Drug Design, Development and Therapy最新文献

Peptide-drug conjugates (PDCs) are modular, targeted therapeutics composed of a homing peptide linked to a cytotoxic or modulating drug payload via a cleavable/non-cleavable linker. PDCs utilize peptide targeting to enhance the delivery of potent drugs to tumors, providing advantages such as superior tissue penetration, reduced immunogenicity, and simpler manufacture compared to antibody-drug conjugates (ADCs). A comparison of PDCs versus ADCs highlights that PDCs' small size (~1-3 kDa) enables deeper tumor penetration and faster clearance, whereas ADCs (~150 kDa) benefit from prolonged circulation but suffer from limited tissue diffusion. This review surveys recent advances in PDC design and application. We discuss key design elements (targeting peptides, cleavable/non-cleavable linkers, and payloads) and how these drive mechanisms of tumor delivery and intracellular drug release. Mechanistically, PDCs bind receptors or translocate across membranes, undergo endocytosis, and exploit stimuli-responsive linkers or cell-penetrating peptides to release drugs. Many PDCs can self-assemble into nanoscale structures in aqueous environments. We illustrate PDC concepts through specific instances, such as the brain-penetrant paclitaxel trevatide (ANG1005, paclitaxel-Angiopep-2), the radiotherapeutic lutetium (¹⁷⁷Lu)-DOTATATE (Lutathera), and the LyP-1-conjugated doxorubicin-loaded liposomes (LyP-1-doxorubicin conjugate) for triple-negative breast cancer. Persistent challenges include in vivo stability (premature drug release and metabolic clearance), tumor heterogeneity (variable receptor expression), and manufacturing scale-up. We also address regulatory hurdles that have limited PDC clinical success; for example, currently, only lutetium (¹⁷⁷Lu)-DOTATATE is FDA-approved (others, like melphalan flufenamide (melflufen), have faced setbacks). Finally, we outline future directions, including theranostic PDCs, AI-assisted peptide optimization, dual-stimuli linkers, and integration with nanomaterials, to further enhance targeting and efficacy. This comprehensive review integrates findings from recent literature and provides an in-depth perspective on the design, advantages, limitations, and future prospects of PDCs in cancer therapy.

Introduction: The genus Vitex L. (Verbenaceae) comprises ~250 species globally, with long-standing ethnopharmacological value. Notably, only Traditional Chinese Medicine (TCM) explicitly applies Vitex negundo for ischemic stroke (documented in classic Materia medica), distinguishing it from other regional uses (eg, menstrual disorders, malaria) and providing a unique basis for anti-stroke research.

Materials and methods: Through systematic searches of English and Chinese databases such as Web of Science, Pubmed, CNKI, and Wanfang Data. This review systematically summarizes the natural constituents of Vitex L. their anti-ischemic stroke efficacy, and underlying mechanisms, emphasizing the uniqueness of Vitex-specific components and guiding preclinical optimization and clinical translation.

Results: Over 200 constituents were identified, with flavonoids (vitexin, isovitexin, casticin), terpenoids (vitexilactone, rotundifuran), and phenols as core active components. High-evidence compounds (validated by both in vitro and in vivo experiments) such as vitexin (10-50 mg/kg) reduced rat MCAO infarct volume by 30-40% via blocking NMDA receptor-mediated Ca²⁺ overload. Mechanistically, components target neurons, glia, and vascular endothelial cells, regulating both classic pathways (Nrf2, NF-κB, PI3K/Akt) and frontier mechanisms (ferroptosis, pyroptosis, epigenetic regulation). Synergistic effects of multi-component mixtures and optimized extraction/synthesis address low-content challenges.

Conclusion: Vitex L. exhibits significant anti-ischemic stroke potential, with unique components and multi-pathway regulation as core advantages. Future research should focus on multi-center validation, synergistic mechanism exploration, and clinical trials of high-evidence components to advance translation.

Kadsura coccinea (Lem). A.C.Sm. has a long history of use in traditional Dong medicine for activating Qi, relieving pain, and dispersing blood stasis. It has garnered increasing attention for treating rheumatoid arthritis (RA), a condition associated with synovial inflammation and tissue damage. K. coccinea L. effects anti-RA by eliminating reactive oxygen species and directly or indirectly inhibiting lipid peroxidation. This review summarizes its potential therapeutic effects on RA through regulating inflammatory cytokines, reducing oxidative stress, and targeting specific cells and pathways, forecasting its future application prospects.

Bixin, a vibrant apocarotenoid derived from the seeds of Bixa orellana Linn. (commonly known as annatto), has been traditionally used as a natural colorant. However, recent advances have unveiled its diverse pharmacological and therapeutic potential, positioning it as a promising candidate in modern drug discovery and delivery systems. This review presents a comprehensive overview of bixin, encompassing its chemical structure, biosynthetic pathways, physicochemical characteristics, extraction techniques and novel nanodrug delivery systems. We critically examine its biological activities, including antioxidant, anti-inflammatory, anticancer, antimicrobial, neuroprotective, hepatoprotective, nephroprotective, and photoprotective effects, supported by mechanistic insights such as activation of the NRF2 pathway, suppression of STAT6 signaling, and modulation of oxidative stress and inflammatory mediators. Despite its wide-ranging bioactivities, the clinical application of bixin remains limited due to challenges related to its solubility, stability, and bioavailability. To address these limitations, innovative formulation strategies, including nanoparticle encapsulation, sustained-release systems, and polymer conjugates have been explored to enhance its pharmacokinetic profile and therapeutic efficacy. Majorly, field of nano-pharmaceutical technologies provides deep insights to overcome physiochemical challenges and enhance the therapeutic potential of bioactive agents. Nowadays, lipid-based nanodrug delivery approaches contribute in an efficient manner. Additionally, its integration into functional foods, cosmeceuticals, and photoprotective applications highlights its interdisciplinary relevance. This review uniquely bridges the gap between traditional knowledge and contemporary pharmaceutical science by consolidating current findings on bixin's pharmacological roles and delivery challenges. It also proposes future directions for translating bixin into a next-generation phytopharmaceutical through advanced formulation, mechanistic validation, and clinical evaluation. Collectively, the evidence positions bixin not merely as a natural colorant, but as a versatile bioactive molecule with significant promise in drug design, development, therapy, and delivery.

Moringa oleifera Lamk. a highly valued multipurpose plant, has gained increasing attention owing to its diverse pharmacological properties, including immunomodulatory, antioxidant, and antidiabetic effects. This narrative review evaluates published human studies and case reports from 2015 to 2025 to assess the efficacy and safety of M. oleifera and the underlying mechanisms of its pharmacological effects. A narrative review was chosen over a systematic review because it is flexible, broad-focused, and interpretive, and thus is suitable for mapping emerging fields. A total of 22 clinical trials and nine case reports met the inclusion criteria. This review focuses on five major clinical themes: immunological and nutritional effects, metabolic and endocrine disorders, inflammatory and oxidative stress-related diseases, maternal and child health outcomes, and other clinical applications. Evidence from human studies indicates consistent improvements in immune function, glycemic control, and antioxidant status, particularly among individuals with HIV infection, prediabetes, and malnutrition. Maternal supplementation also enhances the vitamin A content and nutritional outcomes in infants. Mechanistically, these effects are linked to the immune system (modulation of cytokine activity, activation of AMP-activated protein kinase, and antioxidant activity) and to metabolic pathways (inhibition of α-glucosidase and dipeptidyl peptidase IV). Although it is generally well tolerated, rare hypersensitivity and thrombotic events have been reported. Collectively, M. oleifera shows promising potential as a safe and accessible functional food and a nutraceutical or adjunct therapeutic candidate for immune and metabolic disorders, thus warranting further standardized, large-scale randomized controlled trials to confirm its long-term efficacy and safety.

Background/objectives: Hip osteoarthritis (OA) induces chronic pain and disability in aging populations. Opioids are increasingly prescribed for refractory hip OA pain; however, comparative safety data are limited. This study aimed to compare the psychiatric, cardiovascular and skeletal outcomes between codeine and oxycodone in patients with hip OA.

Methods: A population-based retrospective cohort using Korean Health Insurance Review and Assessment Service (HIRA) claims data was performed in hip OA (M16) patients who initiated codeine or oxycodone. Propensity score matching (PSM) was applied with sensitivity analyses performed using inverse probability of treatment weighting (IPTW). Outcomes included composite psychiatric outcomes (depression, anxiety, bipolar disorder, sleep disorders, and schizophrenia), major adverse cardiovascular outcomes (MACE; myocardial infarction, stroke, cardiovascular death/arrest, heart failure hospitalization), and fractures. Hazard ratios (HR) with 95% confidence intervals (CIs) were estimated using Cox proportional hazard models.

Results: A total of 16,162 patients were included in the cohort after 1:1 PSM. Codeine was associated with a higher risk of psychiatric disorders (HR 1.11, 95% CI 1.04-1.19), particularly anxiety (HR 1.14, 95% CI 1.03-1.26) and sleep disorders (HR 1.15, 95% CI 1.02-1.30). Risks of MACE (HR 1.02, 95% CI 0.92-1.14) and death (HR 1.03, 95% CI 0.92-1.14) were comparable between groups. Codeine was associated with a higher risk of non-femoral fractures (HR 1.10, 95% CI 1.04-1.16). Subgroup analyses revealed differentiated risks across age, sex, comorbidities, and concomitant medications.

Conclusion: Codeine use in patients with hip osteoarthritis was associated with a higher risk of psychiatric disorders and distinct fracture patterns. The observed risks varied according to patient characteristics, comorbidities, and concomitant medications, emphasizing the need for individualized opioid prescribing strategies that incorporate psychiatric monitoring, fracture risk assessment, and patient-specific factors. Further controlled studies integrating clinical, lifestyle, and genetic data are warranted to confirm these findings and refine personalized opioid therapy in hip osteoarthritis.

Purpose: This study aimed to compare the efficacy and safety of ciprofol and propofol for sedation in critically ill patients after cardiac surgery.

Patients and methods: In this prospective, randomized controlled trial, 123 patients undergoing coronary artery bypass grafting (CABG) and/or valve surgery were randomly assigned to receive either ciprofol (Group C) or propofol (Group P) for postoperative sedation in the intensive care unit (ICU). Midazolam was administered if additional sedation was required, and remifentanil was used for analgesia. Sedation and analgesia were titrated to a target Richmond Agitation-Sedation Scale (RASS) score of -2 to +1 and a Critical-Care Pain Observation Tool (CPOT) score < 3. The primary endpoint was the mean sedation compliance rate, defined as the percentage of RASS scores within the target range during the initial 24 hours. Secondary endpoints included safety events, extubation time, length of ICU stay, mortality, delirium incidence, and postoperative recovery.

Results: In the per-protocol (PP) population, sedation compliance was 92.77% (Group C) and 94.30% (Group P). Ciprofol showed non-inferior sedation to propofol in cardiac surgery patients; the lower limit of the one-sided 95% confidence interval (CI) for rate difference (RD) exceeded the -8% non-inferiority margin in both PP and intention-to-treat (ITT) populations. The incidence of hypotension was numerically lower in Group C (31.3% vs 40.7%; P = 0.276), with no significant differences in other safety or secondary outcomes (all P > 0.05).

Conclusion: In summary, ciprofol provides non-inferior sedation efficacy and a comparable safety profile to propofol in critically ill patients following cardiac surgery. A numerical trend toward lower hypotension incidence was observed with ciprofol, which warrants further validation in future studies.

Purpose: Acute myeloid leukemia (AML) remains the most aggressive form of leukemia, underscoring the urgent need for novel treatment strategies. Drug repurposing offers a promising approach to accelerate drug development process. Cardiac glycosides (CGs), traditionally used for heart conditions, have shown potential for AML therapy. As leukemic stem cells (LSCs) are key contributors to AML relapse and chemotherapy resistance, this study aims to elucidate the potential shared mechanisms of proscillaridin (PSN) and ouabain (OUA), two CGs with anti-LSC activity, focusing on their multitarget effects-an emerging strategy in cancer therapy.

Methods: An integrative in silico framework combining network pharmacology, bioinformatics, and molecular docking was employed to elucidate the molecular mechanisms, identify clinically relevant targets, and evaluate the binding potential of PSN and OUA, with predictions were subsequently supported by in vitro validation.

Results: Seventeen shared core targets of PSN-OUA in AML were identified by intersecting compound-predicted targets from SwissTargetPrediction with AML-relevant genes curated from clinical databases. Enrichment analyses using Gene Ontology, KEGG, and CancerGeneNet revealed strong associations of these core targets with key biological pathways involved in aggressive cancer phenotypes, including cell growth, apoptosis, and motility, which were subsequently validated to be affected by CGs in vitro. Protein-protein interaction mapping identified 10 hub targets-MTOR, PTGS2, ALB, ICAM1, SYK, PRKCA, MAPK14, MET, PRKCB, and MAP2K1-that are functionally interconnected and associated with clinical outcomes. Molecular docking and molecular dynamics simulations supported the high-affinity binding of PSN and OUA, particularly to MTOR and PTGS2. Consistently, both compounds suppressed MTOR- and PTGS2-associated downstream signaling in vitro.

Conclusion: Our findings elucidate multiple mechanisms by which CGs may exert anti-LSC activity, which could be crucial for the design of novel therapeutic strategies for AML. The proposed in silico framework is broadly applicable and may accelerate drug repurposing in AML and other cancers.

Background: At present, the median effective dose (ED50) and effective dose for 95% of patients (ED95) of liposomal bupivacaine for local infiltration analgesia following cesarean section have not been established. This study aimed to determine the ED95 of liposomal bupivacaine for local infiltration analgesia in patients following cesarean section.

Methods: A total of 72 primiparas scheduled to undergo lower segment cesarean sections, were randomly divided into four groups: Group 1, Group 2, Group 3, and Group 4, with 18 cases in each group. When suturing to the fascial layer, the four groups received 66.5 mg, 133 mg, 199.5 mg, and 266 mg of liposomal bupivacaine for incision infiltration analgesia, respectively. The pain intensity at coughing was assessed using a visual analog scale (VAS) within 48 hours postoperatively. Effective analgesia was defined as a VAS score of ≤ 3. The ED95 and the 95% confidence interval (CI) of liposomal bupivacaine for local infiltration analgesia after cesarean section were calculated using probit regression analysis.

Results: The ED50 and ED95 of liposomal bupivacaine for local infiltration analgesia following cesarean section were 128.5mg (95% CI, 106.8 to 194.4mg) and 206.1 (95% CI, 178.6 to 262.5mg), respectively.

Conclusion: This study indicated that the ED95 of liposomal bupivacaine for local infiltration analgesia following cesarean section was 206.1 mg (95% CI, 178.6, 262.5 mg). (registration number: ChiCTR2300076315).

Background: Postoperative delirium (POD) is a common complication that hinders recovery in older patients. This study aimed to compare the effects of glycopyrrolate and atropine, used to counteract the peripheral effects of neostigmine, on POD incidence in older patients undergoing laparoscopic colorectal surgery.

Methods: This single-centre, double-blind, randomized controlled trial recruited patients (aged 65-80 years) undergoing laparoscopic colorectal surgery. Patients were randomized to receive either glycopyrrolate (0.04 mg kg^-1 neostigmine and 0.008 mg kg^-1glycopyrrolate) or atropine (0.04 mg kg^-1 neostigmine and 0.016 mg kg^-1 atropine) during emergence from anaesthesia. The primary outcome was the incidence of POD within the first 3 postoperative days, assessed using the 3-minute Diagnostic Interview for Confusion Assessment Method. Secondary outcomes included comparing the hemodynamic effects of glycopyrrolate and atropine and examining POD biomarkers.

Results: Among 121 patients, the glycopyrrolate group had a significantly lower incidence of POD compared with the atropine group (11.7% vs 27.9%; relative risk, 0.42; 95% confidence interval, 0.19-0.94; p = 0.045). Glycopyrrolate better maintained baseline heart rate and mean arterial pressure. No significant differences were observed in plasma levels of neurofilament light chain, neuron-specific enolase, and Tau protein between groups at different time points.

Conclusion: The combination of glycopyrrolate and neostigmine was associated with a lower incidence of POD than atropine in older adults undergoing laparoscopic colorectal surgery.

Registration: Chinese Clinical Trial Registry, ChiCTR2300072798.