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In this work, we have developed and tested a dry powder form of niclosamide made by thin-film freezing (TFF) and administered it by inhalation to rats and hamsters to gather data ...about its toxicology and pharmacokinetics. Niclosamide, a poorly water-soluble drug, is an interesting drug candidate because it was approved over 60 years ago for use as an anthelmintic medication, but recent studies demonstrated its potential as a broad-spectrum antiviral with pharmacological effect against SARS-CoV-2 infection. TFF was used to develop a niclosamide inhalation powder composition that exhibited acceptable aerosol performance with a fine particle fraction (FPF) of 86.0% and a mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of 1.11 µm and 2.84, respectively. This formulation not only proved to be safe after an acute three-day, multi-dose tolerability and exposure study in rats as evidenced by histopathology analysis, and also was able to achieve lung concentrations above the required IC90 levels for at least 24 h after a single administration in a Syrian hamster model. To conclude, we successfully developed a niclosamide dry powder inhalation that overcomes niclosamide’s limitation of poor oral bioavailability by targeting the drug directly to the primary site of infection, the lungs.
Immunogenic cell death (ICD) is a way of reengaging the tumor-specific immune system. ICD can be induced by treatment with chemotherapeutics. However, only a limited number of drugs and other ...treatment modalities have been shown to elicit the biomarker responses characteristic of ICD and to provide an anticancer benefit in vivo. Here, we report a rationally designed redox-active Au(I) bis-N-heterocyclic carbene that induces ICD both in vitro and in vivo. This work benefits from a synthetic pathway that allows for the facile preparation of asymmetric redox-active Au(I) bis-N-heterocyclic carbenes.
A major mouse model widely adopted in recent years to induce pronounced ethanol intake is the ethanol vapor model known as “CIE” or “Chronic Intermittent Ethanol.” One critical question concerning ...this model is whether the rapid induction of high blood ethanol levels for such short time periods is sufficient to induce alterations in N-methyl-d-aspartate receptor (NMDAR) function which may contribute to excessive ethanol intake. In this study, we determined whether such short term intermittent ethanol exposure modulates NMDAR function as well as other prominent electrophysiological properties and the expression of plasticity in both D1 (D1+) and D2 (D1−) dopamine receptor expressing medium spiny neurons (MSNs) in the nucleus accumbens (NAc) shell. To distinguish between the two subtypes of MSNs in the NAc we treated Drd1a-TdTomato transgenic mice with CIE vapor and electrophysiological recordings were conducted 24 h after the last vapor exposure. To investigate CIE induced alterations in plasticity, long-term depression (LTD) was induced by pairing low frequency stimulation (LFS) with post synaptic depolarization. In ethanol naïve mice, LFS induced synaptic depression (LTD) was apparent exclusively in D1+ MSNs. Whereas in slices prepared from CIE treated mice, LFS induced synaptic potentiation (LTP) in D1+ MSNs. Furthermore, following CIE exposure, LFS now produced LTD in D1− MSNs. We found that CIE exposure induced an increase in excitability in D1+ MSNs with no change in D1− MSNs. After CIE, we found a significant increase in spontaneous EPSCs (sEPSCs) frequency in D1+ but not D1− MSNs suggesting alterations in baseline α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) mediated signaling. CIE induced changes in NMDAR function were measured using the NMDA/AMPA ratio and input-output curves of isolated NMDAR currents. We observed a significant increase in NMDAR function in D1+ MSNs and a decrease in D1− MSNs after ethanol vapor exposure. The reversal of NMDAR function may account for the CIE induced alterations in the expression of plasticity. The cell type specific alterations in excitatory signaling in the NAc shell may constitute an important neuroadaptation necessary for the expression of increased ethanol consumption induced by intermittent ethanol vapor exposure.
This article is part of the Special Issue entitled ‘Ionotropic glutamate receptors’.
•NMDAR-dependent LTD is expressed only in D1 MSNs of EtOH naïve mice.•After CIE, the LTD induction protocol results in LTP in D1 MSNs and LTD in D2 MSNs.•CIE induces an increase in excitability and sEPSC frequency in D1 MSNs.•NMDAR function is increased and decreased in D1 and D2 MSNs respectively after CIE.•Altered NMDAR function may be important for the development of EtOH dependence.
To harness the intrinsic transport properties of albumin yet improve the therapeutic index of current in situ albumin-binding prodrugs, we developed albumin-drug conjugates with a controlled loading ...that achieved better antitumor efficacy. Here, model drug monomethyl auristatin E (MMAE) was conjugated ex vivo to Cys34 of albumin via a cathepsin B-sensitive dipeptide linker to ensure that all drug would be bound specifically to albumin. The resulting albumin-drug conjugate with a drug to albumin ratio (DAR) of 1 (ALDC1) retained the native secondary structure of albumin compared to conjugate with a higher DAR of 3 (ALDC3). ALDC1 exhibited improved drug release and cytotoxicity compared to ALDC3 in vitro. Slower plasma clearance and increased drug exposure over time of ALDC1 were observed compared to ALDC3 and MMAE prodrug. In single dose studies with MIA PaCa2 xenografts, cohorts treated with ALDC1 had the highest amount of MMAE drug in tumor tissues compared to other treatment arms. After multiple dosing, ALDC1 significantly delayed the tumor growth compared to control treatment arms MMAE, MMAE-linker conjugate and ALDC3. When dosed with the maximum tolerated dose of ALDC1, there was complete eradication of 83.33% of the tumors in the treatment group. Ex vivo conjugated ALDC1 also significantly inhibited tumor growth in an immunocompetent syngeneic mouse model that better recapitulates the phenotype and clinical features of human pancreatic cancers. In summary, site-specific loading of drug to albumin at 1:1 ratio allowed the conjugate to better maintain the native structure of albumin and its intrinsic properties. By conjugating the drug to albumin prior to administration minimized premature cleavage and instability of the drug in plasma and enabled higher drug accumulation in tumors compared to in situ albumin-binding prodrugs. This strategy to control drug loading ex vivo ensures complete drug binding to the albumin carrier and achieves excellent antitumor efficacy, and it has the potential to greatly improve the outcomes of anticancer therapy.
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•Albumin-drug conjugates with site-specific conjugation at Cys34 ex vivo enhanced drug delivery and antitumor efficacy.•Controlled loading of drugs minimized the change in albumin structure and is crucial to higher drug accumulation in tumors.•Ex vivo conjugation reduced premature release of the active drug compared to in situ albumin binding prodrug.•Ex vivo conjugation improved tumor regression in different models of pancreatic cancer compared to in situ binding prodrugs.
This paper thoroughly reviews the mechanism of veterinary drug carryover in feed manufacturing facilities, factors resulting in varying concentrations of drug carryover in processing equipment, the ...impact of chemical and physical properties of drugs, and the effect of equipment type and design. The Google Scholar database (from 1998 to 2023) was searched with words and phrases such as drug carryover, feed manufacturing, equipment cleaning and validation, food allergen control, sources of drug carryover, and process parameters in drug carryover. Some papers were from the Iowa State University Library database and PubMed. Drug carryover is a function of ingredients, nature of drugs, equipment type, process parameters, and cleaning procedures. The gaps are the lack of commercial feed mills data on the role and interaction of nanomaterials, molasses, equipment type, and process parameters in drug carryover in animal feed. Modification of process parameters, e.g., airflow in bucket elevators and the interaction of feed ingredients, composition, equipment type, and design, need to be investigated in the commercial setting to address drug carryover. Rhetorically, can big data facilitate the standardization of cleaning procedures at feed mills? The findings can result in drug carryover prevention/control in animal feed and animal-based human food.
Cancer treatments targeting DNA repair deficiencies often encounter drug resistance, possibly due to alternative metabolic pathways that counteract the most damaging effects. To identify such ...alternative pathways, we screened for metabolic pathways exhibiting synthetic lethality with inhibition of the DNA damage response kinase Ataxia-telangiectasia-mutated (ATM) using a metabolism-centered Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 library. Our data revealed Kelch-like ECH-associated protein 1 (KEAP1) as a key factor involved in desensitizing cancer cells to ATM inhibition both in vitro and in vivo. Cells depleted of KEAP1 exhibited an aberrant overexpression of the cystine transporter SLC7A11, robustly accumulated cystine inducing disulfide stress, and became hypersensitive to ATM inhibition. These hallmarks were reversed in a reducing cellular environment indicating that disulfide stress was a crucial factor. In The Cancer Genome Atlas (TCGA) pan-cancer datasets, we found that ATM levels negatively correlated with KEAP1 levels across multiple solid malignancies. Together, our results unveil ATM and KEAP1 as new targetable vulnerabilities in solid tumors.
Fluorine magnetic resonance imaging (19F MRI) has emerged as an attractive alternative to conventional 1H MRI due to enhanced specificity deriving from negligible background signal in this modality. ...We report a dual nanoparticle conjugate (DNC) platform as an aptamer‐based sensor for use in 19F MRI. DNC consists of core–shell nanoparticles with a liquid perfluorocarbon core and a mesoporous silica shell (19F‐MSNs), which give a robust 19F MR signal, and superparamagnetic iron oxide nanoparticles (SPIONs) as magnetic quenchers. Due to the strong magnetic quenching effects of SPIONs, this platform is uniquely sensitive and functions with a low concentration of SPIONs (4 equivalents) relative to 19F‐MSNs. The probe functions as a “turn‐on” sensor using target‐induced dissociation of DNA aptamers. The thrombin binding aptamer was incorporated as a proof‐of‐concept (DNCThr), and we demonstrate a significant increase in 19F MR signal intensity when DNCThr is incubated with human α‐thrombin. This proof‐of‐concept probe is highly versatile and can be adapted to sense ATP and kanamycin as well. Importantly, DNCThr generates a robust 19F MRI “hot‐spot” signal in response to thrombin in live mice, establishing this platform as a practical, versatile, and biologically relevant molecular imaging probe.
We report a novel dual nanoparticle conjugate sensor (DNCThr) for visualizing thrombin in live mice by fluorine‐19 magnetic resonance imaging. DNCThr consists of mesoporous silica‐coated perfluorocarbon nanoparticles (19F‐MSNs) linked to superparamagnetic iron oxide nanoparticles (SPIONs) via an aptamer and a complementary DNA strand. Target‐induced dissociation results in particle separation and robust signal turn‐on.
Fluorine magnetic resonance imaging (
F MRI) has emerged as an attractive alternative to conventional
H MRI due to enhanced specificity deriving from negligible background signal in this modality. We ...report a dual nanoparticle conjugate (DNC) platform as an aptamer-based sensor for use in
F MRI. DNC consists of core-shell nanoparticles with a liquid perfluorocarbon core and a mesoporous silica shell (
F-MSNs), which give a robust
F MR signal, and superparamagnetic iron oxide nanoparticles (SPIONs) as magnetic quenchers. Due to the strong magnetic quenching effects of SPIONs, this platform is uniquely sensitive and functions with a low concentration of SPIONs (4 equivalents) relative to
F-MSNs. The probe functions as a "turn-on" sensor using target-induced dissociation of DNA aptamers. The thrombin binding aptamer was incorporated as a proof-of-concept (DNC
), and we demonstrate a significant increase in
F MR signal intensity when DNC
is incubated with human α-thrombin. This proof-of-concept probe is highly versatile and can be adapted to sense ATP and kanamycin as well. Importantly, DNC
generates a robust
F MRI "hot-spot" signal in response to thrombin in live mice, establishing this platform as a practical, versatile, and biologically relevant molecular imaging probe.
Short 50-kilohertz (kHz) range frequency-modulated ultrasonic vocalizations (USVs) produced by rats and mice are unconditionally elicited by drugs of abuse or electrical stimulation that increase ...dopamine activity in the nucleus accumbens, and it has been suggested that they reflect “positive affect” or incentive motivational states associated with appetitive behavior. The repeated administration of amphetamine is known to not only produce “psychomotor” sensitization, but also to facilitate a number of appetitive behaviors, including conditioned drug pursuit behavior. We were interested, therefore, in whether amphetamine-induced 50-kHz USVs would also increase with repeated drug exposure. USV recordings were made during 5-min sessions immediately after a saline infusion, and again 4–5
h later after 1.0
mg/kg intravenous amphetamine exposure. These sessions took place every other day over a 5-day period. A challenge dose of 1.0
mg/kg amphetamine was administered 2 weeks later to determine whether sensitization would persist. The initial amphetamine infusion increased 50-kHz USVs relative to the saline infusion. This effect was enhanced over trials and during the amphetamine challenge 2 weeks later. Classification of 50-kHz range call types revealed that complex frequency-modulated trill calls were sensitized by amphetamine, but not flat 50-kHz calls. It is possible that 50-kHz USV recordings could provide a potentially valuable behavioral measure of sensitization linked to enhanced incentive salience and increased tendency to self-administer drugs of abuse.
Remdesivir dry powder for inhalation was previously developed using thin film freezing (TFF). A single-dose 24-h pharmacokinetic study in hamsters demonstrated that pulmonary delivery of TFF ...remdesivir can achieve plasma remdesivir and GS-441524 levels higher than the reported EC50s of both remdesivir and GS-441524 (in human epithelial cells) over 20 h. The half-life of GS-4412524 following dry powder insufflation was about 7 h, suggesting the dosing regimen would be twice-daily administration. Although the remdesivir-Captisol® (80/20 w/w) formulation showed faster and greater absorption of remdesivir and GS-4412524 in the lung, remdesivir-leucine (80/20 w/w) exhibited a greater Cmax with shorter Tmax and lower AUC of GS-441524, indicating lower total drug exposure is required to achieve a high effective concentration against SAR-CoV-2. In conclusion, remdesivir dry powder for inhalation would be a promising alternative dosage form for the treatment of COVID-19 disease.
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