Drug Development Research最新文献

{"title":"Benzyl-Functionalised Imidazolium Ionic Liquids as Lead Candidates Against Human Breast Cancer: An Integrated In Vitro and In Silico Screening Approach","authors":"Boon-Keat Khor,&nbsp;Jia En Lau,&nbsp;Fatini Syazana Sharul Azman,&nbsp;Eng Poh Ng,&nbsp;Vikneswaran Murugaiyah,&nbsp;Nelson Jeng-Yeou Chear,&nbsp;WanSinn Yam","doi":"10.1002/ddr.70194","DOIUrl":"10.1002/ddr.70194","url":null,"abstract":"<div>\u0000 \u0000 <p>The unique physicochemical and structural flexibility of ionic liquids (ILs) allows for fine modulation of biological activity, thus offering potential as the next-generation anticancer lead compounds with improved selectivity and efficacy. In this study, a new series of benzyl functionalised imidazolium ILs with varying <i>para</i> substituents (R = H, CH₃, F, Cl, Br, NO₂, CN) is reported. Their cytotoxicity against human neuroblastoma (SHSY-5Y), estrogen-positive breast cancer cells (MCF-7), neuroblastoma (SHSY-5Y), lung carcinoma (A549), liver cancer cells (HepG2), colorectal adenocarcinoma (HT-29), and mouse embryonic fibroblasts (NIH 3T3) was evaluated. The ILs were cytotoxic against all tested cell lines but were generally more selective toward MCF-7. ILs bearing H, CH₃, F, Cl, and Br exhibited similar growth inhibition strength against MCF-7 (IC₅₀ ranged between 3.99 and 5.20 µM) that was superior to that of tamoxifen (IC₅₀ = 15.41 µM). However, the presence of NO₂ (IC₅₀ = 8.10 µM) and CN (IC₅₀ = 17.52 µM) significantly reduced their growth inhibition potentials (two- to four-fold) in NIH 3T3 (IC₅₀ &gt; 40 µM). The NO₂-containing IL had a broad safety window against MCF-7 (selectivity index &gt; 4). All the ILs have high drug-likeness (complied with all criteria stated in Lipinski's rule of five and Veber's rule). The most selective IL against MCF-7 (R = NO₂) induced caspase-dependent but reactive oxygen species independent pro-apoptosis in MCF-7 cells. Substituent modifications in the benzyl group regulated cytotoxicity and selectivity, thus reinforcing ILs as a valuable platform for the development of a new class of effective anticancer lead compounds.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 8","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145596251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Screening Natural Phenolic Compounds for Blood-Brain Barrier Permeability, Alongside GSK-3β, CK-1δ, and AChE Inhibition, for the Treatment of Alzheimer's Disease","authors":"Perihan Gürbüz,&nbsp;Şengül Dilem Doğan,&nbsp;Miyase Gözde Gündüz,&nbsp;Loreto Martínez-González,&nbsp;Concepción Pérez,&nbsp;Ana Martinez","doi":"10.1002/ddr.70193","DOIUrl":"10.1002/ddr.70193","url":null,"abstract":"<div>\u0000 \u0000 <p>Alzheimer's Disease (AD) is a neurological disorder characterized by progressive cognitive impairment and memory loss. In vitro artificial membrane permeability assays targeting the blood-brain barrier (BBB), such as the parallel artificial membrane permeability assay (PAMPA), are useful for pre-evaluating the BBB penetration of molecules during the early stages of drug development. Inhibitors of glycogen synthase kinase-3<i>β</i> (GSK-3<i>β</i>), casein kinase-1<i>δ</i> (CK-1<i>δ</i>), and acetylcholinesterase (AChE) exhibit neuroprotective effects, indicating a potential therapeutic approach for AD. This study aimed to assess the ability of 23 phenolic compounds derived from natural sources to penetrate the central nervous system (CNS) and examine their potential neuroprotective effects. Following the prediction of BBB penetration of the compounds by PAMPA, neuroprotective effects of CNS+ compounds were evaluated through in vitro inhibition of GSK-3<i>β</i>, CK-1<i>δ</i>, and AChE. Based on the data obtained, five flavonoids (hispidulin, nepetin, platanoside, apigenin, and kaempferol) and two furanocoumarins (isopimpinellin and bergapten) were predicted to penetrate the CNS. Apigenin (<b>API</b>) and kaempferol (<b>KEM</b>) exhibited the most potent dual inhibitory activity against CK-1<i>δ</i> and GSK-3<i>β</i>. Furthermore, <b>API</b> and <b>KEM</b> did not exhibit cytotoxic effects in SH-SY5Y cells. Molecular modeling studies, including molecular docking, molecular dynamics simulations, and dynophore analysis, were performed to understand the binding mechanism of these most potent compounds to their target enzymes. Overall, the current study offers a rational approach to designing new molecules inspired by natural compounds to treat Alzheimer's Disease.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 8","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145586359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic Potential of Trolox and Its Synthetic Derivatives as Multifunctional Bioactive Molecules in Periodontal Disease Management","authors":"Mohammad Amin Valipour,&nbsp;Elaheh Abdollahi,&nbsp;Abbas Yadegar,&nbsp;Hamed Morad,&nbsp;Mohammad Sheibani,&nbsp;Maryam Noori,&nbsp;Mehdi Valipour","doi":"10.1002/ddr.70200","DOIUrl":"10.1002/ddr.70200","url":null,"abstract":"<div>\u0000 \u0000 <p>Periodontal disease is a chronic inflammatory problem that has destructive effects on the tooth-supporting tissues. This disease affects a large portion of the population, influencing overall health and quality of life, and significant socioeconomic burden. Therefore, efforts to more effectively manage the problems caused by this disease are a necessity. This review describes the therapeutic potential of Trolox (a water-soluble analogue of vitamin E) and its modified derivatives as potential candidates for managing periodontal disease, highlighting their multifaceted pharmacological properties. Unlike the lipophilic molecule vitamin E, Trolox can be formulated into aqueous solutions, gels, mouthwashes, or rinses, ensuring optimal bioavailability at sites of inflammation and infection in the oral cavity. This compound can also help treat periodontal disease by combating oxidative stress, where its antioxidant properties neutralize harmful reactive oxygen species (ROS), reducing tissue damage and bone loss caused by undesired conditions such as bacterial imbalance. In addition to antioxidant and anti-inflammatory properties, Trolox and its derivatives exhibit various pharmacological activities against diabetes, Alzheimer's disease, <i>Plasmodium falciparum</i> malaria infection, and periodontopathogens, all of which are associated with the development of periodontal disease. In conclusion, this review suggests that Trolox and some of its derivatives with favorable activity/toxicity profiles have significant potential to be considered as new drug candidates for combating periodontal diseases.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 8","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145563009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lysosome-Mediated Targeted Protein Degradation: Emerging Chimeric Platforms for Extracellular and Intracellular Therapeutics","authors":"Shayan Asadi,&nbsp;Mina Taheri-Torbati,&nbsp;Prashant Kesharwani,&nbsp;Amirhossein Sahebkar","doi":"10.1002/ddr.70197","DOIUrl":"10.1002/ddr.70197","url":null,"abstract":"<div>\u0000 \u0000 <p>Targeted protein degradation (TPD) is an emerging drug discovery approach aimed at enabling the selective removal of disease-associated proteins. While proteolysis-targeting chimeras (PROTACs) have advanced intracellular degradation via the ubiquitin–proteasome system, their limitation to cytosolic proteins excludes ~40% of the human proteome that is extracellular or membrane-bound. Lysosome-targeting chimeras (LYTACs) address this gap by harnessing lysosomal trafficking receptors, thereby mediating the degradation of extracellular and membrane proteins. More recently, methylarginine-targeting chimeras (MrTACs) have extended lysosomal strategies to certain intracellular targets, bypassing proteasomal dependence. This review critically examines the mechanistic underpinnings, design strategies, and bioanalytical challenges associated with lysosome-mediated degradation platforms. Emphasis is placed on their therapeutic implications, analytical evaluation, and potential for expanding druggable targets. Together, these emerging lysosomal chimeras offer a paradigm shift in TPD, with far-reaching applications in precision medicine and chemical biology.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 8","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145563033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Decade of Mitochondria-Targeting Drugs in Cancer Treatment: Case Review on Mitochondria-Targeting Curcumin or Mitocurcumin","authors":"Rahul Shah,&nbsp;Ryan Varghese,&nbsp;Harsh Anchan,&nbsp;Sanidhya Pai,&nbsp;Tanmay Zagade,&nbsp;Mitul Oswal,&nbsp;Sparsh Agarwal,&nbsp;Purab Sood,&nbsp;Gargi Digholkar,&nbsp;Abha Deshpande,&nbsp;Ravi Vamsi Peri,&nbsp;Pooja Tiwary,&nbsp;Krishil Oswal,&nbsp;Rohit Sharma","doi":"10.1002/ddr.70188","DOIUrl":"10.1002/ddr.70188","url":null,"abstract":"<div>\u0000 \u0000 <p>Mitochondrial targeting is of particular interest to researchers, as it presents as a personalized medicine approach in cancer cell metabolism and survival. By specifically targeting mitochondria, targeted therapies can disrupt energy production, induce apoptosis, and overcome drug resistance in cancer cells, potentially improving therapeutic outcomes. This review discusses the advancements in mitochondrial drug delivery over the last decade. It explores the potential of mitochondrial targeting using mitocurcumin (MTC), a novel small molecule curcumin analog that has been engineered to specifically target mitochondria in cancer cells, thereby augmenting its therapeutic efficacy. The antiproliferative activity of MTC demonstrates its ability to induce reactive oxygen species (ROS) production and promote oxidative stress-mediated apoptosis, oxidative damage, and cellular senescence in diverse cancer cell lines, thereby enhancing its specificity for cancer cells. Despite these encouraging attributes, current research on MTC remains limited. Further comprehensive investigations are imperative to fully elucidate the efficacy and potential applications of mitochondrial targeting, especially MTC, in oncological therapeutics, including in vivo efficacy trials, pharmacokinetic profiling, toxicology studies, and combination therapy assessments. Although mitochondrial targeting presents a promising avenue for cancer therapy, rigorous scientific inquiry is essential to validate its clinical potential and optimize its therapeutic application for improved patient compliance.</p></div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 8","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145562993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug Design and Delivery for Intracellular Bacteria: Emerging Paradigms","authors":"Babatunde Ibrahim Olowu,&nbsp;Maryam Ebunoluwa Zakariya,&nbsp;Abdulmuheez Abiola Abdulkareem,&nbsp;Olalekan Toheeb Okewale,&nbsp;Muhammad Halima Idris,&nbsp;Halimah Oluwayemisi Olayiwola","doi":"10.1002/ddr.70198","DOIUrl":"10.1002/ddr.70198","url":null,"abstract":"<p>Intracellular bacteria exploit host cell niches, such as lysosomes, phagosomes, cytosol, entire cells, and even erythrocytes, to evade immune clearance and escape conventional antibiotics. These environments pose numerous therapeutic challenges, including crossing host cell membranes, navigating endosomal trafficking, tolerating acidic and redox conditions, bypassing efflux mechanisms, and countering phenotypic tolerance. Although recent advancements in nanotechnology—such as carriers, prodrugs, and host-directed therapies—offer promising solutions, current strategies remain narrowly focused on “getting the drug inside the cell”, leaving therapeutic agents vulnerable to off-site targeting, degradation, and functional failure. This review introduces a next-generation approach for intracellular antibacterial therapy, incorporating subcellular targeting, dual-function delivery systems, innovative biomimetic carriers, precise intracellular pharmacokinetics/pharmacodynamics (PK/PD) assessment, and artificial intelligence-assisted drug design. Highlighting frameworks for multimodal regimens targeting intracellular bacteria, we advocate a transition from solely facilitating cellular entry to achieving precise spatiotemporal regulation of drug activity within infected host cells. This paradigm informs the development of therapeutics designed to persist within the intracellular bacterial niche, minimizing relapse and reducing the emergence of antimicrobial resistance.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 8","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.70198","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145556360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From Sulfa Drugs to New Antibacterial Agents: Advances in Chemical Modification of Approved Sulfonamides","authors":"Ayşe Karagüzel,&nbsp;Ebru Koçak Aslan,&nbsp;Miyase Gözde Gündüz","doi":"10.1002/ddr.70191","DOIUrl":"10.1002/ddr.70191","url":null,"abstract":"<div>\u0000 \u0000 <p>Sulfonamides, the oldest synthetic antibacterial agents, specifically target the enzyme dihydropteroate synthase (DHPS), which is essential for the folic acid biosynthesis pathway. In contrast, humans do not use this mechanism as they produce no endogenous folic acid and therefore lack the DHPS enzyme. Despite this unique mechanism and selective action against bacteria, their crucial role in fighting bacterial infections has been diminished by the rise of resistance and allergies to sulfa drugs. To overcome these factors that restrict the application of antibacterial sulfonamides, molecular modification of approved sulfa drugs, such as sulfanilamide, sulfathiazole, and sulfadiazine, appears to be a promising strategy for drug design. This review, for the first time, focuses on the molecular modifications directly performed on sulfa drugs to develop new antibacterial agents that address the resistance and safety problems associated with clinical sulfonamides. These modifications involve the conjugation of commercial sulfa drugs with various heterocycles (triazole, thiazole, thiophene, etc.), functional groups (hydrazone, Schiff base, azo dye, urea/thiourea), phytochemicals (thymol, eugenol, etc.), and drug molecules, leading to new antibacterial candidates and insights into their structure–activity relationships. Given the growing global threat of antibiotic resistance, this review may help restore the importance of traditional sulfa drugs in treating bacterial infections through effective chemical modifications.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 8","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145556439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploration Novel of Pyrazole and Isoxazole Derivatives as Potential Antimicrobial Agents: Design, Synthesis, Structure Activity Relationship Study, and Antibiofilm Activity With Molecular Docking Simulation","authors":"Khadija E. Saadon,&nbsp;Ahmed Ragab,&nbsp;Nadia M. H. Taha,&nbsp;N. A. Mahmoud,&nbsp;Ali Kh. Khalil,&nbsp;Gameel A. M. Elhagali","doi":"10.1002/ddr.70189","DOIUrl":"https://doi.org/10.1002/ddr.70189","url":null,"abstract":"<div>\u0000 \u0000 <p>Developing new antimicrobial drugs is crucial for combating global drug resistance caused by microbial infections. Here, a new series of pyrazole and isoxazole derivatives were synthesized using a multicomponent reaction based on ethylvanillin and active methylene group as well as binucleophile reagents under basic conditions. The designed derivatives were confirmed using FT-IR, ¹H NMR, ¹³C NMR, Mass spectrum, and elemental analysis. Subsequently, all the designed derivatives were evaluated against four bacterial and one fungal strain. The synthesized derivatives demonstrated significant to good antimicrobial activity with low MIC values against the tested strains, especially against <i>Bacillus subtilis</i>, <i>Staphylococcus aureus</i>, and <i>Candida albicans</i>. Notably, four compounds <b>14</b>, <b>17</b>, <b>20</b>, and <b>24</b> showed promising MIC values ranging from 7.8 to 62.5 µg/mL) against gram-positive strains and for gram-negative strains (MIC = 31.25–125 µg/mL), compared to gentamycin (15.62 and 31.25 µg/mL), respectively. In addition, these derivatives revealed MIC values from 15.62 to 31.25 µg/mL compared to fluconazole (MIC = 15.62 µg/mL) against <i>C. albicans</i>. Additionally, the structure activity relationships (SAR) were discussed. Moreover, the MBC and MFC values were evaluated and the results exhibited bactericidal and fungicidal properties, except for 5-hydroxy-1<i>H</i>-pyrazole-1-carbothioamide derivative <b>14</b> that demonstrated bacteriostatic activity against <i>B. subtilis</i>. Moreover, the biofilm inhibitory activity of the most promising derivatives demonstrated a dose-dependent effect and inhibit biofilm formation from 96.17 ± 0.004% to 66.04 ± 0.004%. Among these compounds, the 5-hydroxy-1<i>H</i>-pyrazole-1-carbothioamide derivative <b>14</b> emerged as the most active, exhibiting a biofilm inhibitory percentage (BIP) of 96.17 ± 0.004% compared to gentamicin's BIP of 96.44 ± 0.004% at 75% MIC. Finally, a docking simulation of the most promising derivatives was conducted within the active site of Las R, suggesting a potential mode of action, where these derivatives displayed different binding interaction with low binding affinity. Moreover, in-silico oral bioavailability and toxicity profile was predicted for the most promising derivatives and exhibited promising physicochemical properties with a safe toxicity profile, opening up the possibility of the discovery of new antibiotics.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 8","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145533580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leveraging the Fragment Merging Approach for Synthetizing Novel Selanyl Phenyl Acetamide Thiazolidinedione Hybrids Endowed With Apoptotic Potential for Cancer Treatment","authors":"Saad Shaaban,&nbsp;Ayman Abo Elmaaty,&nbsp;Aya Yaseen Mahmood Alabdali,&nbsp;Hussein Ba-Ghazal,&nbsp;Marwa Sharaky,&nbsp;Mohamed Alaa Mohamed,&nbsp;Mai A. E. Mourad,&nbsp;Mohamed Alaasar,&nbsp;Fatema Suliman Alatawi,&nbsp;Tarek A. Yousef,&nbsp;Arwa Omar Al Khatib,&nbsp;Ahmed A. Al-Karmalawy","doi":"10.1002/ddr.70190","DOIUrl":"https://doi.org/10.1002/ddr.70190","url":null,"abstract":"<div>\u0000 \u0000 <p>Designing novel selenium-containing compounds (organoselenium compounds, OSe) has shown growing interest owing to their chemoprotective and antioxidant properties. Consequently, by harnessing a fragment merging approach, a series of novel OSe hybrid compounds bearing selanyl phenyl acetamide and thiazolidinedione scaffolds were designed and synthesized (<b>8–10</b>, <b>11a–c</b>, <b>12a–c</b>, <b>13a–c</b>, and <b>14</b>). The growth inhibition percentages (GI%) of the newly afforded OSe were evaluated using seven human cancer cells along with one normal cell line to ensure selectivity and safety. Interestingly, it was revealed that compound <b>9</b> exhibited the best mean GI% (75.54%), surpassing the doxorubicin (Dox) mean GI% of 72.28%. In addition, the inhibitory concentration 50 (IC₅₀) values of the frontier compounds <b>9</b>, <b>13a</b>, <b>13c</b>, <b>12b</b>, and <b>12c</b> were assessed against cancer cell lines PC3, MCF7, and HCT₁₁₆. Compound <b>13c</b> displayed the lowest IC₅₀ value (5.195 µM) at the PC3 cancer cell line, surpassing doxorubicin (8.065 µM). Besides, compounds <b>9</b> and <b>12c</b> revealed the lowest IC₅₀ values (21.045 and 13.575 µM) against MCF7 and HCT₁₁₆, respectively. Moreover, analogues <b>9</b> and <b>13c</b> were chosen to examine their ability to induce apoptosis and showed the upregulation of proapoptotic proteins: Caspases (3, 7, and 9) and BAX, besides the downregulation of the antiapoptotic BCL2, MMP2, and MMP9 proteins. Furthermore, <i>in silico</i> molecular docking studies targeting BCL-2, along with ADMET analyses, were performed. The results indicated that the tested compounds demonstrated favourable binding affinity to the selected target and exhibited acceptable pharmacokinetic properties. Consequently, these compounds can be considered promising lead candidates for inducing apoptosis in cancer cells, warranting further optimization.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 8","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145533582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enzyme Responsive Magnetic Nanoparticles for Targeted Drug Delivery and Precision Medicine","authors":"Zhenchen Du,&nbsp;Ebraheem Abdu Musad Saleh,&nbsp;M. M.Moharam,&nbsp;Safia Obaidur Rab,&nbsp;Suhas Ballal,&nbsp;Abhayveer Singh,&nbsp;A. Sabarivani,&nbsp;Samir Sahoo,&nbsp;Chou-Yi Hsu","doi":"10.1002/ddr.70185","DOIUrl":"10.1002/ddr.70185","url":null,"abstract":"<div>\u0000 \u0000 <p>Enzyme-responsive magnetic nanoparticles (MNPs) represent an emerging class of multifunctional drug delivery systems that combine spatial precision with biochemical selectivity. By integrating magnetic guidance with enzyme-triggered activation, these nanocarriers address a critical limitation of conventional chemotherapy, namely the lack of specificity that often leads to systemic toxicity and reduced therapeutic efficacy. Enzymes such as proteases, phospholipases, and oxidoreductases are frequently dysregulated in pathological tissues, providing endogenous signals that can be harnessed for site-specific drug release. Enzyme-responsive MNPs exploit these biochemical signatures by incorporating cleavable linkers, enzyme-sensitive coatings, or catalytic cascades, ensuring that therapeutic payloads are released selectively in tumor microenvironments, inflamed regions, or infection sites. Advances in nanoparticle synthesis have further enabled fine-tuning of magnetic cores, polymer shells, and functionalized surfaces, thereby enhancing stability, drug loading capacity, and responsiveness. Preclinical studies demonstrate substantial benefits, including enhanced tumor accumulation, alleviation of hypoxia, improved drug penetration through stromal barriers, and reduction of off-target toxicity. Applications extend beyond oncology to infectious diseases, where pathogen-derived enzymes activate antibiotic release, and to metabolic disorders, where glucose oxidase-based systems regulate insulin delivery. Despite these promising outcomes, translation to clinical practice is constrained by manufacturing challenges, variable enzyme expression, limited in vivo data, and stringent regulatory requirements. This review critically examines the principles, design strategies, release mechanisms, and biomedical applications of enzyme-responsive MNPs, while highlighting unresolved barriers and future directions. Ultimately, enzyme-responsive MNPs exemplify the potential of precision nanomedicine, offering a platform for highly adaptable, multimodal, and patient-tailored therapeutic interventions.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 7","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145481074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}