Drug Development Research最新文献

Recently, a series of N- and C-modified hemorphins have been synthesized, characterized and evaluated for their antibacterial potency. These analogues included amino acids such as cysteine (Cys), glutamic acid (Glu), and histidine (His), as well as 1-adamantanecarboxylic acid (Adam), and niacin (nicotinic acid) (Nic). The current study aimed to explore the anti-seizure potential of these compounds in mice. The role of opioid receptors (ORs) in their mechanism of action was evaluated both pharmacologically and through in silico methods. A battery of tests were used, including the 6-Hz and maximal electroshock seizures (MES) tests, as well as kainate (KA)-induced status epilepticus (SE), pentylenetetrazol (PTZ) and corneal kindling models. The intracerebroventricular infusion of peptide analogues, specifically those containing Cys, Glu, His and Adam but not Nic, showed reduced psychomotor seizures and seizure spread. The effective dosages were as follows: C-V (25 μg/5 μl—6 Hz and MES), H-V (6 and 12 μg/5 μl—6 Hz and MES), AC-V (12 μg/5 μl—MES) and AH-V (25 μg/5 μl—6 Hz). The efficacy of the compounds in preventing clonic seizures in PTZ-kindled mice was observed, except NCH7. Furthermore, C-V and AC-V were found to be effective in corneal-kindled mice and C-V against the KA-induced SE. Naloxone blocked the anti-seizure effect of C-V and AC-V, which was also confirmed by docking analysis. Our findings suggest that insertion of Cys and Glu (C-V and AC-V) and Cys, Adam, and Glu (AC-V) enhances the potential of these novel hemorphin analogues as effective anti-seizure agents.

The future of drug research is intrinsically connected to the continuous advancement and prudent integration of Artificial intelligence (AI) and mathematics. By addressing challenges and leveraging possibilities, the pharmaceutical industry may fully harness the potential of AI to develop innovative and effective treatments for diverse diseases. In our opinion, finding new drugs takes long time and funds, and in the past, it was mostly done manually. AI has changed this sector completely, making drug manufacturing faster, cheaper, and more specific. This review presents the pertinent literature on drug discovery utilizing mathematical modeling and AI tools and methodologies implemented at every stage of drug development to expedite the research process and mitigate risk and costs in clinical trials, it also presents that how mathematical modeling and AI algorithms can be used together at several stages of drug development. There is a lot of focus on how mathematical frameworks like Linear Algebra, optimization, statistical modeling, graph theory and differential equations may operate along with the techniques of AI like machine learning (ML), deep learning (DL), reinforcement learning (RL), natural language processing (NLP) and transfer learning (TL) and the problems that are now being faced, the tools and datasets that are accessible, and what the future holds for this field, which is changing quickly.

Psoriasis is a chronic, immune-mediated dermatological disorder characterized by keratinocyte hyperproliferation and persistent inflammation, representing a significant therapeutic challenge. Conventional topical therapies are often limited by inadequate skin penetration, poor drug stability, and systemic toxicity, necessitating the development of advanced drug delivery platforms. Recent progress in colloid and interface science has enabled the design of nanocarrier systems including solid lipid nanoparticles, nanostructured lipid carriers, nanoemulsions, and liposomes that optimize drug–skin interactions at the nanoscale. Through interface engineering, these carriers improve drug solubility, stability, and controlled release, while enhancing epidermal localization and minimizing off-target exposure. Lipid-based nanosystems, in particular, leverage the skin's lipid pathways to achieve higher drug accumulation in psoriatic lesions, thereby improving therapeutic outcomes and patient compliance. Preclinical and early clinical studies with drugs such as methotrexate and cyclosporine have demonstrated enhanced lesion resolution, reduced side effects, and superior safety profiles when delivered via nanocarriers. Nevertheless, the clinical translation of these systems is often hindered by challenges such as large-scale reproducibility, formulation stability, and regulatory complexity. Interface-engineered nanocarriers address these limitations by employing biocompatible materials, scalable synthesis techniques, and targeted design strategies that enhance safety, efficacy, and translational feasibility. This review integrates mechanistic insights from colloid and interface engineering with translational perspectives on formulation scalability, regulatory pathways, and long-term safety evaluation. Collectively, interface-tailored nanocarriers represent a transformative approach for precision-driven, effective, and patient-centered topical therapy of psoriasis.

Breast cancer is the most commonly diagnosed cancer globally, predominantly affecting older women. Thymoquinone (TQ) is a natural therapeutic agent that exerts anticancer efficacy. However, its pharmacological effects are restricted by inadequate aqueous solubility and bioavailability. The present study aimed to develop TQ-encapsulated polyethyleneimine/poly(lactic acid) nanoparticles (TQ-PEI/PLA-NPs) to enhance the delivery of TQ into breast cancer cells. The solvent evaporation-emulsification method was employed to synthesize TQ-PEI/PLA-NPs, and their physicochemical properties were subsequently examined. TQ-PEI/PLA-NPs had a crystalline structure, a zeta potential of +1 mV, and a spherical shape with a diameter of 80–90 nm. The encapsulation efficiency was 85.77 ± 2.21% (w/w), while the drug loading capacity was 9.32 ± 1.14% (w/w). The release rate of TQ from TQ-PEI/PLA-NPs was marginally elevated at pH: 5.8 (81.21 ± 0.87%) compared to pH 3.5 and 7.2. MTT assay using TQ-PEI/PLA-NPs confirmed concentration-dependent cytotoxicity against MCF-7 cells after 24 h of treatment, and IC₅₀ was found to be 21.99 μg/mL. The intracellular delivery of TQ in MCF-7 cells caused cell death, as indicated by AO/EBr staining, mitochondrial transmembrane potential assay, and Caspase-3 and -9 investigations. The observed MCF-7 cell death attributed to TQ was induced by reactive oxygen species (ROS) and impaired mitochondrial membrane potential. The ROS potentially damaged the mitochondrial membrane, and further studies supported the induction of apoptosis. Our results indicated that TQ-PEI/PLA-NPs, which cause cytotoxicity to breast cancer cells, as evidenced by the decreased MCF-7 cell counts, may exhibit significant therapeutic potential for breast cancer therapies.

Bone cancer remains a challenging malignancy, with high mortality rates in advanced or metastatic stages. Recent therapeutic advances have increasingly focused on integrating targeted therapy, immunotherapy, and chemotherapy with nanodrug delivery systems (NDDS) to enhance treatment efficacy. Chemotherapy remains a cornerstone, with optimized regimens improving outcomes while reducing systemic toxicity. Immunotherapy (including checkpoint inhibitors, adoptive T-cell transfer, and CAR-T cell therapy) has demonstrated promising clinical potential. Targeted therapy disrupts key molecular pathways critical for tumor progression, offering a more selective approach with fewer adverse effects. NDDS amplify these strategies by improving drug bioavailability, enabling sustained and controlled release, enhancing tumor penetration, and overcoming drug resistance within the bone tumor microenvironment. They also facilitate the co-delivery of multiple agents for synergistic effects. This review provides a comprehensive analysis of the clinical applications of targeted therapy and immunotherapy in primary and secondary bone cancers, critically evaluates recent advances in NDDS, and highlights their transformative potential in precise drug targeting and multimodal regimens. By bridging established treatment modalities with emerging nanodelivery innovations, it offers an integrated framework to guide future translational research in bone cancer therapy.

A novel series of triazole hydrazide derivatives 8a-o was rationally designed, synthesized, and systematically evaluated for their anticancer potential. Cytotoxicity screening against A549 lung adenocarcinoma cells identified compounds 8a-d as the most potent, exhibiting IC₅₀ values of 3.15–4.93 µM, which are comparable to doxorubicin (IC₅₀ = 2.77 µM). Mechanistic studies revealed that lead compound 8a induced apoptosis through upregulation of Bax and caspase-3 and downregulation of Bcl-2. Additionally, 8a significantly inhibited A549 cell migration (34.46% wound closure vs. 61.61% in controls) and reduced clonogenic survival (surviving fraction = 0.5725). Importantly, 8a displayed low cytotoxicity toward normal lung fibroblasts (WI-38, IC₅₀ = 47.21 µM). Enzyme inhibition assays demonstrated potent EGFR kinase inhibition by 8a and 8 d (IC₅₀ = 74.85 and 75.87 nM, respectively), comparable to erlotinib (IC₅₀ = 34.89 nM). Moreover, in silico ADMET profiling predicted favorable drug-likeness and oral bioavailability, while molecular docking supported the stable binding of 8a within the EGFR active site. These findings identify compound 8a as a promising therapeutic lead for the development of targeted EGFR inhibitors in non-small cell lung cancer (NSCLC) therapy.

The poor bioavailability and low therapeutic indices of conventional cancer therapeutics hinder their efficacy despite their promising anticancer potential. This study presents an improved solubility and enhanced drug delivery system against breast cancer by complexing Bromo-Noscapine (9-Br-Nos) with Methyl-β-cyclodextrin (Mβ-CD). After synthesizing the inclusion complex, it was characterized using ultraviolet-visible (UV-Vis) spectroscopy, proton nuclear magnetic resonance (¹H NMR), Fourier-transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), scanning electron microscopy (SEM), and thermogravimetric analysis (TGA). In addition, the arrangement of the drug molecule within the Mβ-CD cavity was confirmed by molecular docking and molecular dynamic simulation. The drug release profile, bioavailability, and anticancer activity of the complex were also evaluated in vitro. Moreover, the toxicity and metabolic clearance kinetics were assessed in vivo using animal model. Furthermore, to explore the molecular mechanism of the anticancer activity of the 9-Br-Nos-Mβ-CD inclusion complex FITC-annexin V apoptosis and western blot analysis were performed to explore the enhanced apoptotic cell death and the modulation of cancer-related proteins in breast cancer cells. In summary, this report demonstrated that the Noscapine-Cyclodextrin inclusion complex enhances the anticancer potential of 9-Br-Nos by modulating its bioavailability and persistence in breast cancer cells.

This study was designed to explore the effects of esketamine on cognitive deficits and blood–brain barrier (BBB) dysfunction in sepsis-associated encephalopathy (SAE). An in vivo SAE model was generated through the administration of lipopolysaccharide (LPS), and LPS-induced cognitive impairment in rats was evaluated using the Morris water maze (MWM) test. BBB disruption in vivo was assessed by measuring brain water content together with Evans blue dye penetration, while LPS-induced endothelial hyperpermeability in vitro was examined through FITC–dextran leakage. The protein expression of claudin-3 and ZO-1 was determined by western blotting. In addition, the levels of pro-inflammatory cytokines, cell apoptosis, autophagy, and the activity of the BDNF/TrkB pathway were examined. Rapamycin (Rap, an autophagy inducer) and K252a (a BDNF inhibitor) were used to determine whether the protective effects of esketamine were associated with autophagy and BDNF/TrkB signaling. Esketamine treatment significantly improved the LPS-induced cognitive dysfunction and neurological injury observed in vivo, and it also inhibited the production of pro-inflammatory cytokines and reduced cell apoptosis both in vivo and in LPS-treated hCMEC/D3 cells. Importantly, esketamine alleviated BBB hyperpermeability in vivo and prevented LPS-induced endothelial leakage in vitro. Moreover, esketamine suppressed LPS-induced autophagy, and the influence of esketamine on claudin-3 and ZO-1 expression was reversed when Rap was applied. Esketamine activated the BDNF/TrkB pathway, and the protective effects of esketamine on BBB integrity and autophagy in response to LPS were abolished by K252a. Taken together, these findings indicate that esketamine protects the BBB against SAE by activating the BDNF/TrkB pathway and inhibiting autophagy, providing a potential therapeutic strategy for SAE.

Spleen tyrosine kinase (SYK), a non-receptor tyrosine kinase, serves as a pivotal regulator in multiple intracellular signaling pathways, particularly those involved in immune responses. Dysregulated SYK activation has been strongly implicated in the pathogenesis of various hematological malignancies and autoimmune disorders, making it an attractive therapeutic target. Consequently, significant progress has been made in developing SYK inhibitors as a targeted treatment strategy. This article comprehensively reviews recent advances in SYK inhibitor research, focusing on their therapeutic potential in autoimmune diseases and hematologic cancers. Furthermore, we highlight representative SYK inhibitors, discuss their clinical applications, outline current challenges, and future directions in this evolving field.

The inception of molecularly imprinted polymer technology at the nanoscale has marked a major advancement in targeted cancer therapy and diagnostics, representing the first systematic distribution of synthetic substitute to monoclonal antibodies in cancer therapeutics. Nano molecularly imprinted polymers (nanoMIPs) present a significant shift in cancer intervention with an antibody free strategy owing to its high specificity and adaptive recognition potential. Unlike conventional drug delivery platforms, nanoMIPs function as smart nanoscale scaffolds, capable of selectively encapsulating, accumulating and strategically releasing the chemotherapeutic agent in highly aggressive carcinomas and sarcomas. A key advantage of nanoMIPs based drug delivery system is their ability to create molecularly imprinted cavities that retain an exquisite structural memory of the target molecules after their removal establishing the first clinically viable, non biological alternative to therapeutic antibodies. This review provides an in-depth overview of the development, current state, and prospect of nanoMIPs, emphasizing their distinct molecular recognition properties and advantages over conventional antibody-based approach in cancer therapy. Several relevant chemotherapeutic drugs have been discussed for controlled and sustained delivery using nanoMIPs, for an improved biocompatibility, stability, solubility, biodegradability, and targeting efficiency across various cancer types. By integrating recent advancements in nanoMIPs based anticancer drug delivery system, this review seeks to provide a comprehensive framework for their continued development, optimization, and eventual clinical translation as the next generation antibody substitute in precision cancer therapeutics.