Introduction: Sites associated with gadolinium (Gd) deposition in the brain (e.g., the globus pallidus) are known to contain high concentrations of ferric iron. There is considerable debate over the mechanism of Gd deposition in the brain. The role of iron transport mechanisms in Gd deposition has not been determined. Thus, we seek to identify if Gd deposition can be controlled by modifying iron exposure.Methods: Female Sprague-Dawley rats were given diets with controlled iron levels at 2–6 ppm, 6 ppt (20 g/kg Fe carbonyl) or 48 ppm for 3 weeks to induce iron deficiency, overload or normalcy. They were kept on those diets while receiving a cumulative 10 mmol/kg dose of gadodiamide intravenously over 2 weeks, then left to washout gadodiamide for 3 days or 3 weeks before tissues were harvested. Gd concentrations in tissues were analyzed by ICP-MS.Results: There were no significant effect of dietary iron and total Gd concentrations in the organs, but there was a significant effect of iron status on Gd distribution in the brain. For the 3-week washout cohort, there was a non-significant trend of increasing total brain deposition and decreasing dietary iron, and about 4-fold more Gd in the olfactory bulbs of the low iron group compared to the other groups. Significant brain accumulation was observed in the low iron group total brain Gd in the 3-week washout group relative to the 3-day washout group and no accumulation was observed in other tissues. There was a strong negative correlation between femur Gd concentrations and concentrations in other organs when stratifying by dietary iron.Discussion: Gd brain deposition from linear Gd-based contrast agents (GBCAs) are dependent upon iron status, likely through variable transferrin saturation. This iron dependence appears to be associated with redistribution of peripheral deposited Gd (e.g., in the bone) into the brain.

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. However, site specific delivery avoiding off target effect remain critical and challenging. We have developed radioactive 166Holmium loaded mesoporous silica nanoparticles (166Ho-MSNs) that exhibited predominant accumulation to peritoneal metastases of ovarian cancer upon intraperitoneal administration. It was observed that fluorescence labeled radioactive 166Ho-MSNs distributed throughout the tumor tissues, while non-radioactive fluorescent 165Ho-MSNs showed mainly tumor surface deposition of MSNs. The deep penetration leads to uniform therapeutic radiation distribution and absorbed doses within tumors as demonstrated by the dosimetry analysis. The radiation dosing regimen consisting of two 100 µCi 166Ho-MSN doses separated by 7 days decreased tumor activity and increased the overall lifespan and ascites free survival in several models of IP tumor-bearing mice. These findings illustrate that 166Ho-MSN is promising for the treatment of ovarian peritoneal metastasis, with selective targeting advantage of the nanoparticles and limited off-target radiation exposure.

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. Real-time drug distribution was unveiled by the CT contrast agent, iohexol, where it shows a core-shell structure of the deposition. The incorporation of leuprolide acetate (LA) led to a reduced extent of burst release, prolongated release profile, and extended implant size expansion. LA was found to interact with the solvent and slowed down the polymer phase inversion, thus significantly changed the drug distribution in the implant and reduced the drug release. The implant inner structure identified through SEM, implant size change, and polymer degradation along with the CT real time imaging all consistently support the implant formation differences and their implant on the drug release. Similar patterns of implant size expansion and iohexol distribution in the implants were observed both in vitro and in vivo for the implants with and without LA. The comprehensive understanding of the impact of implant formation on drug release through real time CT imaging facilitates the ISFI product development and evaluation.

C2E5, the penta-ethyl ester prodrug of radionuclide decorporation agent diethylenetriamine pentaacetic acid (DTPA), was designed to address the logistical challenges of IV administration of DTPA in a mass casualty setting. The in vivo conversion of orally-dosed C2E5 to DTPA was evaluated in rat and dog plasma samples using LC-MS/MS methods developed with reference materials and stable-label internal standards for both analytes. C2E5 instability in plasma ex vivo was identified and addressed, but when C2E5 dosed samples revealed minimal C2E5 and DTPA, it became crucial to identify metabolites produced by degradation of C2E5 in vivo that could account for therapeutic efficacy reported. Development of an LC-MS/MS method that identified and estimated levels of eight de-esterified metabolites of C2E5 was initiated without availability of corresponding reference material by relying on predictions of their analyte-specific LC-MS/MS properties. Four de-esterified analogs of C2E5, suspected as active metabolites, were identified in rat or dog plasma. When complementary isomers, not in samples but in reference materials (including impurities identified), became available, they were used to estimate levels of the metabolites identified in dosed samples. Results affording measurement of C2E5 and metabolites in rat and dog plasma provided fit-for-purpose information that supported a timely advancement of the DTPA prodrug program.

The coronavirus disease 2019 pandemic has escalated the ongoing problem of critical medication shortages, which has serious implications for the health of our patients. Currently, active pharmaceutical ingredients (APIs) are synthesized in large-scale batch operations and shipped to drug product manufacturers, where they are produced on a large scale at centralized facilities. In the centralized drug manufacturing process, the formulation components, operations, and packaging are structured to favor long-term storage and shipment of resultant medicines to the point of care, making this process vulnerable to supply chain disruptions. We propose a rethinking of the drug manufacturing paradigm with an upgraded pharmaceutical compounding-based manufacturing paradigm. This paradigm will be based on integration of continuous manufacturing of APIs and manufacturing of medicines at the point of care with application of machine learning, artificial intelligence, and 3-dimensional printing. This paradigm will support implementation of precision medicine and customization according to patients' needs. The new model of drug manufacturing will be less dependent on the supply chain while ensuring availability of medicines in a cost-effective manner.

The current investigation was carried out to identify appropriate parameters for measuring the in vitro release of tobramycin (TOB) ophthalmic ointments and to evaluate the feasibility of in vitro release testing methods to assess the product performance. Drug release was assessed using USP dissolution apparatus IV and a modified USP dissolution apparatus I with simulated tear solution (STS) as the dissolution medium. The study variables included temperature, membrane material, source and pore size. The results demonstrated a significant influence of the membrane source and pore size on the release of TOB from the ointments. A dissolution medium temperature of 40 °C was found to be appropriate for the release studies. Both of the apparatuses were able to discriminate between the release profiles of ointments with different physicochemical/rheological properties. Maximum release rate of TOB was observed in the first hour which followed a logarithmic time dependent release. The correlation between the release rates/amounts and yield stress of the ointments was observed in both the dissolution apparatuses. These results support a rational approach to guide the in vitro release testing of TOB ophthalmic ointments.

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. We also investigated the components of the peritoneal tumor stroma that facilitated nanoparticle-tumor interaction. The tumor extracellular matrix is the main factor driving these interactions, specifically the interaction of nanoparticles with collagen. Upon disruption of the collagen matrix, nanoparticle accumulation was reduced by 50%. It is also notable that the incorporation of targeting ligands did not increase overall tumor accumulation in vivo while it significantly increased nanoparticle accumulation in vitro. The use of other particle chemistries did not grossly affect the tumor targetability, but additional concerns arose when those tested particles exhibited significant systemic exposure. Mesoporous silica nanoparticles are advantageous for intraperitoneal administration for the treatment of peritoneal metastasis due to their physical stability, tumor targetability, strong interaction with the collagen matrix, and extended peritoneal residence time. Maximizing nanoparticle interaction with the tumor extracellular matrix is critical for developing strategies to deliver emerging therapeutics for peritoneal cancer treatment using nanocarriers.

Nonspecific high-energy radiation for treatment of metastatic ovarian cancer is limited by damage to healthy organs, which can be mitigated by the use of radiosensitizers and image-guided radiotherapy. Gold (Au) and tantalum oxide (TaOx) nanoparticles (NPs), by virtue of their high atomic numbers, find utility in the design of bimetallic NP systems capable of high-contrast computed tomography (CT) imaging as well as a potential radiosensitizing effect. These two radio-dense metals are integrated into dendritic mesoporous silica NPs (dMSNs) with radial porous channels for high surface-area loading of therapeutic agents. This approach results in stable, monodispersed dMSNs with a uniform distribution of Au on the surface and TaOx in the core that exhibits CT attenuation up to seven times greater than iodine or monometallic dMSNs without either TaOx or Au. Tumor targeting is assessed in a metastatic ovarian cancer mouse model. Ex vivo micro-CT imaging of collected tumors shows that these NPs not only accumulate at tumor sites but also penetrate inside tumor tissues. This study demonstrates that after intraperitoneal administration, rationally designed bimetallic NPs can simultaneously serve as targeted contrast agents for imaging tumors and to enhance radiation therapy in metastatic ovarian cancer.

In article number 1900058, Kashfi and co-workers develop a radio-dense nanosystem composed of a tantalum oxide core and a gold decorated dendritic mesoporous silica shell. These nanoparticles specifically target peritoneal metastases, exhibit strong contrast on CT images, and can potentially serve as radiosensitizers for radiotherapy.

Objective: To determine if gadolinium (Gd) can be rechelated once released from Gd-based contrast agents (GBCAs) and deposited in vivo. Despite extensive research comparing GBCAs and GBCA formulations as well as the ongoing debate about their risks of deposition and the role of Gd release, it remains unknown if retained Gd can be eliminated by administering chelating agents. Materials and methods: Rats were injected intravenously with 10 doses of 1 mmol/kg gadodiamide and treated with intravenous Zn-DTPA (30 mu mol/kg) concomitantly or 1, 4 or 8 h after GBCA administration (N = 3 rats per group). After euthanization, tissues were harvested three days after the last dose of gadodiamide and tissue Gd concentrations were assessed by ICP-MS. Additionally, a simulation of a single 0.1 mmol/kg gadopentetate dose with 30 mu mol/kg DTPA given either concomitantly or within the first 24 h after GBCA was run; simulated tissue Gd concentrations were compared with those observed in rats to determine if simulated trends were accurate. Results: Concomitant DTPA did not produce a significant reduction in Gd concentration in any organ for rats. There was a time-dependent trend in liver Gd reduction. The 1 h timepoint was associated with a non-significant increase in kidney, brain and femur Gd relative to untreated controls. There were no significant deviations from the model-predicted Gd changes. Discussion: Both the simulation and rat study did not identify major benefits for chelation at the doses given, despite the simulation assuming all Gd deposited in tissues is unchelated. The potential redistribution in the rat study provide a compelling result that may impact the clinical relevance of further work investigating rechelation of Gd. Future work should further describe the three-dimensional dose-time-response relationship for preventing Gd deposition, and how that relates to long-term Gd toxicities.

PURPOSE:The main purpose of this study was to evaluate qualitative (Q1) and quantitative (Q2) equivalent oleaginous ophthalmic ointments of tobramycin (TOB) with different physicochemical properties and identify critical process/quality attributes using various in vitro methods of characterization.METHODS:Various sources of petrolatum and TOB, and two mixing methods were employed to generate Q1/Q2 equivalent ointments. Characterization studies included content uniformity, microscopy, modulated temperature differential scanning calorimetry (MTDSC), gas chromatography-mass spectrometry (GC/MS), thermogravimetric analysis (TGA) and rheology.RESULTS:The particle size distribution of TOB influenced the content uniformity of ointments. Differences in the MTDSC endothermic and exothermic peaks of TOB suggested the presence of different polymorphic forms. GC/MS revealed variations in the composition and distribution of linear and branched hydrocarbons of petrolatums. Differences were also observed in the TGA derivative weight loss peaks demonstrating differences in the composition of petrolatum that may be the source of the observed variations in the rheological parameters of the ointments.CONCLUSIONS:Source and composition of the petrolatum played a more critical role in determining the rheological properties compared to the method of preparation. Results demonstrated the impact of the source of TOB, excipients and manufacturing processes on the quality attributes of TOB ophthalmic ointments.

The present work investigated the physical and thermal characteristics of three polymorphic forms (namely, PF1, PF2, and PF3) of a diethyl ester analog of diethylenetriaminepentaacetic acid (C2E2) produced under varying conditions. The identity of each form of C2E2 was confirmed by 1 H-NMR, 13 C-NMR, and mass spectroscopy. The different polymorphic forms exhibited solubilities ranging from 40 to 150 mg/mL. Powder X-ray diffraction (PXRD) and electron microscopy confirmed that all three forms were crystalline, two of which being scaly, and the third being well-formed. Infrared and Raman spectroscopy revealed differences in the C = O bonding region while differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA) showed widely different melting points with only one thermal event for each compound. The comparison of the melting points and heats of fusion show that the PF1 is monotropically related to both PF2 and PF3, while PF2 and PF3 are enantropically related. Our finding indicates that PF3 is the thermodynamically stable polymorph and will be used for in vitro and in vivo experiments.

OBJECTIVES:The aim of this study was to report the use of intravenous calcium (Ca)-/zinc (Zn)-diethylene triamine penta-acetic acid (DTPA) for the treatment of 25 symptomatic patients diagnosed with gadolinium deposition disease (GDD).MATERIALS AND METHODS:Written informed consent was obtained. Twenty-five patients (18 women; mean age, 46.8 ± 15.3 years) with a diagnosis of GDD were included. All patients had received at least 1 administration of a gadolinium (Gd)-based contrast agent. Patients received 3 treatment sessions with Ca-/Zn-DTPA, 15 with treatments spaced 1 month apart, and 10 with treatments spaced 1 week apart. In all cases, every treatment consisted of an application of Ca-DTPA and Zn-DTPA separated by 24 hours. Measurements of 24-hour urine Gd content before dosing and on the first and second days of therapy were performed. Symptomatic improvement of patients was determined by use of a 10-point scale of patient symptoms. Serum electrolytes were quantified.RESULTS:Gadolinium content increased in the urine, with an overall mean of 30.3-fold increase in the monthly regimen (P < 0.001) and 12.9-fold in the weekly regimen (P < 0.001). Eleven patients experienced transient worsening of at least some of their symptoms, termed a "flare-up" phenomenon, in most of whom symptoms improved or receded. Overall, symptoms improved in 13 patients, unchanged in 10, and worse in 2. Significant clinical improvement was present for headache, brain fog, and bone pain for the monthly regimen and arm pain and leg pain for the weekly regimen. There were no significant changes in major serum electrolytes.CONCLUSIONS:Three courses of intravenous Ca-/Zn-DTPA therapy results in significantly increased urine content of Gd after treatment and moderate symptomatic improvement.

The role of gadolinium (Gd)-based contrast agents (GBCAs) in the pathophysiology of nephrogenic systemic fibrosis (NSF) is now uncontested. Although the definitive mechanism has not been established, the association with weaker GBCA ligands and with reduced renal clearance supports a hypothesis that Gd release from the GBCAs is a key process in precipitating the disease. Prevention strategies often include the use of more stable GBCA ligands in patients with reduced kidney function, but animal models and some clinical data suggest that better patient outcomes can be achieved when excess ligand is administered with weaker GBCAs; this is particularly significant for OptiMARK, which contains a nonionic, linear ligand similar to gadodiamide, the active ingredient in Omniscan, but contains twice the amount of excess ligand. Here we review evidence regarding the use of OptiMARK over Omniscan for prevention of NSF and perform a pharmacokinetic-based simulation to determine if the presented evidence is consistent with the established kinetics of GBCAs and Gd.

Purpose: To reanalyze literature data of gadolinium (Gd)-based contrast agents (GBCAs) in plasma with a kinetic model of dissociation to provide a comprehensive assessment of equilibrium conditions for linear GBCAs.Methods: Data for the release of Gd from GBCAs in human serum was extracted from a previous report in the literature and fit to a kinetic dissociation/association model. The conditional stabilities (logK(cond)) and percent intact over time were calculated using the model rate constants. The correlations between clinical outcomes and logK(cond) or other stability indices were determined.Results: The release curves for Omniscan, gadodiamide, OptiMARK, gadoversetamide Magnevist and Multihance (R) were extracted and all fit well to the kinetic model. The logK(cond)s calculated from the rate constants were on the order of similar to 4-6, and were not significantly altered by excess ligand or phosphate. The stability constant based on the amount intact by the initial elimination half-life of GBCAs in plasma provided good correlation with outcomes observed in patients.Conclusions: Estimation of the kinetic constants for GBCA dissociation/association revealed that their stability in physiological fluid is much lower than previous approaches would suggest, which correlates well with deposition and pharmacokinetic observations of GBCAs in human patients. (C) 2017 Elsevier Inc. All rights reserved.

Radionuclide therapy with nano-sized carriers is a very promising approach to treat various types of cancer. The preparation of radioactive nanocarriers can be achieved with minimum handling using a neutron-activation approach. However, the nanocarrier material must possess certain characteristics such as low density, heat-resistance, high metal adsorption, easy surface modification and low toxicity in order to be useful. Mesoporous Carbon Nanoparticles (MCNs) in which holmium oxide is formed in their pores by a wet-impregnation process are investigated as a suitable material for this application. Holmium (165Ho) has a natural abundance of 100% and possesses a large cross-section for capturing thermal neutrons. After irradiation of Ho-containing MCNs in a neutron flux, 166Ho, which emits therapeutic high energy beta particles as well as diagnostic low energy gamma photons that can be imaged externally, is produced. The wet impregnation process (16 w/w% Ho loading) is shown to completely prevent the leaching of radioactive holmium from the MCNs without compromising their structural integrity. In vitro studies showed that the MCNs containing non-radioactive holmium do not exhibit toxicity and the same formulation with radioactive holmium (166Ho) demonstrated a tumoricidal effect. Post-irradiation PEGylation of the MCN surfaces endows dispersibility and biocompatibility.

The objective of this study was to develop oral disintegrating tablet (ODT) formulations of a heptapeptide, [Lys(5), MeLeu(9), Nle(10)]-NKA(4-10), for the treatment of neurogenic bladder dysfunction. A design of experiment approach was applied to determine the optimal ratio of chosen excipients: gelatin (X-1), glycine (X-2), and sorbitol (X-3). These formulations were optimized for efficacy studies to produce ODTs exhibiting rapid disintegration times (Y-1) and appropriate structural integrity (Y-2) using JMP((R)) 12.0.1 software. Based on theoretically predicted values from 12 experimental runs, the optimal ODT formulation was determined to be 3% (w/v) gelatin, 2% (w/v) glycine, and 1% (w/v) sorbitol in deionized water. Using this formulation, blank and drug-loaded ODTs containing 1.5 mg or 5 mg of [Lys(5), MeLeu(9), Nle(10)]-NKA(4-10) were manufactured by a lyophilization process. The peptide-loaded tablets disintegrated in less than 30 s and released 97% of the peptide within 15 min. The peptide was stable for 90 days under 25 degrees C/60% relative humidity (RH) and 40 degrees C/75% RH. In vivo efficacy of the peptide-loaded ODTs was confirmed in a rat acute spinal cord injury model under isovolumetric bladder pressure recording conditions, concluding that sublingual administration of peptide-containing ODTs evoke a rapid doserelated neurokinin 2-mediated increase in bladder pressure.