Drugs in Research & Development最新文献

{"title":"Optimizing Drug-Resistant Epilepsy Management: Cenobamate's role in the Surgery/Neuromodulation Pathway.","authors":"Giancarlo Di Gennaro, Paolo Bonanni, Francesco Deleo, Antonio Gambardella, Roberto Michelucci, Giada Pauletto, Nicola Specchio, Alfredo D'Aniello","doi":"10.1007/s40268-026-00548-7","DOIUrl":"10.1007/s40268-026-00548-7","url":null,"abstract":"","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"197-201"},"PeriodicalIF":2.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13433652/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148551020","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":"Ustekinumab in the Management of Perianal Fistulizing Crohn's Disease: Current Evidence and Practical Strategies.","authors":"Bolin Yang","doi":"10.1007/s40268-026-00545-w","DOIUrl":"10.1007/s40268-026-00545-w","url":null,"abstract":"<p><p>Perianal fistulizing Crohn's disease (PFCD) is a severe and complex manifestation associated with high morbidity and limited treatment durability. Ustekinumab is a monoclonal antibody targeting the interleukin-12/23 pathway, which is involved in the pathogenesis of PFCD. Evidence from post hoc analyses and real-world studies has shown the therapeutic potential of ustekinumab in both anti-tumor necrosis factor-experienced and selected biologic-naïve patients with PFCD. Preliminary evidence has indicated that the treatment effect may be improved when used in combination with surgical interventions such as seton placement or sphincter-preserving procedures. Adjunctive antibiotics during induction and early monitoring of clinical and radiologic response may further enhance outcomes. While ustekinumab is increasingly being incorporated into multidisciplinary PFCD management, prospective fistula-specific trials are needed to clarify its optimal positioning. Future research should also focus on predictive biomarkers and treatment algorithms to support personalized and durable care.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"141-153"},"PeriodicalIF":2.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13433709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147989717","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":"A Combination of the Tryptophan Hydroxylase Inhibitor Telotristat with the mTOR Inhibitor Everolimus as an Effective Strategy Against Neuroendocrine Tumors.","authors":"Javier Molina-Cerrillo, Arantzazu Sierra-Ramirez, José L López-Aceituno, Marinela Méndez-Pertuz, Teresa Alonso-Gordoa, Michael Linnebacher, Matteo Santoni, Pablo J Fernandez-Marcos, Enrique Grande","doi":"10.1007/s40268-026-00544-x","DOIUrl":"10.1007/s40268-026-00544-x","url":null,"abstract":"<p><strong>Background and objectives: </strong>Neuroendocrine tumors are a rare and heterogeneous group of neoplasms that frequently cause carcinoid syndrome, characterized by diarrhea, flushing, and carcinoid heart disease. A recent therapy for carcinoid syndrome involves inhibition of tryptophan hydroxylase, the rate-limiting enzyme in serotonin synthesis, using telotristat ethyl. Telotristat has demonstrated clinical control of carcinoid syndrome; however, its potential antitumoral effects remain unclear. This study aimed to evaluate the antitumor activity of telotristat ethyl alone and in combination with everolimus in neuroendocrine tumor models.</p><p><strong>Methods: </strong>Cell viability was assessed in three neuroendocrine tumor cell lines of pancreatic (BON-1, QGP-1) and intestinal (HROC57) origin following treatment with telotristat ethyl. Combination treatments with telotristat ethyl and everolimus or other antitumoral agents were evaluated for effects on cell viability, apoptosis, and cell cycle distribution. In vivo efficacy was examined in nude mice bearing BON-1-derived xenografts treated with telotristat ethyl, everolimus, or the combination. Tumor growth, toxicity, proliferation (Ki67), and apoptosis (active caspase-3) were analyzed.</p><p><strong>Results: </strong>Telotristat ethyl reduced cell viability in all three neuroendocrine tumor cell lines. Combination with everolimus, but not with other antitumoral treatments, synergistically decreased cell viability, induced apoptosis, and reduced the proportion of cells in the G2/M phase. In nude mice bearing BON-1 xenografts, combined treatment with telotristat ethyl and everolimus arrested tumor growth without signs of toxicity compared with single treatments. At the end of treatment, tumors from combination-treated mice showed a reduction in proliferation (Ki67) comparable to single-treated groups and an increase in apoptosis as indicated by active caspase-3.</p><p><strong>Conclusions: </strong>Telotristat ethyl exhibits antitumoral activity in neuroendocrine tumor models in vivo. Moreover, the combination of telotristat ethyl and everolimus, two therapies already used in clinical practice, may represent a safe and effective therapeutic strategy for neuroendocrine tumors.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"155-167"},"PeriodicalIF":2.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13433658/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148007264","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":"Gabapentin Extended Release Tablets in Healthy Subjects Under Fed Conditions: A Randomized, Open-Label, Two-Treatment, Two-Period, Two-Sequence, Single Dose, Crossover, Comparative Bioavailability Study.","authors":"Sudershan Kumar, Arshad Khuroo, Sanjay Jagannath Gurule, Sachin Mehra, Hari Krishan Tiwari, Y Zala, Venkata Rama Rao Kamala, Madhu Kandukuri, Shruti Dharmadhikari, Prashant Devkare, Chintan Khandhedia","doi":"10.1007/s40268-026-00547-8","DOIUrl":"10.1007/s40268-026-00547-8","url":null,"abstract":"<p><strong>Background: </strong>Gabapentin is effective for treating post-herpetic neuralgia and neuropathic pain by stabilizing nerve activity through blocking calcium channels and reducing neurotransmitter release. Gabapentin is available in immediate-release (IR) and extended-release (ER) formulations. A comparative bioavailability study was conducted between Gabapentin ER 600 mg tablets once-daily (OD) (Gabantin^® GRS) [Test (T)] (manufactured by Sun Pharmaceuticals Industries Limited), and Gabapentin Tablets 600 mg OD (Gralise^®) [Reference (R)] (distributed by Almatica Pharma LLC) in healthy human male adults under fed conditions.</p><p><strong>Methods: </strong>In this open-label, balanced, randomized, crossover study each subject received a 600 mg single dose of either T or R in Period 1, followed by crossover treatment in Period 2, with a washout period of 12 days in-between. Pharmacokinetic parameters, including C_max, AUC_0-t, and AUC_0₋∞, were assessed. Safety was monitored through treatment-emergent adverse events (AEs).</p><p><strong>Results: </strong>All 24 enrolled subjects completed the study. The test formulation demonstrated comparable pharmacokinetic profile to the reference product, meeting the criteria for bioequivalence within acceptable limits (0.80-1.25). The percentage ratio for T vs R product was 0.9171 (90% confidence interval [CI] 0.826-1.0183) for AUC_0-t, 0.9191 (90%CI 0.8279-1.0203) for AUC_0-∞ and 0.9135 (90%CI 0.8324-1.0026) for C_max. Plasma concentration-time profiles were similar. One AE of fever was reported after administration of T; no serious adverse event was reported.</p><p><strong>Conclusions: </strong>Gabantin^® GRS 600 Tablet ER OD of Sun Pharma had a similar pharmacokinetic profile and was bioequivalent to Gralise^® in healthy subjects under fed conditions with good safety and tolerability profiles.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"187-196"},"PeriodicalIF":2.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13433685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148370638","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":"Development and Optimization of a Biphasic-Release Acetazolamide Tablet-in-Tablet Formulation.","authors":"Si-Kai Wang, Wei Li, Miao-Miao Guo, Man Han, Ze-Chun Long, Jin-Hui He, Xiang-Yang Xie, Yuan Zeng, Hui Liu","doi":"10.1007/s40268-026-00546-9","DOIUrl":"10.1007/s40268-026-00546-9","url":null,"abstract":"<p><strong>Background and objective: </strong>High-altitude illness (HAI) poses health risks to individuals at high altitudes, and acetazolamide (ACZ) is the only Food and Drug Administration (FDA)-approved prophylactic drug. Conventional immediate-release (IR) tablets and extended-release (ER) capsules do not simultaneously provide early drug availability and prolonged coverage. This study aimed to develop a biphasic-release ACZ tablet-in-tablet (ACZ-TIT) formulation as a proof-of-concept oral dosage form integrating IR and ER.</p><p><strong>Methods: </strong>ACZ-excipient compatibility was assessed using Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD), and solubility was evaluated in physiologically relevant media. Formulation optimization was performed via single-factor studies and response surface methodology (RSM). Quality control included weight, hardness, friability, content, and related substances. In vitro dissolution studies were conducted, and drug release kinetics were analyzed using multiple models.</p><p><strong>Results: </strong>No new incompatibility signals were observed between ACZ and the selected excipients, and only small solubility differences were found across the tested media. ACZ-TIT showed a biphasic-release profile, with 25.3% drug release at 0.5 h and 86.5% at 10 h. Physical properties were within pharmacopeial limits (weight variation ≤ 2.65%, hardness 112.0 ± 21.2 N, friability 0.18%, and assay relative standard deviation < 1.2%), and the related substances were found to be within the specified limits. Release kinetics were best described by the Ritger-Peppas model (R² = 0.993), supporting diffusion-dominated ER.</p><p><strong>Conclusion: </strong>ACZ-TIT may provide rapid initial release followed by sustained exposure, which could help address limitations of currently available ACZ dosage forms. In vivo pharmacokinetic and clinical studies are still required to establish clinical applicability.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"169-186"},"PeriodicalIF":2.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13433672/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148206825","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":"The Influence of Renal or Hepatic Impairment on the Pharmacokinetics of Iclepertin (BI 425809): Results from Two Phase I Open-Label, Non-randomised, Single Dose, Parallel Design Studies.","authors":"HeeJae Choi, Shilpa Madari, Elmar Daalman, Brett A English, Atef Halabi, Kathrin Hohl, Yury Shatillo, Nathalie Weidinger, Michael Desch","doi":"10.1007/s40268-026-00537-w","DOIUrl":"10.1007/s40268-026-00537-w","url":null,"abstract":"<p><strong>Background and objectives: </strong>Iclepertin, a selective GlyT1 inhibitor undergoes metabolism mainly via hepatic CYP3A4, with only a small fraction undergoing urinary excretion. Patients with kidney or liver problems can have reduced CYP3A4 levels or activity, which may affect the levels of iclepertin in the blood and, in turn, its safety. Here, we present the results of two studies investigating the safety and pharmacokinetics of iclepertin in participants with various degrees of renal or hepatic impairment.</p><p><strong>Methods: </strong>In these two phase I, open-label, non-randomised, parallel studies, a single oral dose of iclepertin 10 mg was administered to participants with mild, moderate or severe renal impairment or mild or moderate hepatic impairment, together with healthy matched participants (based on age, sex, weight and race [only for renal impairment]; n = 8 for each impairment group. Primary and secondary endpoints included maximum plasma concentration (C_max) and exposure metrics (area under the concentration-time curve [AUC]) of iclepertin. Safety was also assessed (adverse events [AEs]).</p><p><strong>Results: </strong>In the renal impairment study (N = 36), exposure of iclepertin was minimally affected by renal impairment across trial groups except for the severe renal impairment group, which showed increased iclepertin exposure (AUC_0-tz and AUC_0-∞ geometric mean ratio impaired versus matched participants [90% CI]: 126.1% [104.1, 152.8] and 146.0% [109.9, 193.9]), but similar C_max. In the hepatic impairment study (N = 29), participants with mild hepatic impairment showed similar C_max of iclepertin and exposure parameters to matched participants (geometric mean ratio [90% CI]: 102.1% [82.4, 126.4]), whereas participants with moderate hepatic impairment showed reduced C_max (geometric mean ratio impaired versus matched participants [90% CI]: 81.9% [67.2, 99.7]) and increased AUC_0-tz and AUC_0-∞ (128.7% [104.0, 159.3] and 157.2% [119.1, 207.5], respectively. Headache was the only drug-related AE reported in > 1 participant in each study, which was resolved within the treatment period, and no severe AEs were reported.</p><p><strong>Conclusions: </strong>These findings indicate that although some increased exposure to iclepertin is expected in patients with severe renal impairment or moderate hepatic impairment, iclepertin 10 mg demonstrated a favourable safety profile, was well-tolerated, and can be administered in patients with varying degrees of renal or hepatic impairment without dose modification.</p><p><strong>Study registration: </strong>ClinicalTrials.gov (NCT05718843, NCT05731895).</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"83-100"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13076746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147576533","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":"Treatment Outcomes with Lanadelumab Every 2 Weeks and Garadacimab are Very Similar in Patients with Hereditary Angioedema.","authors":"Irmgard Andresen, Natalie Khutoryansky, Sarah L Feeny, Alissa Dangel","doi":"10.1007/s40268-026-00539-8","DOIUrl":"10.1007/s40268-026-00539-8","url":null,"abstract":"","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"31-33"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13076730/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147576479","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":"Updated Viloxazine Pharmacology: Experiments Establish Norepinephrine Transporter Occupancy and Serotonin 5-HT_2C, 5-HT_2B, and 5-HT₇ Receptor Binding at Therapeutically Relevant Concentrations.","authors":"Jennie Garcia-Olivares, Brittney Yegla, Jennifer Koch, Chungping Yu, Jonathan Rubin","doi":"10.1007/s40268-026-00543-y","DOIUrl":"10.1007/s40268-026-00543-y","url":null,"abstract":"<p><strong>Background and objectives: </strong>Viloxazine, which has been used to treat depression and attention-deficit/hyperactivity disorder (ADHD), has been termed a moderate-affinity, selective norepinephrine reuptake inhibitor based on high selectivity for norepinephrine relative to serotonin and dopamine transporters. However, accumulated research suggests a more complex mechanism of action, based on studies showing activity at serotonin 5-HT_2C, 5-HT_2B, and 5-HT₇ receptors, as well as findings that viloxazine increases extracellular serotonin (along with norepinephrine and dopamine) in the rat prefrontal cortex. This in vitro pharmacology study aimed to replicate and expand prior experiments to better characterize viloxazine's affinity for and activity at the norepinephrine transporter (NET) and individual serotonin receptors and to clarify how these effects contribute to the mechanism of action.</p><p><strong>Methods: </strong>Using in vitro binding competition and functional assays and ex vivo receptor occupancy studies in rats, we assessed viloxazine activity at human NET isoforms and 5-HT_2C, 5-HT_2B, and 5-HT₇ receptors relative to clinically relevant unbound viloxazine plasma concentrations (0.4-3.6 μM).</p><p><strong>Results: </strong>Viloxazine showed moderate binding affinity for NET (inhibition constant [K_i] = 0.13 µM) and 5-HT_2C (K_i = 0.66 µM), 5-HT_2B (K_i = 0.83 µM), and 5-HT₇ (K_i = 1.90 µM) receptors. In vitro functional studies showed viloxazine acted as a NET inhibitor, 5-HT_2C partial agonist, and 5-HT_2B and 5-HT₇ antagonist. At clinically relevant concentrations, viloxazine could potentially occupy nearly 95% of NET, more than 80% of 5-HT_2C and 5-HT_2B, and 65% of 5-HT₇ receptors. Subsequent ex vivo studies in rats confirmed high NET occupancy (67-94%) at clinically relevant concentrations.</p><p><strong>Conclusions: </strong>These results validate previous experiments showing that viloxazine, in addition to displaying high NET occupancy, acts as a partial agonist at 5-HT_2C receptors and an antagonist at 5-HT_2B and 5-HT₇ receptors at clinically relevant concentrations for ADHD treatment. Therefore, both NET inhibition and serotonin receptor activity may contribute to viloxazine's clinical efficacy. These findings are contributing to a renewed understanding of viloxazine's pharmacodynamic profile and likely multimodal mechanism of action.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"129-139"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13076852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147610332","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":"HIF-1α siRNA Enhances the Efficacy of Erlotinib in Non-small Cell Lung Cancer: A Novel Strategy to Reverse Hypoxia-Induced Drug Resistance.","authors":"Haojie Jiang, Shunhui Cai, Xiaojun Zhang, Shijie Chen, Chunyan Yue, Wu Yin, Yiqiao Hu","doi":"10.1007/s40268-025-00534-5","DOIUrl":"10.1007/s40268-025-00534-5","url":null,"abstract":"<p><strong>Background: </strong>Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality. While EGFR tyrosine kinase inhibitors (EGFR-TKIs) have improved survival, acquired resistance mediated by tumor hypoxia and HIF-1α stabilization often leads to treatment failure. This study investigated the regulatory role of HIF-1α in NSCLC drug resistance and evaluated a combined therapeutic strategy to overcome EGFR-TKI resistance.</p><p><strong>Methods: </strong>HIF-1α expression and downstream targets were assessed in H1975 and A549 cell lines using RT-qPCR and Western blot. Functional assays, including cell proliferation, apoptosis, invasion, lactate production, and ROS measurements, were performed following HIF-1α siRNA transfection and/or erlotinib treatment. Bioinformatics analyses of public datasets evaluated clinical relevance and pathway enrichment.</p><p><strong>Results: </strong>HIF-1α knockdown inhibited glycolysis, reduced lactate production, and alleviated hypoxia-induced oxidative stress. Combined treatment with HIF-1α siRNA and erlotinib synergistically suppressed cell proliferation, induced apoptosis, and inhibited invasion more effectively than single-agent treatments. Mechanistically, EGFR signaling positively regulated HIF-1α stability via the PI3K/AKT and MEK/ERK pathways. Bioinformatics confirmed that high HIF-1α expression correlates with poor prognosis in NSCLC patients.</p><p><strong>Conclusion: </strong>Targeting HIF-1α disrupts metabolic reprogramming and hypoxia adaptation, thereby enhancing erlotinib efficacy. This combined approach highlights the therapeutic potential of HIF-1α inhibition as a novel strategy to overcome EGFR-TKI resistance in NSCLC.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"101-115"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13076752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147610403","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":"Advanced Drug Delivery Strategies for Overcoming Biological Barriers: Tumor Microenvironment and Blood-Brain Barrier.","authors":"Yicong Lei, Tingyu Xiao, Xin Hu, Huaqing Lin","doi":"10.1007/s40268-026-00538-9","DOIUrl":"10.1007/s40268-026-00538-9","url":null,"abstract":"<p><p>Therapeutic efficacy for malignancies and neurological disorders is fundamentally restricted by biological barriers, particularly the complex tumor microenvironment (TME) and selective blood-brain barrier (BBB). This review analyzes advanced drug delivery technologies engineered to overcome these obstacles. For TME penetration, stimuli-responsive nanocarriers enable spatiotemporally controlled drug release, while tumor-penetrating peptide functionalized nanoparticles enhance deep tumor diffusion; metal-organic frameworks further facilitate combinatorial therapy via microenvironment-triggered payload release. Regarding BBB transcendence, receptor-mediated transcytosis strategies significantly improve brain uptake, and physical-assisted approaches achieve localized barrier modulation. Bioinspired platforms-notably cell-membrane-coated nanoparticles and exosomes-demonstrate superior immune evasion and tissue-specific accumulation. Despite promising clinical progress exemplified by ANG1005 and focused ultrasound-assisted liposomal doxorubicin, translation challenges persist, including TME heterogeneity, scalable manufacturing complexities, and long-term biosafety. Future development prioritizes multifunctional theranostic systems integrating barrier-remodeling agents, artificial intelligence (AI)-optimized nanocarrier design, and sustainable manufacturing processes. Collectively, these innovations are transforming advanced drug delivery into a core therapeutic paradigm for intractable diseases.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"1-30"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13076871/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147327964","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}