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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 235 records · Page 13
All sourcesNASA NTRSDOE OSTI
NASA NTRS1998

Intestinal transport of gentamicin with a novel, glycosteroid drug transport agent

PURPOSE: The objective was to investigate the ability of a glycosteroid (TC002) to increase the oral bioavailability of gentamicin. METHODS: Admixtures of gentamicin and TC002 were administered to the rat ileum by injection and to dogs by ileal or jejunal externalized ports, or PO. Bioavailability of gentamicin was determined by HPLC. 3H-TC002 was injected via externalized cannulas into rat ileum or jejunum, or PO and its distribution and elimination was determined. The metabolism of TC002 in rats was evaluated by solid phase extraction and HPLC analysis of plasma, urine and feces following oral or intestinal administration. RESULTS: The bioavailability of gentamicin was substantially increased in the presence of TC002 in both rats and dogs. The level of absorption was dependent on the concentration of TC002 and site of administration. Greatest absorption occurred following ileal orjejunal administration. TC002 was significantly more efficacious than sodium taurocholate, but similar in cytotoxicity. TC002 remained primarily in the GI tract following oral or intestinal administration and cleared rapidly from the body. It was only partly metabolized in the GI tract, but was rapidly and completely converted to its metabolite in plasma and urine. CONCLUSIONS: TC002 shows promise as a new drug transport agent for promoting intestinal absorption of polar molecules such as gentamicin.

Non-NASA Center↗
DOE OSTI2023

Breast tumor-targeted drug delivery via polymer nanocarriers: Endogenous and exogenous strategies

Breast cancer, one of the most common types of cancer worldwide, has a high degree of malignancy while lacking efficient treatments. The off-target events frequently occurring in drug administration have been a major obstacle, which causes severe side effects to patients and reduces the therapeutic efficacy. An ideal medication should precisely target the specific site with precise control over concentration and duration. In recent years, there has been immense progress in polymer nanocarriers that demonstrate great potential in the targeted delivery. These nanocarriers are constructed from materials sensitive to a wide range of endogenous (e.g., pH, enzyme, redox) and exogenous stimuli (e.g., light, ultrasound, magnetic waves), driving cargo release to the targeted tissue or cells. Here, we elucidate the mechanism of current targeting strategies and the engineering methods to construct these targeting systems or to improve their targeting efficiency. Here we capture the recent progress in the targeted nanocarriers derived from polymers which span hydrogels and micelles, demonstrating their design and applications in chemo, hyperthermia, immuno, and gene therapies.

36 MATERIALS SCIENCE↗
DOE OSTI2020

A Ligand-Directed Nitrophenol Carbonate for Transient in situ Bioconjugation and Drug Delivery

Here we report the first use of ligand-directed proximity accelerated bioconjugation chemistry in the tandem delivery and release of a therapeutic payload. To do this, we designed a nitrophenol carbonate for ligand-directed in situ bioconjugation of a prodrug payload to a protein. The transient nature of our conjugation chemistry renders the protein a depot for timedependent release of active drug following hydrolysis and selfimmolation. In our model system, using an immunostimulant prodrug, biotin ligand, and avidin protein, we observe release of bioavailable immunostimulant both spectroscopically and with an immune cell line over 48 h. Avidin co-crystalized with the nitrophenolate directing group verified the binding pose of the ligand and offered insight into the mechanism of in situ bioconjugation. Overall, this scaffold warrants further investigation for the time-dependent delivery of therapeutics and use in protein ligand pairs beyond biotin and avidin used for this work.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2020

Mechanistic Models as Framework for Understanding Biomarker Disposition: Prediction of Creatinine‐Drug Interactions

Creatinine is widely used as a biomarker of glomerular filtration, and, hence, renal function. However, transporter‐mediated secretion also contributes to its renal clearance, albeit to a lesser degree. Inhibition of these transporters causes transient serum creatinine elevation, which can be mistaken as impaired renal function. The current study developed mechanistic models of creatinine kinetics within physiologically based framework accounting for multiple transporters involved in creatinine renal elimination, assuming either unidirectional or bidirectional‐OCT2 transport (driven by electrochemical gradient). Robustness of creatinine models was assessed by predicting creatinine‐drug interactions with 10 perpetrators; performance evaluation accounted for 5% intra‐individual variability in serum creatinine. Models showed comparable predictive performances of the maximum steady‐state effect regardless of OCT2 directionality assumptions. However, only the bidirectional‐OCT2 model successfully predicted the minimal effect of ranitidine. The dynamic nature of models provides clear advantage to static approaches and most advanced framework for evaluating interplay between multiple processes in creatinine renal disposition.

Scotcher, Daniel↗
DOE OSTI2024

Identification of Potent and Selective Inhibitors of Acanthamoeba : Structural Insights into Sterol 14α-Demethylase as a Key Drug Target

Acanthamoeba are free-living pathogenic protozoa that cause blinding keratitis, disseminated infection, and granulomatous amebic encephalitis, which is generally fatal. The development of efficient and safe drugs is a critical unmet need. Acanthamoeba sterol 14α-demethylase (CYP51) is an essential enzyme of the sterol biosynthetic pathway. Repurposing antifungal azoles for amoebic infections has been reported, but their inhibitory effects on Acanthamoeba CYP51 enzymatic activity have not been studied. Here, we report catalytic properties, inhibition, and structural characterization of CYP51 from Acanthamoeba castellanii. The enzyme displays a 100-fold substrate preference for obtusifoliol over lanosterol, supporting the plant-like cycloartenol-based pathway in the pathogen. The strongest inhibition was observed with voriconazole (1 h IC 50 0.45 μM), VT1598 (0.25 μM), and VT1161 (0.20 μM). The crystal structures of A. castellanii CYP51 with bound VT1161 (2.24 Å) and without an inhibitor (1.95 Å), presented here, can be used in the development of azole-based scaffolds to achieve optimal amoebicidal effectiveness.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2026

Chemoproteomic Elucidation of β-Lactam Drug Targets in Mycobacterium abscessus

The pathogen Mycobacterium abscessus (Mab) can cause severe and difficult-to-treat chronic lung infections. Despite the rising incidence and clinical concern of Mab infections, treatment options are limited and often ineffective. Treatment is complicated by Mab’s ability to persist in a nonreplicating, drug-resistant state. Several β-lactam antibiotics are potently bactericidal against Mab but are underutilized because their molecular mechanisms of action against Mab are incompletely understood. In the current study, we used β-lactam-derived activity-based probes and chemoproteomics to report the first comprehensive list of Mab enzymes targeted by β-lactams. We compared β-lactam targets across two Mab subspecies in actively replicating and nonreplicating cultures, using a new carbon starvation model of persistence. We identified 17 targets that were active in every condition tested, seven of which were previously unknown to bind β-lactams. Lastly, we characterized the β-lactamase activity and β-lactam inhibition profiles of nine Mab enzymes, demonstrating that imipenem inhibits these targets more effectively than cefoxitin. These findings demonstrate β-lactam target engagement in persistent Mab and provide clarity on the mechanisms of action of clinically relevant β-lactams in Mab, crucial steps toward fully realizing their potential for treating infections caused by this opportunistic pathogen.

Mycobacterium abscessus↗
DOE OSTI2022

Structural basis for inhibition of the Cation-chloride cotransporter $\mathrm{NKCC1}$ by the diuretic drug bumetanide

Cation-chloride cotransporters (CCCs) NKCC1 and NKCC2 catalyze electroneutral symport of 1 Na + , 1K + , and 2 Cl - across cell membranes. NKCC1 mediates trans-epithelial Cl - secretion and regulates excitability of some neurons and NKCC2 is critical to renal salt reabsorption. Both transporters are inhibited by the so-called loop diuretics including bumetanide, and these drugs are a mainstay for treating edema and hypertension. Here, our single-particle electron cryo-microscopy structures supported by functional studies reveal an outward-facing conformation of NKCC1, showing bumetanide wedged into a pocket in the extracellular ion translocation pathway. Based on these and the previously published inward-facing structures, we define the translocation pathway and the conformational changes necessary for ion translocation. We also identify an NKCC1 dimer with separated transmembrane domains and extensive transmembrane and C-terminal domain interactions. We further define an N-terminal phosphoregulatory domain that interacts with the C-terminal domain, suggesting a mechanism whereby (de)phosphorylation regulates NKCC1 by tuning the strength of this domain association.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2025

Green genes from blue greens: challenges and solutions to unlocking the potential of cyanobacteria in drug discovery

Cyanobacteria are prolific producers of biologically active compounds that are important in influencing ecology, behavior of interacting organisms, and as leads in drug discovery efforts. Here we discuss the challenges faced by all natural product researchers, especially those that focus on cyanobacteria, and then describe progress that has been made in these areas. We also propose some solutions, paths forward, and thoughts for consideration on these challenges.

Philmus, Benjamin↗
DOE OSTI2020

Leveraging Framework Instability: A Journey from Energy Storage to Drug Delivery

Amorphous pharmaceuticals often suffer from poor physical stability, which can negate their high solubility, fast dissolution rate, and better oral bioavailability vs. crystalline forms. This represents a major hurdle to processing, storage, and delivery of amorphous pharmaceuticals. Several approaches to addressing these problems have been pursued, but there is still a need for a general method for stabilizing the amorphous form. We describe a novel approach using a water-unstable metal-organic framework as a drug delivery vehicle that demonstrates improved amorphous form stability accompanied by remarkably enhanced solubility and a fast dissolution rate. This research project spanned eleven years from conception to realization and dissemination. With origins in understanding the stability or porous solids for energy storage materials, the work also highlights potential of basic science understanding to illuminate new areas of application.

Chemistry↗
DOE OSTI2020

Magnetic properties of γ-Fe 2 O 3 nanoparticles in a porous SiO 2 shell for drug delivery

A method is presented for synthesizing core–shell nanoparticles with a magnetic core and a porous shell suitable for drug delivery and other medical applications. The core contains multiple γ -Fe 2 O 3 nanoparticles (~15 nm) enclosed in a SiO 2 (~100–200 nm) matrix using either methyl (denoted TMOS- γ -Fe 2 O 3 ) or ethyl (TEOS- γ -Fe 2 O 3 ) template groups. Low-temperature Mössbauer spectroscopy showed that the magnetic nanoparticles have the maghemite structure, γ -Fe 2 O 3 , with all the vacancies in the octahedral sites. Saturation magnetization measurements revealed that the density of γ -Fe 2 O 3 was greater in the TMOS- γ -Fe 2 O 3 nanoparticles than TEOS- γ -Fe 2 O 3 nanoparticles, presumably because of the smaller methyl group. Magnetization measurements showed that the blocking temperature is around room temperature for the TMOS- γ -Fe 2 O 3 and around 250 K for the TEOS- γ -Fe 2 O 3 . Three dimensional topography analysis shows clearly that the magnetic nanoparticles are not only at the surface but have penetrated deep in the silica to form the core–shell structure.

Physics↗
DOE OSTI2023

Symptoms and Systemic Drug Reactions in Persons Receiving Weekly Rifapentine Plus Isoniazid (3HP) Treatment for Latent Tuberculosis Infection

Abstract Background Three months of weekly rifapentine plus isoniazid (3HP) therapy for latent tuberculosis infection (LTBI) is recommended worldwide. The development of symptoms and systemic drug reactions (SDRs) on 3HP have not been fully characterized. We aimed to determine the patterns of symptom development and identify SDRs and associated factors in patients taking 3HP. Methods We analyzed symptoms data in participants receiving 3HP in the Tuberculosis Trials Consortium's iAdhere study (Study 33). We examined the patterns of symptom reporting across participants from baseline and 4 monthly visits. Bivariate analyses and multivariable regression models were used to identify factors associated with SDRs. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated. Results Among 1002 participants receiving 3HP, 768 (77%) reported at least 1 symptom; 97% of these symptoms were grade 1 (79%) or grade 2 (18%). Most symptoms developed in the first month and resolved. A total of 111 (11%) participants had symptoms that met criteria for SDRs; however, 53 (48%) of these participants completed therapy. Factors associated with SDRs and discontinuation included female sex (RR: 2.05; 95% CI: 1.19–3.54), age ≥45 years (RR: 1.99; 95% CI: 1.19–3.31), and use of concomitant medications (RR: 2.26; 95% CI: 1.15–4.42). Conclusions Although most patients receiving 3HP reported symptoms, most were mild, occurred early, and resolved without stopping treatment. Among patients experiencing SDRs, nearly half were able to complete therapy. Patient and provider education should focus on differentiating severe reactions where 3HP should be stopped from minor symptoms that will resolve. Clinical Trials Registration. NCT01582711.

Immunology↗