasticity depends on previous synaptic modifications, analogous to "synaptic metaplasticity" in the brain, and how memory is consolidated via strengthening and pruning of synaptic conductance pathways.

Water and tissue equivalence of a new PRESAGE(®) formulation for 3D proton beam dosimetry: a Monte Carlo study.

PURPOSE: To evaluate the water and tissue equivalence of a new PRESAGE(®) 3D dosimeter for proton therapy. METHODS: The GEANT4 software toolkit was used to calculate and compare total dose delivered by a proton beam with mean energy 62 MeV in a PRESAGE(®) dosimeter, water, and soft tissue. The dose delivered by primary protons and secondary particles was calculated. Depth-dose profiles and isodose contours of deposited energy were compared for the materials of interest. RESULTS: The proton beam range was found to be ≈27 mm for PRESAGE(®), 29.9 mm for soft tissue, and 30.5 mm for water. This can be attributed to the lower collisional stopping power of water compared to soft tissue and PRESAGE(®). The difference between total dose delivered in PRESAGE(®) and total dose delivered in water or tissue is less than 2% across the entire water∕tissue equivalent range of the proton beam. The largest difference between total dose in PRESAGE(®) and total dose in water is 1.4%, while for soft tissue it is 1.8%. In both cases, this occurs at the distal end of the beam. Nevertheless, the authors find that PRESAGE(®) dosimeter is overall more tissue-equivalent than water-equivalent before the Bragg peak. After the Bragg peak, the differences in the depth doses are found to be due to differences in primary proton energy deposition; PRESAGE(®) and soft tissue stop protons more rapidly than water. The dose delivered by secondary electrons in the PRESAGE(®) differs by less than 1% from that in soft tissue and water. The contribution of secondary particles to the total dose is less than 4% for electrons and ≈1% for protons in all the materials of interest. CONCLUSIONS: These results demonstrate that the new PRESAGE(®) formula may be considered both a tissue- and water-equivalent 3D dosimeter for a 62 MeV proton beam. The results further suggest that tissue-equivalent thickness may provide better dosimetric and geometric accuracy than water-equivalent thickness for 3D dosimetry of this proton beam.

A study of surface dosimetry for breast cancer radiotherapy treatments using Gafchromic EBT2 film.

The present study quantified surface doses on several rectangular phantom setups and on curved surface phantoms for a 6 MV photon field using the Attix parallel-plate chamber and Gafchromic EBT2 film. For the rectangular phantom setups, the surface doses on a homogenous water equivalent phantom and a water equivalent phantom with 60 mm thick lung equivalent material were measured. The measurement on the homogenous phantom setup showed consistency in surface and near-surface doses between an open field and enhanced dynamic wedge (EDW) fields, whereas physical wedged fields showed small differences. Surface dose measurements made using the EBT2 film showed good agreement with results of the Attix chamber and results obtained in previous studies which used other dosimeters within the measurement uncertainty of 3.3%. The surface dose measurements on the phantom setup with lung equivalent material showed a small increase without bolus and up to 6.9% increase with bolus simulating the increase of chest wall thickness. Surface doses on the cylindrical CT phantom and customized Perspex chest phantom were measured using the EBT2 film with and without bolus. The results indicate the important role of the presence of bolus if the clinical target volume (CTV) is quite close to the surface. Measurements on the cylindrical phantom suggest that surface doses at the oblique positions of 60° and 90° are mainly caused by the lateral scatter from the material inside the phantom. In the case of a single tangential irradiation onto Perspex chest phantom, the distribution of the surface dose with and without bolus materials showed opposing inclination patterns, whereas the dose distribution for two opposed tangential fields gave symmetric dose distribution. This study also demonstrates the suitability of Gafchromic EBT2 film for surface dose measurements in megavoltage photon beams.

Water equivalence evaluation of PRESAGE(®) formulations for megavoltage electron beams: a Monte Carlo study.

To investigate the radiological water equivalency of three different formulations of the radiochromic, polyurethane based dosimeter PRESAGE(®) for three dimensional (3D) dosimetry of electron beams. The EGSnrc/BEAMnrc Monte Carlo package was used to model 6-20 MeV electron beams and calculate the corresponding doses delivered in the three different PRESAGE(®) formulations and water. The depth of 50 % dose and practical range of electron beams were determined from the depth dose calculations and scaling factors were calculated for these electron beams. In the buildup region, a 1.0 % difference in dose was found for all PRESAGE(®) formulations relative to water for 6 and 9 MeV electron beams while the difference was negligible for the higher energy electron beams. Beyond the buildup region (at a depth range of 22-26 mm for the 6 MeV beam and 38 mm for the 9 MeV beam), the discrepancy from water was found to be 5.0 % for the PRESAGE(®) formulations with lower halogen content than the original formulation, which was found to have a discrepancy of up to 14 % relative to water. For a 16 MeV electron beam, the dose discrepancy from water increases and reaches about 7.0 % at 70 mm depth for the lower halogen content PRESAGE(®) formulations and 20 % at 66 mm depth for the original formulation. For the 20 MeV electron beam, the discrepancy drops to 6.0 % at 90 mm depth for the lower halogen content formulations and 18 % at 85 mm depth for the original formulation. For the lower halogen content PRESAGE(®), the depth of 50 % dose and practical range of electrons differ from water by up to 3.0 %, while the range of differences from water is between 6.5 and 8.0 % for the original PRESAGE(®) formulation. The water equivalent depth scaling factor required for the original formulation of PRESAGE(®) was determined to be 1.07-1.08, which is larger than that determined for the lower halogen content formulations (1.03) over the entire beam energy range of electrons. All three of the PRESAGE(®) formulations studied require a depth scaling factor to convert depth in PRESAGE(®) to water equivalent depth for megavoltage electron beam dosimetry. Compared to the original PRESAGE(®) formulation, the lower halogen content formulations require a significantly smaller scaling factor and are thus recommended over the original PRESAGE(®) formulation for electron beam dosimetry.

Investigation of radiological properties and water equivalency of PRESAGE dosimeters.

PURPOSE: PRESAGE is a dosimeter made of polyurethane, which is suitable for 3D dosimetry in modern radiation treatment techniques. Since an ideal dosimeter is radiologically water equivalent, the authors investigated water equivalency and the radiological properties of three different PRESAGE formulations that differ primarily in their elemental compositions. Two of the formulations are new and have lower halogen content than the original formulation. METHODS: The radiological water equivalence was assessed by comparing the densities, interaction probabilities, and radiation dosimetry properties of the three different PRESAGE formulations to the corresponding values for water. The relative depth doses were calculated using Monte Carlo methods for 50, 100, 200, and 350 kVp and 6 MV x-ray beams. RESULTS: The mass densities of the three PRESAGE formulations varied from 5.3% higher than that of water to as much as 10% higher than that of water for the original formulation. The probability of photoelectric absorption in the three different PRESAGE formulations varied from 2.2 times greater than that of water for the new formulations to 3.5 times greater than that of water for the original formulation. The mass attenuation coefficient for the three formulations is 12%-50% higher than the value for water. These differences occur over an energy range (10-100 keV) in which the photoelectric effect is the dominant interaction. The collision mass stopping powers of the relatively lower halogen-containing PRESAGE formulations also exhibit marginally better water equivalency than the original higher halogen-containing PRESAGE formulation. Furthermore, the depth dose curves for the lower halogen-containing PRESAGE formulations are slightly closer to that of water for a 6 MV beam. In the kilovoltage energy range, the depth dose curves for the lower halogen-containing PRESAGE formulations are in better agreement with water than the original PRESAGE formulation. CONCLUSIONS: Based on the results of this study, the new PRESAGE formulations with lower halogen content are more radiologically water equivalent overall than the original formulation. This indicates that the new PRESAGE formulations are better suited to clinical applications and are more accurate dosimeters and phantoms than the original PRESAGE formulation. While correction factors are still needed to convert the dose measured by the dosimeter to an absorbed dose in water in the kilovoltage energy range, these correction factors are considerably smaller for the new PRESAGE formulations compared to the original PRESAGE and the existing polymer gel dosimeters.

Direct dose to water dosimetry for pretreatment IMRT verification using a modified EPID.

PURPOSE: Electronic portal imaging devices (EPIDs) are high resolution systems that produce electronic dose maps with minimal time required for equipment setup, and therefore potentially present a time-saving alternative for intensity modulated radiation therapy (IMRT) pretreatment verification. A modified commercial EPID was investigated operated with an opaque sheet blocking the optical signal produced in the phosphor layer as a precursor to a switched mode dual dosimetry-imaging EPID system. The purpose of this study was to investigate the feasibility of using this system for direct dose to water dosimetry for pretreatment IMRT verification. METHODS: A Varian amorphous silicon EPID was modified by placing an opaque sheet between the Gd(2)S(2)O:Tb phosphor layer and the photodiode array to block the optical photons. The EPID was thus converted to a direct-detecting system (dEPID), in which the high energy radiation deposits energy directly in the photodiode array. The copper build-up was replaced with d(max) solid water. Sixty-one IMRT beams of varying complexity were delivered to the EPID, to EDR2 dosimetric film and to a 2D ion chamber array (MapCheck). EPID data was compared to film and MapCheck data using gamma analysis with 3%, 3mm pass criteria. RESULTS: The fraction of points that passed the gamma test was on average 98.1% and 98.6%, for the EPID versus film and EPID versus MapCheck comparisons, respectively. In the case of comparison with film, the majority of observed discrepancies were associated with problems related to film sensitivity or processing. CONCLUSIONS: The very close agreement between EPID and both film and MapCheck data demonstrates that the modified EPID is suitable for direct dose to water measurement for pretreatment IMRT verification. These results suggest a reconfigured EPID could be an efficient and accurate dosimeter. Alternatively, optical switching methods could be developed to produce a dual-mode EPID with both dosimetry and imaging capabilities.

Avalanches and edge-of-chaos learning in neuromorphic nanowire networks.

The brain's efficient information processing is enabled by the interplay between its neuro-synaptic elements and complex network structure. This work reports on the neuromorphic dynamics of nanowire networks (NWNs), a unique brain-inspired system with synapse-like memristive junctions embedded within a recurrent neural network-like structure. Simulation and experiment elucidate how collective memristive switching gives rise to long-range transport pathways, drastically altering the network's global state via a discontinuous phase transition. The spatio-temporal properties of switching dynamics are found to be consistent with avalanches displaying power-law size and life-time distributions, with exponents obeying the crackling noise relationship, thus satisfying criteria for criticality, as observed in cortical neuronal cultures. Furthermore, NWNs adaptively respond to time varying stimuli, exhibiting diverse dynamics tunable from order to chaos. Dynamical states at the edge-of-chaos are found to optimise information processing for increasingly complex learning tasks. Overall, these results reveal a rich repertoire of emergent, collective neural-like dynamics in NWNs, thus demonstrating the potential for a neuromorphic advantage in information processing.

Information dynamics in neuromorphic nanowire networks.

Neuromorphic systems comprised of self-assembled nanowires exhibit a range of neural-like dynamics arising from the interplay of their synapse-like electrical junctions and their complex network topology. Additionally, various information processing tasks have been demonstrated with neuromorphic nanowire networks. Here, we investigate the dynamics of how these unique systems process information through information-theoretic metrics. In particular, Transfer Entropy (TE) and Active Information Storage (AIS) are employed to investigate dynamical information flow and short-term memory in nanowire networks. In addition to finding that the topologically central parts of networks contribute the most to the information flow, our results also reveal TE and AIS are maximized when the networks transitions from a quiescent to an active state. The performance of neuromorphic networks in memory and learning tasks is demonstrated to be dependent on their internal dynamical states as well as topological structure. Optimal performance is found when these networks are pre-initialised to the transition state where TE and AIS are maximal. Furthermore, an optimal range of information processing resources (i.e. connectivity density) is identified for performance. Overall, our results demonstrate information dynamics is a valuable tool to study and benchmark neuromorphic systems.

Quantum Dot Nanomedicine Formulations Dramatically Improve Pharmacological Properties and Alter Uptake Pathways of Metformin and Nicotinamide Mononucleotide in Aging Mice.

Orally administered Ag2S quantum dots (QDs) rapidly cross the small intestine and are taken up by the liver. Metformin and nicotinamide mononucleotide (NMN) target metabolic and aging processes within the liver. This study examined the pharmacology and toxicology of QD-based nanomedicines as carriers of metformin and NMN in young and old mice, determining if their therapeutic potency and reduced effects associated with aging could be improved. Pharmacokinetic studies demonstrated that QD-conjugated metformin and NMN have greater bioavailability, with selective accumulation in the liver following oral administration compared to unconjugated formulations. Pharmacodynamic data showed that the QD-conjugated medicines had increased physiological, metabolic, and cellular potency compared to unconjugated formulations (25× metformin; 100× NMN) and highlighted a shift in the peak induction of, and greater metabolic response to, glucose tolerance testing. Two weeks of treatment with low-dose QD-NMN (0.8 mg/kg/day) improved glucose tolerance tests in young (3 months) mice, whereas old (18 and 24 months) mice demonstrated improved fasting and fed insulin levels and insulin resistance. High-dose unconjugated NMN (80 mg/kg/day) demonstrated improvements in young mice but not in old mice. After 100 days of QD (320 µg/kg/day) treatment, there was no evidence of cellular necrosis, fibrosis, inflammation, or accumulation. Ag2S QD nanomedicines improved the pharmacokinetic and pharmacodynamic properties of metformin and NMN by increasing their therapeutic potency, bypassing classical cellular uptake pathways, and demonstrated efficacy when drug alone was ineffective in aging mice.

The water equivalence of solid phantoms for low energy photon beams.

PURPOSE: To compare and evaluate the dosimetric water equivalence of several commonly used solid phantoms for low energy photon beams. METHODS: A total of ten different solid phantom materials was used in the study. The PENELOPE Monte Carlo code was used to calculate depth doses and beam profiles in all the phantom materials as well as the dose to a small water voxel at the surface of the solid phantom. These doses were compared to the corresponding doses calculated in a water phantom. The primary photon beams used ranged in energy from 50 to 280 kVp. RESULTS: A number of phantom materials had excellent agreement in dose compared to water for all the x-ray beam energies studied. RMI457 Solid Water, Virtual Water, PAGAT, A150, and Plastic Water DT all had depth doses that agreed with those in water to within 2%. For these same phantom materials, the dose changes in the water voxel at the surface of the solid phantom were within 2%, except for A150, which agreed to within 2.7%. By comparison, the largest differences in depth doses occurred for Plastic Water (-21.7%) and polystyrene (17.6%) for the 50 kVp energy photon beam and 8 cm diameter field size. Plastic Water gave the largest difference in the normalized beam profiles with differences of up to 3.5% as compared to water. Surface dose changes, due to the presence of the solid phantom acting as the backscatter material, were found to be up to 9.1% for polystyrene with significant differences also found for Plastic Water, PMMA, and RW3 phantoms. CONCLUSIONS: The following solid phantoms can be considered water equivalent and are recommended for relative dosimetry of low energy photon beams: A150, PAGAT, Plastic Water DT, RMI457 Solid Water, and Virtual Water. However, the following solid phantoms give significant differences, compared to water, in depth doses, profiles, and/or in surface doses due to backscatter changes: Plastic Water, PMMA, polystyrene, PRESAGE, and RW3.

High-sensitivity in vivo contrast for ultra-low field magnetic resonance imaging using superparamagnetic iron oxide nanoparticles.

Magnetic resonance imaging (MRI) scanners operating at ultra-low magnetic fields (ULF; <10 mT) are uniquely positioned to reduce the cost and expand the clinical accessibility of MRI. A fundamental challenge for ULF MRI is obtaining high-contrast images without compromising acquisition sensitivity to the point that scan times become clinically unacceptable. Here, we demonstrate that the high magnetization of superparamagnetic iron oxide nanoparticles (SPIONs) at ULF makes possible relaxivity- and susceptibility-based effects unachievable with conventional contrast agents (CAs). We leverage these effects to acquire high-contrast images of SPIONs in a rat model with ULF MRI using short scan times. This work overcomes a key limitation of ULF MRI by enabling in vivo imaging of biocompatible CAs. These results open a new clinical translation pathway for ULF MRI and have broader implications for disease detection with low-field portable MRI scanners.

Positron annihilation localization by nanoscale magnetization.

In positron emission tomography (PET), the finite range over which positrons travel before annihilating with an electron places a fundamental physical limit on the spatial resolution of PET images. After annihilation, the photon pair detected by the PET instrumentation is emitted from a location that is different from the positron-emitting source, resulting in image blurring. Here, we report on the localization of positron range, and hence annihilation quanta, by strong nanoscale magnetization of superparamagnetic iron oxide nanoparticles (SPIONs) in PET-MRI. We found that positron annihilations localize within a region of interest by up to 60% more when SPIONs are present (with [Fe] = 3 mM) compared to when they are not. The resulting full width at half maximum of the PET scans showed the spatial resolution improved by up to [Formula: see text] 30%. We also found evidence suggesting that the radiolabeled SPIONs produced up to a six-fold increase in ortho-positronium. These results may also have implications for emerging cancer theranostic strategies, where charged particles are used as therapeutic as well as diagnostic agents and improved dose localization within a tumor is a determinant of better treatment outcomes.

Topological Properties of Neuromorphic Nanowire Networks.

Graph theory has been extensively applied to the topological mapping of complex networks, ranging from social networks to biological systems. Graph theory has increasingly been applied to neuroscience as a method to explore the fundamental structural and functional properties of human neural networks. Here, we apply graph theory to a model of a novel neuromorphic system constructed from self-assembled nanowires, whose structure and function may mimic that of human neural networks. Simulations of neuromorphic nanowire networks allow us to directly examine their topology at the individual nanowire-node scale. This type of investigation is currently extremely difficult experimentally. We then apply network cartographic approaches to compare neuromorphic nanowire networks with: random networks (including an untrained artificial neural network); grid-like networks and the structural network of C. elegans. Our results demonstrate that neuromorphic nanowire networks exhibit a small-world architecture similar to the biological system of C. elegans, and significantly different from random and grid-like networks. Furthermore, neuromorphic nanowire networks appear more segregated and modular than random, grid-like and simple biological networks and more clustered than artificial neural networks. Given the inextricable link between structure and function in neural networks, these results may have important implications for mimicking cognitive functions in neuromorphic nanowire networks.

A Radio-Nano-Platform for T1/T2 Dual-Mode PET-MR Imaging.

PURPOSE: This study aimed to develop a chelate-free radiolabeled nanoparticle platform for simultaneous positron emission tomography (PET) and magnetic resonance (MR) imaging that provides contrast-enhanced diagnostic imaging and significant image quality gain by integrating the high spatial resolution of MR with the high sensitivity of PET. METHODS: A commercially available super-paramagnetic iron oxide nanoparticle (SPION) (Feraheme®, FH) was labeled with the [89Zr]Zr using a novel chelate-free radiolabeling technique, heat-induced radiolabeling (HIR). Radiochemical yield (RCY) and purity (RCP) were measured using size exclusion chromatography (SEC) and radio-thin layer chromatography (radio-TLC). Characterization of the non-radioactive isotope 90Zr-labeled FH was performed by transmission electron microscopy (TEM). Simultaneous PET-MR phantom imaging was performed with different 89Zr-FH concentrations. The MR quantitative image analysis determined the contrast-enhancing properties of FH. The signal-to-noise ratio (SNR) and full-width half-maximum (FWHM) of the line spread function (LSF) were calculated before and after co-registering the PET and MR image data. RESULTS: High RCY (92%) and RCP (98%) of the [89Zr]Zr-FH product was achieved. TEM analysis confirmed the 90Zr atoms adsorption onto the SPION surface (≈ 10% average radial increase). Simultaneous PET-MR scans confirmed the capability of the [89Zr]Zr-FH nano-platform for this multi-modal imaging technique. Relative contrast image analysis showed that [89Zr]Zr-FH can act as a dual-mode T1/T2 contrast agent. For co-registered PET-MR images, higher spatial resolution (FWHM enhancement ≈ 3) and SNR (enhancement ≈ 8) was achieved at a clinical dose of radio-isotope and Fe. CONCLUSION: Our results demonstrate FH is a highly suitable SPION-based platform for chelate-free labeling of PET tracers for hybrid PET-MR. The high RCY and RCP confirmed the robustness of the chelate-free HIR technique. An overall image quality gain was achieved compared to PET- or MR-alone imaging with a relatively low dosage of [89Zr]Zr-FH. Additionally, FH is suitable as a dual-mode T1/T2 MR image contrast agent.

A Chelate-Free Nano-Platform for Incorporation of Diagnostic and Therapeutic Isotopes.

PURPOSE: Using our chelate-free, heat-induced radiolabeling (HIR) method, we show that a wide range of metals, including those with radioactive isotopologues used for diagnostic imaging and radionuclide therapy, bind to the Feraheme (FH) nanoparticle (NP), a drug approved for the treatment of iron anemia. MATERIAL AND METHODS: FH NPs were heated (120°C) with nonradioactive metals, the resulting metal-FH NPs were characterized by inductively coupled plasma mass spectrometry (ICP-MS), dynamic light scattering (DLS), and r1 and r2 relaxivities obtained by nuclear magnetic relaxation spectrometry (NMRS). In addition, the HIR method was performed with [90Y]Y3+, [177Lu]Lu3+, and [64Cu]Cu2+, the latter with an HIR technique optimized for this isotope. Optimization included modifying reaction time, temperature, and vortex technique. Radiochemical yield (RCY) and purity (RCP) were measured using size exclusion chromatography (SEC) and thin-layer chromatography (TLC). RESULTS: With ICP-MS, metals incorporated into FH at high efficiency were bismuth, indium, yttrium, lutetium, samarium, terbium and europium (>75% @ 120 oC). Incorporation occurred with a small (less than 20%) but statistically significant increases in size and the r2 relaxivity. An improved HIR technique (faster heating rate and improved vortexing) was developed specifically for copper and used with the HIR technique and [64Cu]Cu2+. Using SEC and TLC analyses with [90Y]Y3+, [177Lu]Lu3+ and [64Cu]Cu2+, RCYs were greater than 85% and RCPs were greater than 95% in all cases. CONCLUSION: The chelate-free HIR technique for binding metals to FH NPs has been extended to a range of metals with radioisotopes used in therapeutic and diagnostic applications. Cations with f-orbital electrons, more empty d-orbitals, larger radii, and higher positive charges achieved higher values of RCY and RCP in the HIR reaction. The ability to use a simple heating step to bind a wide range of metals to the FH NP, a widely available approved drug, may allow this NP to become a platform for obtaining radiolabeled nanoparticles in many settings.

Rapid Intestinal Uptake and Targeted Delivery to the Liver Endothelium Using Orally Administered Silver Sulfide Quantum Dots.

Quantum dots (QDs) are used for imaging and transport of therapeutics. Here we demonstrate rapid absorption across the small intestine and targeted delivery of QDs with bound materials to the liver sinusoidal endothelial cells (LSECs) or hepatocytes in vitro and in vivo following oral administration. QDs were radiolabeled with 3H-oleic acid, with a fluorescent tag or 14C-metformin placed within a drug binding site. Three different biopolymer shell coatings were compared (formaldehyde-treated serum albumin (FSA), gelatin, heparin). Passage across the small intestine into mesenteric veins is mediated by clathrin endocytosis and micropinocytosis. 60% of an oral dose of QDs was rapidly distributed to the liver within 30 min, and this increased to 85% with FSA biopolymer coating. Uptake into LSECs also increased 3-fold with FSA coating, while uptake into hepatocytes was increased from 40% to 85% with gelatin biopolymer coating. Localization of QDs to LSECs was confirmed with immunofluorescence and transmission electron microscopy. 85% of QDs were cleared within 24 h of administration. The bioavailability of 14C-metformin 2 h post-ingestion was increased 5-fold by conjugation with QD-FSA, while uptake of metformin into LSECs was improved 50-fold by using these QDs. Endocytosis of QDs by SK-Hep1 cells (an LSEC immortal cell line) was via clathrin- and caveolae-mediated pathways with QDs taken up into lysosomes. In conclusion, we have shown high specificity targeting of the LSEC or hepatocytes after oral administration of QDs coated with a biopolymer layer of FSA or gelatin, which improved the bioavailability and delivery of metformin to LSECs.