Tumor specific delivery and radiation-enhanced tumor penetration of mesoporous silica nanoparticles for effective radionuclide therapy of ovarian peritoneal metastasis.

Advanced ovarian cancer with peritoneal metastasis is challenging to treat. Limited tumor delivery and penetration of the therapeutics to deep tumor regions are significant barriers to effective treatment. The rising radiopharmaceuticals offer hopes for patients through targeted delivery.

Implant dynamics, inner structure, and their impact on drug release of in situ forming implants uncovered through CT imaging.

In situ forming implants (ISFIs) composed of biodegradable polymers and biocompatible solvents are generally designed for sustained drug release. In this study, a non-invasive computed tomography (CT) imaging approach is used to achieve real time imaging of ISFIs in vivo and in vitro using leuprolide acetate in situ forming implant as a model drug product. The process of implant formation, inner structure change and their impact on drug release were elucidated.

Mitigation strategies for time-resolved x-ray diagnostic data degradation due to high neutron yield of ICF experiments at the NIF.

Inertial confinement fusion experiments taking place at the National Ignition Facility are generating ever increasing amounts of fusion energy, with the deuterium tritium fusion neutron yield growing a hundredfold over the past ten years. Strategies must be developed to mitigate this harsh environment's deleterious effects on the operation and the performance of the time-resolved x-ray imagers deployed in the National Ignition Facility target bay to record the dynamics of the implosions. We review the evolution of these imagers in recent years and detail some of the past and present efforts undertaken to maintain or improve the quality of the experimental data collected on high neutron yield experiments.

Stealth oxime ether lipid vesicles promote delivery of functional DsiRNA in human lung cancer A549 tumor bearing mouse xenografts.

We previously reported that hydroxylated oxime ether lipids (OELs) efficiently deliver functional Dicer substrate siRNAs (DsiRNAs) in cells. Here, we explored in vivo utility of these OELs, using OEL4 as a prototype and report that surface modification of the OEL4 formulations was essential for their in vivo applications. These surface-modified OEL4 formulations were developed by inclusion of various PEGylated lipids.

Bioluminescent imaging in induced mouse models of endometriosis reveals differences in four model variations.

Our understanding of the aetiology and pathophysiology of endometriosis remains limited. Disease modelling in the field is problematic as many versions of induced mouse models of endometriosis exist. We integrated bioluminescent imaging of 'lesions' generated using luciferase-expressing donor mice.

Pharmacological, Pharmacokinetic, Pharmacodynamic and Physicochemical Characterization of FE 205030: A Potent, Fast Acting, Injectable CGRP Receptor Antagonist for the Treatment of Acute Episodic Migraine.

The neuropeptide calcitonin gene-related peptide (CGRP) is known to play a central role in the underlying pathophysiology of migraine. In comparison to the effective triptan class of antimigraine treatments, the CGRP antagonists possess a comparable efficacy but a superior cardiovascular safety profile in patients. This paper describes the development of selective and potent peptidic CGRP antagonist, FE 205030, that has a fast onset of action and an optimal half-life (subcutaneous T ~ 60 min, and t ~ 4.

Tumor-mesoporous silica nanoparticle interactions following intraperitoneal delivery for targeting peritoneal metastasis.

The use of intraperitoneal administration of nanoparticles has been reported to facilitate higher concentrations of nanoparticles in metastatic peritoneal tumors. While this strategy is appealing for limiting systemic exposure of nanocarrier delivered toxic cargoes and increasing nanoparticle concentrations in avascular peritoneal tumors, little is known about the mechanism of nanoparticle accumulation on tumor tissues and currently, no nanoparticle-based product has been approved for intraperitoneal delivery. Here, we investigated the nanoparticle-specific characteristics that led to increased peritoneal tumor accumulation using MCM-41 type mesoporous silica nanoparticles as our model system.

Time-Resolved Fuel Density Profiles of the Stagnation Phase of Indirect-Drive Inertial Confinement Implosions.

The implosion efficiency in inertial confinement fusion depends on the degree of stagnated fuel compression, density uniformity, sphericity, and minimum residual kinetic energy achieved. Compton scattering-mediated 50-200 keV x-ray radiographs of indirect-drive cryogenic implosions at the National Ignition Facility capture the dynamic evolution of the fuel as it goes through peak compression, revealing low-mode 3D nonuniformities and thicker fuel with lower peak density than simulated. By differencing two radiographs taken at different times during the same implosion, we also measure the residual kinetic energy not transferred to the hot spot and quantify its impact on the implosion performance.

Pharmacological Characterization of Apraglutide, a Novel Long-Acting Peptidic Glucagon-Like Peptide-2 Agonist, for the Treatment of Short Bowel Syndrome.

Glucagon-like peptide-2 (GLP-2) agonists have therapeutic potential in clinical indications in which the integrity or absorptive function of the intestinal mucosa is compromised, such as in short bowel syndrome (SBS). Native hGLP-2, a 33-amino acid peptide secreted from the small intestine, contributes to nutritional absorption but has a very short half-life because of enzymatic cleavage and renal clearance and thus is of limited therapeutic value. The GLP-2 analog teduglutide (Revestive/Gattex; Shire Inc.

Discovery of Potent, Selective, and Short-Acting Peptidic V Receptor Agonists.

The vasopressin analogue desmopressin (desamino-d-arginine vasopressin, dDAVP, 1) is a potent vasopressin 2 (V) receptor (VR) agonist approved in many countries for the treatment of diabetes insipidus, primary nocturnal enuresis, nocturia, and coagulation disorders. Since 1 is primarily excreted via the kidneys, an age-related decline in kidney function leads to slower elimination, prolonged antidiuresis, and hyponatremia. In search of novel, potent, selective, and short-acting peptidic VR agonists, we synthesized a series of C-terminally truncated analogues of [Val]dDAVP, 2, modified in positions 2, 3, and 7 and/or at the disulfide bridge.

Investigating the relationship between noise transfer inside the x-ray framing cameras and their imaging ability.

We apply a cascaded linear model analysis to a micro-channel plate x-ray framing camera. We establish a theoretical expression of the Noise Power Spectrum (NPS) at the detector's output and assess its accuracy by comparing it to the NPS of Monte Carlo simulations of the detector's response to a uniform illumination. We also demonstrate that fitting the NPS of experimental data against a parametric model based on this expression can yield valuable information on the imaging ability of framing cameras, offering an alternative approach to the usual method employed to measure their modulation transfer functions.

Selective and non-selective OT receptor agonists induce different locomotor behaviors in male rats via central OT receptors and peripheral V1a receptors.

Oxytocin (OT) continues to inspire much research due to its diverse physiological effects. While the best-understood actions of OT are uterine contraction and milk ejection, OT is also implicated in maternal and bonding behaviors, and potentially in CNS disorders such as autism, schizophrenia, and pain. The dissection of the mechanism of action of OT is complicated by the fact that this peptide activates not only its cognate receptor but also vasopressin type 1a (V1a) receptors.

Additive effect of simultaneous continuous administration of degarelix and TAK-448 on LH suppression in a castrated rat model.

Gonadotropin releasing hormone (GnRH) analogs have long been used in androgen deprivation therapy (ADT) in the treatment of prostate cancer. Chronic administration of either GnRH agonists or antagonists leads to suppression of testosterone production in the testes via either downregulation or direct blockade of the GnRH receptor in the pituitary, respectively. Chronic administration of kisspeptin analogs has more recently been shown to lead to testosterone suppression via desensitization of GnRH neurons in the hypothalamus and an optimized kisspeptin analog, TAK-448, was proven effective in a small phase 1 trial.

Neutron-Activatable Nanoparticles for Intraperitoneal Radiation Therapy.

Intraperitoneal internal radiation therapy is a cancer treatment option that is employed in situations where surgical resection, systemic chemotherapy, and external beam radiotherapy are not amenable for patients. However, exposure of noncancerous tissues to radiation continues to be a hindrance to safe and effective treatment of patients. In addition, reducing prolonged radiation exposure of personnel during preparation of internal radiation therapy agents makes their manufacture complicated and hazardous.

A comparison of "flat fielding" techniques for x-ray framing cameras.

Gain can vary across the active area of an x-ray framing camera by a factor of 4 (or more!) due to the voltage loss and dispersion associated with pulse transmission in a microstripline-coated microchannel plate. In order to make quantitative measurements, it is consequently important to measure the gain variation ("flat field"). Moreover, because of electromagnetic cross talk, gain variation depends on specific operational parameters, and ideally a flat field would be obtained at all operating conditions.

Spatial resolution measurements of the advanced radiographic capability x-ray imaging system at energies relevant to Compton radiography.

Compton radiography provides a means to measure the integrity, ρR and symmetry of the DT fuel in an inertial confinement fusion implosion near peak compression. Upcoming experiments at the National Ignition Facility will use the ARC (Advanced Radiography Capability) laser to drive backlighter sources for Compton radiography experiments and will use the newly commissioned AXIS (ARC X-ray Imaging System) instrument as the detector. AXIS uses a dual-MCP (micro-channel plate) to provide gating and high DQE at the 40-200 keV x-ray range required for Compton radiography, but introduces many effects that contribute to the spatial resolution.

Establishment of reference intervals for osteoarthritis-related soluble biomarkers: the FNIH/OARSI OA Biomarkers Consortium.

Objective: To establish reference intervals for osteoarthritis (OA)-related biomarkers used in the Foundation for the National Institutes of Health (FNIH) OA Biomarkers Consortium Project.

Methods: A total of 129 'multijoint controls' were selected from 2722 African-American and Caucasian men and women in the Johnston County Osteoarthritis Project. The majority (79%) of those eligible (with biospecimens and baseline data) also had one or more follow-up evaluations 5-15 years later.

Predictive validity of biochemical biomarkers in knee osteoarthritis: data from the FNIH OA Biomarkers Consortium.

Objective: To investigate a targeted set of biochemical biomarkers as predictors of clinically relevant osteoarthritis (OA) progression.

Methods: Eighteen biomarkers were measured at baseline, 12 months (M) and 24 M in serum (s) and/or urine (u) of cases (n=194) from the OA initiative cohort with knee OA and radiographic and persistent pain worsening from 24 to 48 M and controls (n=406) not meeting both end point criteria. Primary analyses used multivariable regression models to evaluate the association between biomarkers (baseline and time-integrated concentrations (TICs) over 12 and 24 M, transposed to z values) and case status, adjusted for age, sex, body mass index, race, baseline radiographic joint space width, Kellgren-Lawrence grade, pain and pain medication use.

Protein Microspheres with Unique Green and Red Autofluorescence for Noninvasively Tracking and Modeling Their in Vivo Biodegradation.

Bovine serum albumin (BSA) microspheres were prepared through a facile and low-cost route including a high-speed dispersion of BSA in cross-linking solution followed by spray drying. Interestingly the as-prepared BSA microspheres possess unique blue-green, green, green-yellow, and red fluorescence when excited by specific wavelengths of laser or LED light. The studies of UV-visible reflectance spectra and fluorescence emission spectra indicated that four classes of fluorescent compounds are presumably formed during the fabrication processes.

Improving paclitaxel pharmacokinetics by using tumor-specific mesoporous silica nanoparticles with intraperitoneal delivery.

Mesoporous silica nanoparticles (MSNs) containing paclitaxel for intraperitoneal (i.p.) delivery were developed to exploit the tumor specific accumulation of these nanocarriers after i.

Synthesis and Pharmacological Characterization of Novel Glucagon-like Peptide-2 (GLP-2) Analogues with Low Systemic Clearance.

Glucagon-like peptide-2 receptor agonists have therapeutic potential for the treatment of intestinal diseases. The native hGLP-2, a 33 amino acid gastrointestinal peptide, is not a suitable clinical candidate, due to its very short half-life in humans. In search of GLP-2 receptor agonists with better pharmacokinetic characteristics, a series of GLP-2 analogues containing Gly substitution at position 2, norleucine in position 10, and hydrophobic substitutions in positions 11 and/or 16 was designed and synthesized.

Reduced in vivo toxicity of doxorubicin by encapsulation in cholesterol-containing self-assembled nanoparticles.

We previously reported the development of an amphiphilic brush-like block copolymer composed of polynorbornene-cholesterol/polyethylene glycol (P(NBCh9-b-NBPEG)) that self-assembles in aqueous media to form long circulating nanostructures capable of encapsulating doxorubicin (DOX-NPs). Biodistribution studies showed that this formulation preferentially accumulates in tumor tissue with markedly reduced accumulation in the heart and other major organs. The aim of the current study was to evaluate the in vivo efficacy and toxicity of DOX containing self-assembled polymer nanoparticles in a mouse xenograft tumor model and compare its effects with the hydrochloride non-encapsulated form (free DOX).

Advances in x-ray framing cameras at the National Ignition Facility to improve quantitative precision in x-ray imaging.

We describe an experimental method to measure the gate profile of an x-ray framing camera and to determine several important functional parameters: relative gain (between strips), relative gain droop (within each strip), gate propagation velocity, gate width, and actual inter-strip timing. Several of these parameters cannot be measured accurately by any other technique. This method is then used to document cross talk-induced gain variations and artifacts created by radiation that arrives before the framing camera is actively amplifying x-rays.

A Biocompatible and Biodegradable Protein Hydrogel with Green and Red Autofluorescence: Preparation, Characterization and In Vivo Biodegradation Tracking and Modeling.

Because of its good biocompatibility and biodegradability, albumins such as bovine serum albumin (BSA) and human serum albumin (HSA) have found a wide range of biomedical applications. Herein, we report that glutaraldehyde cross-linked BSA (or HSA) forms a novel fluorescent biological hydrogel, exhibiting new green and red autofluorescence in vitro and in vivo without the use of any additional fluorescent labels. UV-vis spectra studies, in conjunction with the fluorescence spectra studies including emission, excitation and synchronous scans, indicated that three classes of fluorescent compounds are presumably formed during the gelation process.