Iterative Image Processing for Early Diagnostic of Beta-Amyloid Plaque Deposition in Pre-Clinical Alzheimer's Disease Studies.

PURPOSE: To test and evaluate an efficient iterative image processing strategy to improve the quality of sub-optimal pre-clinical PET images. A novel iterative resolution subsets-based method to reduce noise and enhance resolution (RSEMD) has been demonstrated on examples of PET imaging studies of Alzheimer's disease (AD) plaques deposition in mice brains. MATERIALS AND METHODS: The RSEMD method was applied to imaging studies of non-invasive detection of beta-amyloid plaque in transgenic mouse models of AD. Data acquisition utilized a Siemens Inveon® micro PET/CT device. Quantitative uptake of the tracer in control and AD mice brains was determined by counting the extent of plaque deposition by histological staining. The pre-clinical imaging software inviCRO® was used for fitting the recovery PET images to the mouse brain atlas and obtaining the time activity curves (TAC) from different brain areas. RESULTS: In all of the AD studies the post-processed images proved to have higher resolution and lower noise as compared with images reconstructed by conventional OSEM method. In general, the values of SNR reached a plateau at around 10 iterations with an improvement factor of about 2 over sub-optimal PET brain images. CONCLUSIONS: A rapidly converging, iterative deconvolution image processing algorithm with a resolution subsets-based approach RSEMD has been used for quantitative studies of changes in Alzheimer's pathology over time. The RSEMD method can be applied to sub-optimal clinical PET brain images to improve image quality to diagnostically acceptable levels and will be crucial in order to facilitate diagnosis of AD progression at the earliest stages.

Inorganic phosphate-triggered release of anti-cancer arsenic trioxide from a self-delivery system: an in vitro and in vivo study.

On-demand drug delivery is becoming feasible via the design of either exogenous or endogenous stimulus-responsive drug delivery systems. Herein we report the development of gadolinium arsenite nanoparticles as a self-delivery platform to store, deliver and release arsenic trioxide (ATO, Trisenox), a clinical anti-cancer drug. Specifically, unloading of the small molecule drug is triggered by an endogenous stimulus: inorganic phosphate (Pi) in the blood, fluid, and soft or hard tissue. Kinetics in vitro demonstrated that ATO is released with high ON/OFF specificity and no leakage was observed in the silent state. The nanoparticles induced tumor cell apoptosis, and reduced cancer cell migration and invasion. Plasma pharmacokinetics verified extended retention time, but no obvious disturbance of phosphate balance. Therapeutic efficacy on a liver cancer xenograft mouse model was dramatically potentiated with reduced toxicity compared to the free drug. These results suggest a new drug delivery strategy which might be applied for ATO therapy on solid tumors.

Controlled release of therapeutics using interpenetrating polymeric networks.

INTRODUCTION: The ever-increasing developments in pharmaceutical formulations have led to the widespread use of biodegradable polymers in various forms and configurations. In particular, interpenetrating network (IPN) and semi-IPN polymer structures that are capable of releasing drugs in a controlled manner have gained much wider importance in recent years. AREAS COVERED: Recently, IPNs and semi-IPNs have emerged as innovative materials of choice in controlled release (CR) of drugs as the release from these systems depends on pH of the media and temperature in addition to the nature of the system. These networks can be prepared as smart hydrogels following chemical or physical crosslinking methods to show remarkable drug release patterns compared to single polymer systems. EXPERT OPINION: A large number of IPNs and semi-IPNs have been reported in the literature. The present review is focused on the preparation methods and their CR properties with reference to anticancer, anti-asthmatic, antibiotic, anti-inflammatory, anti-tuberculosis and antihypertensive drugs, as majority of these drugs have been reported to be the ideal choices for using IPNs and semi-IPNs.

Use of Fc-Engineered Antibodies as Clearing Agents to Increase Contrast During PET.

UNLABELLED: Despite promise for the use of antibodies as molecular imaging agents in PET, their long in vivo half-lives result in poor contrast and radiation damage to normal tissue. This study describes an approach to overcome these limitations. METHODS: Mice bearing human epidermal growth factor receptor type 2 (HER2)-overexpressing tumors were injected with radiolabeled ((124)I, (125)I) HER2-specific antibody (pertuzumab). Pertuzumab injection was followed 8 h later by the delivery of an engineered, antibody-based inhibitor of the receptor, FcRn. Biodistribution analyses and PET were performed at 24 and 48 h after pertuzumab injection. RESULTS: The delivery of the engineered, antibody-based FcRn inhibitor (or Abdeg, for antibody that enhances IgG degradation) results in improved tumor-to-blood ratios, reduced systemic exposure to radiolabel, and increased contrast during PET. CONCLUSION: Abdegs have considerable potential as agents to stringently regulate antibody dynamics in vivo, resulting in increased contrast during molecular imaging with PET.

Nanoparticulate radiolabelled quinolines detect amyloid plaques in mouse models of Alzheimer's disease.

Detecting aggregated amyloid peptides (Abeta plaques) presents targets for developing biomarkers of Alzheimer's disease (AD). Polymeric n-butyl-2-cyanoacrylate (PBCA) nanoparticles (NPs) were encapsulated with radiolabelled amyloid affinity (125)I-clioquinol (CQ, 5-chloro-7-iodo-8-hydroxyquinoline) as in vivo probes. (125)I-CQ-PBCA NPs crossed the BBB (2.3 +/- 0.9 ID/g) (P < .05) in the WT mouse (N = 210), compared to (125)I-CQ (1.0 +/- 0.4 ID/g). (125)I-CQ-PBCA NP brain uptake increased in AD transgenic mice (APP/PS1) versus WT (N = 38; 2.54 x 10(5) +/- 5.31 x 10(4) DLU/mm(2); versus 1.98 x 10(5) +/- 2.22 x 10(4) DLU/mm(2)) and in APP/PS1/Tau. Brain increases were in mice intracranially injected with aggregated Abeta(42) peptide (N = 17; 7.19 x 10(5) +/- 1.25 x 10(5) DLU/mm(2)), versus WT (6.07 x 10(5) +/- 7.47 x 10(4) DLU/mm(2)). Storage phosphor imaging and histopathological staining of the plaques, Fe(2+) and Cu(2+), validated results. (125)I-CQ-PBCA NPs have specificity for Abeta in vitro and in vivo and are promising as in vivo SPECT ((123)I), or PET ((124)I) amyloid imaging agents.

Quinoline-n-butylcyanoacrylate-based nanoparticles for brain targeting for the diagnosis of Alzheimer's disease.

A survey of research activity on nanoparticles (NPs) based on polymeric devices that could cross the blood-brain barrier (BBB) is given along with the presentation of our own data on the development of NPs of n-butyl-2-cyanoacrylate (BCA) for brain delivery to aid the early diagnosis of Alzheimer's disease (AD), a neurodegenerative disorder of the elderly people, the most prevalent form of dementia. Typical data are presented on in vivo detection of amyloid peptides (A beta) (amyloid plaques) that are used as targets for developing the biological markers for the diagnosis of AD. In order to develop efficient in vivo probes, polymeric n-butyl-2-cyanoacrylate (PBCA) NPs have been prepared and encapsulated with the radio-labeled amyloid affinity drug (125)I-clioquinol (CQ, 5-chloro-7-iodo-8-hydroxyquinoline) to improve the transport to brain and amyloid plaque retention of (125)I-CQ using the NPs of PBCA. The (125)I-CQ discriminately binds to the AD post-mortem brain tissue homogenates versus control. (125)I-CQ-PBCA NPs labeled the A beta plaques from the AD human post-mortem frontal cortical sections on paraffin-fixed slides. Storage phosphor imaging verified preferential uptake by AD brain sections compared to cortical control sections. The (125)I-CQ-PBCA NPs crossed the BBB in wild type mouse, giving an increased brain uptake measured in terms of % ID/g i.e., injected dose compared to (125)I-CQ. Brain retention of (125)I-CQ-PBCA NPs was significantly increased in the AD transgenic mice (APP/PS1) and in mice injected with aggregated A beta 42 peptide versus age-matched wild type controls. The results of this study are verified by in vivo storage phosphor imaging and validated by histopathological staining of plaques and select metal ions, viz. Fe(2+) and Cu(2+). The (125)I-CQ-PBCA NPs had more efficient brain entry and rapid clearance in normal mice and enhanced the retention in AD mouse brain demonstrating the ideal in vivo imaging characteristics. The (125)I-CQ-PBCA NPs exhibited specificity for A beta plaques both in vitro and in vivo. This combination offered radio-iodinated CQ-PBCA NPs as the promising delivery vehicle for in vivo single photon emission tomography (SPECT) ((123)I) or PET ((124)I) amyloid imaging agent. The importance of the topic in relation to brain delivery and other similar type of work published in this area are covered to highlight the importance of this research to medical disciplines.

Gold nanotags for combined multi-colored Raman spectroscopy and x-ray computed tomography.

Multi-color gold-nanoparticle-based tags (nanotags) are synthesized for combined surface-enhanced Raman spectroscopy (SERS) and x-ray computed tomography (CT). The nanotags are synthesized with quasi-spherical gold nanoparticles encoded with a reporter dye (color), each with a unique Raman spectrum. A library of nanotags with six different colors were synthesized for a range of gold nanoparticle sizes and an optimum size has been established to yield the largest SERS intensity and x-ray attenuation that is higher than the iodinated CT contrast agents used in clinics. Proof-of-principle in vivo imaging results with nanotags are presented that, for the first time, demonstrates the combined in vivo dual modality imaging capability of SERS and CT with a single nanoparticle probe.

Vascular imaging of solid tumors in rats with a radioactive arsenic-labeled antibody that binds exposed phosphatidylserine.

PURPOSE: We recently reported that anionic phospholipids, principally phosphatidylserine, become exposed on the external surface of vascular endothelial cells in tumors, probably in response to oxidative stresses present in the tumor microenvironment. In the present study, we tested the hypothesis that a chimeric monoclonal antibody that binds phosphatidylserine could be labeled with radioactive arsenic isotopes and used for molecular imaging of solid tumors in rats. EXPERIMENTAL DESIGN: Bavituximab was labeled with (74)As (beta(+), T(1/2) 17.8 days) or (77)As (beta(-), T(1/2) 1.6 days) using a novel procedure. The radionuclides of arsenic were selected because their long half-lives are consistent with the long biological half lives of antibodies in vivo and because their chemistry permits stable attachment to antibodies. The radiolabeled antibodies were tested for the ability to image subcutaneous Dunning prostate R3227-AT1 tumors in rats. RESULTS: Clear images of the tumors were obtained using planar gamma-scintigraphy and positron emission tomography. Biodistribution studies confirmed the specific localization of bavituximab to the tumors. The tumor-to-liver ratio 72 h after injection was 22 for bavituximab compared with 1.5 for an isotype-matched control chimeric antibody of irrelevant specificity. Immunohistochemical studies showed that the bavituximab was labeling the tumor vascular endothelium. CONCLUSIONS: These results show that radioarsenic-labeled bavituximab has potential as a new tool for imaging the vasculature of solid tumors.

4-Bromo-8-methoxy-quinoline.

The non-H atoms of the title mol-ecule, C(10)H(8)BrNO, are essentially coplanar. In the crystal structure, mol-ecules are linked by weak inter-molecular C-H⋯π(arene) inter-actions, forming one-dimensional chains along the a axis.

Dermatan carriers for neovascular transport targeting, deep tumor penetration and improved therapy.

A new approach to functional tumor imaging and deep interstitial penetration of therapeutic agents is to target the upregulated transport activities of neovascular endothelium. Agents are formulated with the anionic glycosaminoglycan, 435-type dermatan sulfate (DS 435, 22.2 kDa), chemically enriched for oligosaccharide sequences that confer high heparin cofactor II binding and correlate with high tumor uptake. A magnetic resonance (MR) imaging agent is prepared as self-assembling, 5-nm nanoparticles of Fe(+3):deferoxamine (Fe:Df) bound by strong ion pairing to DS, which forms the outer molecular surface (Zeta potential -39 mV). On intravenous (i.v.) injection, Fe:Df-DS rapidly (<7 min) and selectively targets and transports at high capacity across the neovascular endothelium of large (2-cm) Dunning prostate R3327 AT1 rat tumors; releases from the abluminal surface, due to reversible binding of its multivalent, low-affinity (K(d) 10(-4) to 10(-5)) oligosaccharide ligands; and progressively penetrates the interstitium from its initial site of high uptake in the well-perfused outer tumor rim, into the poorly perfused central subregion. By gamma camera imaging of (67)Ga:Df-DS, the agent avoids normal site uptake and clears through the kidneys with a t(1/2) of 18 min. A therapeutic formulation of DS-doxorubicin (DS-dox) is prepared by aqueous high-pressure homogenization of the drug and DS 435, which produces 11-nm nanoparticles of doxorubicin cores coated with DS (Zeta potential -39 mV) that are stable to lyophilization. Microscopic analysis of tumor sections 3 h after i.v. injection shows much higher overall tumor fluorescence and deeper matrix penetration for DS-dox than conventional doxorubicin (dox): >75 vs. <25 microm between the nearest microvessels. DS-dox also results in enhanced tumor-cell internalization and nuclear localization of the drug. Therapeutic efficacies in established (250 +/- 15 mg) MX-1 human breast tumor xenografts at maximum tolerated doses (MTDs) are (control vehicle, dox, dox-DS) (a) median days to 7-fold tumor growth: 8.3, 25.6 (p = 0.0007), 43.2 (p = 0.0001); (b) complete 90-day tumor regressions: 0/10, 0/10, 4/10. These results demonstrate the potential to develop a novel class of carbohydrate-targeted neovascular transport agents for sensitive, high-resolution (100-microm) MR imaging and improved treatment of larger sized human tumor metastases.

Targeted nanoparticles for drug delivery through the blood-brain barrier for Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia among the elderly, affecting 5% of Americans over age 65, and 20% over age 80. An excess of senile plaques (beta-amyloid protein) and neurofibrillary tangles (tau protein), ventricular enlargement, and cortical atrophy characterizes it. Unfortunately, targeted drug delivery to the central nervous system (CNS), for the therapeutic advancement of neurodegenerative disorders such as Alzheimer's, is complicated by restrictive mechanisms imposed at the blood-brain barrier (BBB). Opsonization by plasma proteins in the systemic circulation is an additional impediment to cerebral drug delivery. This review gives an account of the BBB and discusses the literature on biodegradable polymeric nanoparticles (NPs) with appropriate surface modifications that can deliver drugs of interest beyond the BBB for diagnostic and therapeutic applications in neurological disorders, such as AD. The physicochemical properties of the NPs at different surfactant concentrations, stabilizers, and amyloid-affinity agents could influence the transport mechanism.

Dynamics of QT dispersion in acute myocardial infarction.

BACKGROUND: We studied the dynamics of QT dispersion in patients with acute myocardial infarction, and compared them with those in controls. METHODS AND RESULTS: Serial electrocardiograms of patients admitted to our institute with acute myocardial infarction were analyzed for QT dispersion, and compared with those of healthy age- and sex-matched controls. QT dispersion from 12 leads was measured as maximum QT minus minimum QT interval in ms. The mean QT dispersion of 114 +/- 29.6 ms was significantly higher in patients with acute myocardial infarction on admission as compared to 51.45 +/- 5.56 ms in controls (p < 0.001). QT dispersion showed a dynamic change in patients with acute myocardial infarction who were thrombolyzed, being 109.11 +/- 5.77 ms, 87.59 +/- 5.88 ms, 75.89 +/- 18.33 ms, and 68.20 +/- 12.66 ms on admission, post-thrombolysis, and on days 3 and 7, respectively. During a similar time period, nonthrombolyzed patients showed a QT dispersion of 132.38 +/- 36.04 ms, 130.47 +/- 34.42 ms, 111.11 +/- 24.94 ms, and 106.25 +/- 27.64 ms, respectively: the difference between the 2 groups at all periods was significant (p < 0.01). Mean QT dispersion values in patients who developed ventricular tachycardia or ventricular fibrillation were significantly higher than in patients who did not develop ventricular tachycardia or ventricular fibrillation (p < 0.01). CONCLUSIONS: Mean QT dispersion is significantly increased after acute myocardial infarction, and shows a dynamic decrease with time, the difference being more marked in thrombolyzed patients. Mean QT dispersion levels are higher in patients with ventricular tachycardia and ventricular fibrillation compared to patients with acute myocardial infarction without these arrhythmias. The changes in QT dispersion are dynamic, and it may serve as a non-invasive marker of susceptibility to malignant ventricular arrhythmias.