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Nonsteroidal Anti-Inflammatory Drug Conjugated with Gadolinium (III) Complex as an Anti-Inflammatory MRI Agent.

ABSTRACT: Studies have been actively conducted to ensure that gadolinium-based contrast agents for magnetic resonance imaging (MRI) are accompanied by various biological functions. A new example is the anti-inflammatory theragnostic MRI agent to target inflammatory mediators for imaging diagnosis and to treat inflammatory diseases simultaneously. We designed, synthesized, and characterized a Gd complex of 1,4,7-tris(carboxymethylaza) cyclododecane-10-azaacetylamide (DO3A) conjugated with a nonsteroidal anti-inflammatory drug (NSAID) that exerts the innate therapeutic effect of NSAIDs and is also applicable in MRI diagnostics. Gd-DO3A-fen (0.1 mmol/kg) was intravenously injected into the turpentine oil-induced mouse model, with Gd-DO3A-BT as a control group. In the in vivo MRI experiment, the contrast-to-noise ratio (CNR) was higher and persisted longer than that with Gd-DO3A-BT; specifically, the CNR difference was almost five times at 2 h after injection. Gd-DO3A-fen had a binding affinity (K_a) of 6.68 × 10⁶ M^-1 for the COX-2 enzyme, which was 2.1-fold higher than that of fenbufen, the original NSAID. In vivo evaluation of anti-inflammatory activity was performed in two animal models. In the turpentine oil-induced model, the mRNA expression levels of inflammatory parameters such as COX-2, TNF-α, IL-1β, and IL-6 were reduced, and in the carrageenan-induced edema model, swelling was suppressed by 72% and there was a 2.88-fold inhibition compared with the saline group. Correlation analysis between in vitro, in silico, and in vivo studies revealed that Gd-DO3A-fen acts as an anti-inflammatory theragnostic agent by directly binding to COX-2.

SUBMITTER: Sung B

PROVIDER: S-EPMC10095586 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Nonsteroidal Anti-Inflammatory Drug Conjugated with Gadolinium (III) Complex as an Anti-Inflammatory MRI Agent.

Sung Bokyung B Kim Hee-Kyung HK Baek Ah-Rum AR Yang Byeong-Woo BW Kim Yeoun-Hee YH Choi Garam G Park Hyun-Jin HJ Kim Minsup M Lee Jongmin J Chang Yongmin Y

International journal of molecular sciences 20230406 7

Studies have been actively conducted to ensure that gadolinium-based contrast agents for magnetic resonance imaging (MRI) are accompanied by various biological functions. A new example is the anti-inflammatory theragnostic MRI agent to target inflammatory mediators for imaging diagnosis and to treat inflammatory diseases simultaneously. We designed, synthesized, and characterized a Gd complex of 1,4,7-tris(carboxymethylaza) cyclododecane-10-azaacetylamide (DO3A) conjugated with a nonsteroidal an ...[more]

PMID: 37047841

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Project description:BackgroundLipid transfer protein (LTP), an abundant protein in fruits, vegetables, and nuts, is a common food allergen in Mediterranean areas causing diverse allergic reactions. Approximately 40% of food-related anaphylaxis induced by LTPs requires nonsteroidal anti-inflammatory drugs (NSAIDs) as a triggering cofactor.ObjectiveWe sought to better understand the determinants of NSAID-dependent and NSAID-independent LTP-induced anaphylaxis (LTP-A).MethodsSelection of patients was based on a proved clinical history of NSAID-dependent or NSAID-independent anaphylaxis to LTPs, positive skin prick test response to LTPs, and serum LTP IgE. Whole-transcriptome (RNA sequencing) analysis of blood cells from 14 patients with NSAID-related LTP-A (NSAID-LTP-A), 7 patients with LTP-A, and 13 healthy control subjects was performed to identify distinct gene expression signatures.ResultsExpression of genes regulating gastrointestinal epithelial renewal was altered in both patient sets, particularly in those with LTP-A, who also presented with gene expression profiles characteristic of an inflammatory syndrome. These included altered B-cell pathways, increased neutrophil activation markers, and increased reactive oxygen species levels. Increased expression of the IgG receptor (CD64) in patients with LTP-A was mirrored by the presence of LTP-specific IgG1 and IgG3. Conversely, patients with NSAID-LTP-A were characterized by reduced expression of IFN-γ-regulated genes and IFN-γ levels, as well as upregulated expression of adenosine receptor 3 (ADORA3) and genes related to adenosine metabolism.ConclusionsGene ontology analysis suggests disturbances in gut epithelial homeostasis in both groups with LTP-A, with potential integrity breaches in patients with LTP-A that might explain their distinct inflammatory signatures. Differential regulation in patients with LTP-A and those with NSAID-LTP-A of the IFN-γ pathway, IgG receptors, and ADORA3 might provide the pathogenic basis of their distinct responses.

Project description:IntroductionThere is a paucity of information regarding providers' attitudes toward gastric-protective strategies with concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs). We aimed to assess gastric-protective strategies used upon prescribing NSAIDs and providers' awareness of societal guidelines for preventing NSAID-induced gastric complications.MethodsA standardized 10-item questionnaire was sent to all orthopedic providers in North Carolina and South Carolina. The survey design and refinement were based on a literature review, item generation, and small and large focus group discussions.ResultsForty-two orthopedists responded to the survey (response rate 16%). The most frequently used NSAIDs were meloxicam (79%), naproxen (69%), and ibuprofen (64%). NSAIDs were most commonly prescribed on an as-needed basis (52%), followed by <3 months (43%). The most common indications were degenerative arthritis (95%) and herniated disk (45%). Gastrointestinal adverse effects of NSAIDs were managed by discontinuing NSAID therapy (73%) or switching to a cyclooxygenase-2 (COX-2) inhibitor (40%). A small proportion were managed by referring to another physician (36%). Some clinicians prescribed gastric prophylaxis for patients at high risk for NSAID-induced gastric complications (24%). The academic setting was significantly associated with gastric prophylaxis and frequent assessment for NSAID-induced gastric adverse events. Providers with >20 years of experience showed similar trends. In low-risk patients, compliance with gastroprotective prophylaxis prescription was low (5%). Most providers were unaware of the societal guidelines for NSAID-induced gastric complications or the preventive strategies.ConclusionPrescription of gastric-protective medications with concurrent NSAID therapy is relatively low among orthopedists. Academic setting and higher years of experience showed a significant trend toward more gastric-protective medication prescription, COX-2 inhibitor use, and frequent assessments for gastric adverse events when prescribing NSAID therapy. Provider education on the latest societal guidelines and computer-based alerts can increase compliance and assessment for NSAID-induced gastric complications and preventive strategies.

Dataset Information

Nonsteroidal Anti-Inflammatory Drug Conjugated with Gadolinium (III) Complex as an Anti-Inflammatory MRI Agent.

Publications

Nonsteroidal Anti-Inflammatory Drug Conjugated with Gadolinium (III) Complex as an Anti-Inflammatory MRI Agent.

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