ADMET and DMPK最新文献

Background and purpose: Multifunctional hybrid nanoparticles garner heightened interest for prospective biomedical applications, including medical imaging and medication administration, owing to their synergistic benefits of constituent components. Therefore, we demonstrated an optimized protocol for synthesizing magnetofluorescent nanohybrids comprising fluorescent carbon dots with magnetic nanoparticles.

Experimental approach: Carbon dot-coated iron oxide nanoparticles (CDs@Fe₂O₃) were synthesized with varying citric acid concentrations by a one-pot hydrothermal synthesis method for the development of a low-cost and biocompatible contrast agent (CA) for enhanced multimodal imaging (fluorescent and T ₁ and T ₂ weighted magnetic resonance imaging (MRI)) to replace the conventional CAs.

Key results: The physicochemical characterization of the synthesized CDs@Fe₂O₃ revealed that 3 g of citric acid used for the synthesis of nanoparticles, keeping Fe(II) and Fe(III) ratio 1:2 provides higher stability of -78 mV zeta potential, saturation magnetization of 24 emu/g, with a hydrodynamic diameter of 68 nm. Carbon coating affects surface spins on Fe₂O₃, resulting in fewer surface-based relaxation centres, making T ₁ relaxation relatively more prominent. Furthermore, the surface-engineered iron oxide NPs are efficient in producing both T ₁ and T ₂ weighted MRI as well as fluorescence-based imaging. The molar relaxivity and molar radiant efficiency derived from phantom studies demonstrate their effectiveness in multimodal medical imaging. The cytotoxicity assay, haemolysis assay, haematology, and histopathology studies show that the optimized CDs@Fe₂O₃ are biocompatible, haemocompatible, and negligibly toxic.

Conclusion: We can conclude the significant potency of CDs@Fe₂O₃ for multimodal diagnosis.

Background and purpose: Multidrug-resistant tuberculosis (MDR-TB) remains a significant challenge in tuberculosis (TB) treatment, driven by simultaneous mutations in the rpoB and katG genes that confer resistance to rifampicin and isoniazid. While many molecular diagnostic tools focus on rpoB, the katG gene is often overlooked despite its critical role in confirming MDR-TB. This study aims to develop a CRISPR/Cas9-based electrochemical biosensor for the rapid and selective detection of katG mutation.

Experimental approach: A guide RNA (gRNA) specific to the mutation site on katG gene was designed using the Benchling CRISPR tool, considering on-target and off-target scores, specificity, and cleavage sites within the Mycobacterium tuberculosis genome. The selected gRNA achieved the highest on-target score of 61.2 and an off-target score of 49.0 at cut position 2928, with a PAM sequence of AGG. Its cleavage efficiency was validated experimentally using an electrochemical biosensing platform incorporating a gold-modified screen-printed carbon electrode (SPCE/Au). Redox response enhancement by [Fe(CN₆)]^3-/4- confirmed the improved performance of the electrode.

Key results: The biosensor system detects the target DNA through hybridization with DNA probe-Fc, forming double-stranded DNA (dsDNA) that is recognized and cleaved by the Cas9/gRNA complex. This cleavage significantly reduces the ferrocene oxidation signal, indicating the presence of a katG mutation. Non-mutated target DNA produces a nondetectable ferrocene signal, suggesting that the Cas9 enzyme may remain bound to the electrode without cleavage. The CRISPR/Cas9 electrochemical biosensor demonstrated a low detection limit of 7.5530 aM and a detection range of 10¹ to 10⁶ aM.

Conclusion: The CRISPR/Cas9-based electrochemical biosensor exhibits high sensitivity and specificity for the detection katG mutation, offering a promising platform for rapid MDR-TB diagnostics.

Background and purpose: Mitochondrial DNA (mtDNA) mutations can impair oxidative phosphorylation and ATP production, potentially contributing to the pathogenesis of type 2 diabetes mellitus (T2DM). This study aimed to investigate the relationship between mtDNA mutations and ATP levels in blood and urine samples from T2DM patients.

Experimental approach: Samples from 60 patients (30 with T2DM + mitochondrial disease [MD] phenotype and 30 with T2DM alone) were analysed. mtDNA mutations A3243G and G9053A were detected using qPCR with dual-labeled probes (FAM for mutant, HEX for wild type) based on Cq comparisons. ATP concentrations were measured using a screen-printed carbon electrode (SPCE)-based electrochemical aptasensor.

Key results: The A3243G mutation was more frequent and had higher heteroplasmy levels than G9053A, particularly in the T2DM + MD group. Although no statistically significant differences in ATP levels were observed between groups, descriptive ranges showed lower ATP concentrations in the T2DM + MD group (314 to 919 μM) compared to the T2DM group (746 to 1130 μM), both below the physiological range (1.500 to 1.900 μM). A similar pattern was found for A3243G mutation levels, while G9053A levels overlapped between groups. Two-way ANOVA showed a significant association between mutation presence and reduced ATP levels.

Conclusion: The A3243G mutation may be more directly associated with mitochondrial ATP depletion in T2DM, while the role of G9053A remains inconclusive. This study highlights the potential of combining molecular and electrochemical tools to assess mitochondrial contributions in diabetes.

Background and purpose: Warfarin is a widely prescribed oral anticoagulant for the prevention and treatment of thromboembolic events, frequently used in patients with atrial fibrillation. However, its effectiveness is often challenged by a narrow therapeutic range and significant inter-patient variability in dosage requirements and treatment responses. Drug interactions remain a critical concern, as they heighten the risk of supratherapeutic anticoagulation. Reports of interactions between warfarin and mango have documented cases of elevated international normalized ratio (INR) following mango consumption, although the underlying molecular mechanisms remain unclear.

Experimental approach: This study investigates the molecular basis of the warfarin-mango interaction using proton nuclear magnetic resonance (¹H-NMR)-based metabolomics. In a pre-post design study, plasma samples were collected from patients on long-term warfarin therapy (>6 months) who exhibited supratherapeutic INR levels after consuming mango. After a two-week discontinuation of mango consumption, additional plasma samples were collected once INR levels returned to the therapeutic range.

Key results and conclusion: This is the first study to utilize ¹H-NMR metabolomics to explore warfarin-mango interactions, integrating clinical observations with metabolic insights. Findings suggest that a reduction in glycerol 3-phosphate may impair glycolysis, disrupting platelet activation and contributing to the elevated INR levels observed in all patients. These results underscore the potential for ¹H-NMR metabolomics to elucidate drug-food interactions, advancing personalized anticoagulant management and improving patient safety.

Background and purpose: Pharmaceutical crime is becoming an increasingly serious threat. For customs officers and police officers, minimal or no sample preparation before analysis is essential when detecting prohibited compounds/counterfeit products, ideally using on-site analysis.

Experimental approach: Unregistered dietary supplements containing anabolic substances, specifically selective androgen receptor modulators (SARMs) such as andarine, ligandrol, ostarine, and testolone became the subject of investigation. Dietary supplements with these SARMs are often found illegally in various fitness centres and can be purchased online. Furthermore, these illegal supplements may not contain the declared SARMs at all or may contain incorrect amounts. Analytical methods such as Raman spectroscopy, differential scanning calorimetry, thermogravimetry, and X-ray powder diffraction were chosen to identify these banned SARMs in the illegal products.

Key results: Using a combination of these fast and direct analytical techniques, in particular, Raman spectroscopy, it was found that out of 16 samples, SARMs were confirmed in 9 samples, while no testolone (4 samples), ostarine (2 samples), or andarine (1 sample) was reliably identified in 7 samples.

Conclusion: Overall, almost half of the analyzed samples of unregistered/illegal sports dietary supplements purchased anonymously online in the Slovak Republic with declared content of at least one SARM did not contain what is declared on the label. Thus the combination of several solid-state analytical techniques without complex sample preparation has proven valuable for rapid identification of APIs in supplements.

Background and purpose: Bisphosphonates (BPs) are well-known for their strong affinity toward bone mineral matrices and are widely used to inhibit excessive osteoclast activity associated with various bone disorders. Beyond their clinical use, their unique bone-targeting capability has positioned them as promising ligands for drug delivery systems aimed at treating bone-related cancers.

Approach: The review analyses published studies on BP-functionalized drug delivery systems, including direct drug conjugates, calcium-based nanomaterials, carbon-based nanostructures, and self-assembling systems such as micelles and liposomes. In vitro assays (e.g. hydroxyapatite binding, cell viability) and in vivo biodistribution studies are discussed to evaluate targeting efficiency and therapeutic outcomes. The impact of BP structure, linker chemistry, and carrier material on drug release and bone accumulation is examined.

Key results: BP-functionalized systems consistently demonstrate improved bone targeting and enhanced drug accumulation at tumour sites compared to non-targeted approaches. Both direct conjugates and nanocarrier-based systems show promising results, with some formulations offering controlled drug release and reduced systemic toxicity. Despite these advances, certain challenges such as burst release and incomplete clinical validation remain.

Conclusion: This review highlights the significant progress in BP-based drug delivery platforms for bone cancer therapy, demonstrating their potential to concentrate therapeutic agents at bone tumour sites while minimizing off-target effects. The integration of nanotechnology with BP targeting offers new opportunities for treating bone metastases and primary bone tumours. However, further research is needed to address current limitations and translate these findings into clinical practice.

Background and purpose: The evaluation of ADMET properties remains a critical bottleneck in drug discovery and development, contributing significantly to the high attrition rate of drug candidates. Traditional experimental approaches are often time-consuming, cost-intensive, and limited in scalability. This review aims to investigate how recent advances in machine learning (ML) models are revolutionizing ADMET prediction by enhancing accuracy, reducing experimental burden, and accelerating decision-making during early-stage drug development.

Experimental approach: This article systematically examines the current landscape of ML applications in ADMET prediction, including the types of algorithms employed, common molecular descriptors and datasets used, and model development workflows. It also explores public databases, model evaluation metrics, and regulatory considerations relevant to computational toxicology. Emphasis is placed on supervised and deep learning techniques, model validation strategies, and the challenges of data imbalance and model interpretability.

Key results: ML-based models have demonstrated significant promise in predicting key ADMET endpoints, outperforming some traditional quantitative structure - activity relationship (QSAR) models. These approaches provide rapid, cost-effective, and reproducible alternatives that integrate seamlessly with existing drug discovery pipelines. Case studies discussed in this review illustrate the successful deployment of ML models for solubility, permeability, metabolism, and toxicity predictions.

Conclusion: Machine learning has emerged as a transformative tool in ADMET prediction, offering new opportunities for early risk assessment and compound prioritization. While challenges such as data quality, algorithm transparency, and regulatory acceptance persist, continued integration of ML with experimental pharmacology holds the potential to substantially improve drug development efficiency and reduce late-stage failures.

Background and purpose: Polyhydroxyalkanoates (PHAs) are biodegradable polyesters of bacterial origin that are actively studied as matrices for the preparation of nanoparticulate drug delivery systems. The most significant parameters affecting PHAs nanoparticles (NPs) characteristics are polymer composition and the type of surfactant used to stabilize the emulsion during NPs preparation. However, there are only a few studies in the literature investigating the effect of these factors on the characteristics of PHA NPs.

Experimental approach: Blank poly(3-hydroxybutyrate) (P3HB) and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (P3HBV) NPs were produced and characterized in terms of their size, morphology and zeta potential. Poly(vinyl alcohol) (PVA) with various molecular weights (31-50 and 85-124 kDa), as well as Tween 20 (TW20), Tween 80 (TW80), sodium deoxycholate (SDC) and sodium dodecyl sulphate (SDS) were used as surfactants. For NPs that formed stable aqueous suspensions and had the most desirable characteristics (P3HB/PVA_31-50 and P3HBV/PVA_31-50), hemolytic activity and cytotoxicity to HeLa and C2C12 cells in vitro were determined.

Key results: NPs of both P3HB and P3HBV obtained using PVA with the M _w of 31-50 kDa as a surfactant had regular spherical shape, uniform size distribution, average diameter of about 900 nm and zeta potential of -28.5 and -28.7 mV, respectively. PVA_85-124, TW20 and TW80, as well as SDC and SDS as surfactants, did not show satisfactory results due to suspension gelation, formation of hollow NPs with irregular shape and poor resuspension after washing and freeze-drying, respectively. P3HB/PVA_31-50 and P3HBV/PVA_31-50 NPs did not have hemolytic activity and did not show pronounced cytotoxicity to HeLa and C2C12 cells in the concentration range from 10 to 500 μg mL^-1, so these samples were regarded as safe and biocompatible.

Conclusion: In this study, the effect of various non-ionic and anionic surfactants on the characteristics of P3HB and P3HBV NPs was investigated. PVA_31-50 was found to be effective in producing NPs of both studied polymers with good biocompatibility and favorable characteristics, making them suitable for drug delivery applications. In contrast, other studied surfactants, i.e., PVA_85-124, TW20, TW80, SDC and SDS, require further investigation. The obtained findings may promote the development of novel PHA-based nanomedicines.

Background and purpose: Because of its antimetabolic and cytotoxic qualities, epirubicin (EP), a crucial chemotherapeutic drug, has been used to treat a number of cancers, including those of the prostate, breast, ovary, stomach, lung, and colon.

Experimental approach: In this study, CoWO₄/reduced graphene oxide (CoWO₄/rGO) nanocomposite was synthesised and characterised by field emission-scanning electron microscopy and energy-dispersive X-ray spectroscopy. To provide a novel sensing platform for EP determination, a screen-printed electrode (SPE) surface was modified using the as-fabricated CoWO₄/rGO nanocomposite.

Key results: Using voltammetric techniques, the electrochemical behaviour of the CoWO₄/rGO nanocomposite modified SPE (CoWO₄/rGO/SPE) for the EP detection was examined. CoWO₄/rGO significantly reduced the overpotential of the EP redox reaction and increased the rate of electron transfer between the electrode and analyte as compared to bare SPE. EP was quantitatively analysed using differential pulse voltammetry.

Conclusions: It was discovered that the linearity range was 0.01 to 190.0 μM. The sensitivity and limit of detection were 0.1529 μA μM^-1 and 0.007 μM, respectively. Additionally, the constructed CoWO₄/rGO/SPE sensor's practical applicability was investigated in pharmaceutical samples with good recovery outcomes.

Background and purpose: New compounds and innovative therapeutic approaches are trying to prevent antimicrobial resistance, which has become a global health challenge.

Experimental approach: This study includes a series of twelve mono-, di- and trichlorinated 1-hydroxynaphthalene-2-carboxanilides designed as multitarget agents. All compounds were evaluated for their antistaphylococcal activity. Furthermore, MTT assay and chemoproteomic analysis of selected compounds were performed. Cytotoxicity in human cells was also tested.

Key results: N-(3,5-Dichlorophenyl)-1-hydroxynaphthalene-2-carboxamide (10) demonstrated activity comparable to or higher than clinically used drugs, with minimum inhibitory concentrations (MICs) of 0.37 μM. The compound was equally effective against clinical isolates of methicillin-resistant S. aureus. On the other hand, compound 10 showed 96 % inhibition of S. aureus respiration only at a concentration of 16× MIC. Chemoproteomic analysis revealed that the effect of agent 10 on staphylococci resulted in the downregulation of four proteins. This compound expressed no in vitro cytotoxicity up to a concentration of 30 μM.

Conclusion: From the set of tested mono-, di- and trisubstituted derivatives, it is evident that the position of chlorine atoms is decisive for significant antistaphylococcal activity. Inhibition of energy metabolism does not appear to be one of the main mechanisms of action of compound 10; on the contrary, the antibacterial effect may likely be contributed by downregulation of proteins (especially ATP-dependent protease ATPase subunit HslU) involved in processes essential for bacterial survival and growth, such as protein, nucleotide/nucleic acid synthesis and efficient protein repair/degradation.