Molecular Pharmaceutics最新文献

{"title":"Iron Boride Nanostructures as Oral Acid-Responsive Hydrogen Donors for Alzheimer’s Disease Therapy","authors":"Zetao Chen,&nbsp;Danyang Chen,&nbsp;Junjie Zhang,&nbsp;Chao Wang,&nbsp;Jiaji Liu,&nbsp;Yonglin Liang,&nbsp;Qianjun He,&nbsp;Xiubo Du","doi":"10.1021/acs.molpharmaceut.6c00223","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.6c00223","url":null,"abstract":"<p>Alzheimer’s disease (AD) is a progressive neurodegenerative condition with complex causes. Despite extensive research, effective disease-modifying treatment options remain limited. Recent studies have indicated that hydrogen molecule (H₂) possesses therapeutic potential for AD, and it is of vital importance to enhance the bioavailability of H₂ in the gastrointestinal tract based on the gut−brain axis. In this work, we develop iron boride nanostructures (FBN) as a novel acid-responsive hydrogen-releasing material with a high hydrogen release capacity to enhance the H₂ delivery efficacy towards the gastrointestinal tract for AD treatment. In male 5×FAD and 3×Tg-AD mice, oral FBN administration generated H₂ under gastric conditions and was associated with AD-like behavioral and pathological improvements, including improved learning and memory and attenuation of neuronal and synaptic damage. FBN treatment was associated with increased synaptophysin (SYP) expression and dendritic spine density. Additionally, FBN treatment was associated with reduced amyloid-beta (Aβ) accumulation and attenuated tau pathology, two key pathological features of AD. FBN treatment was also associated with increased expression of mitochondrial fusion-related proteins and improved mitochondrial morphology. Furthermore, FBN treatment increased antioxidant defense-related proteins and reduced apoptosis-related markers, suggesting a possible enhancement of neuroprotective responses. In addition, FBN treatment induced changes in gut microbiota-related metabolites, suggesting a possible contribution of the gut−brain axis. These findings provide valuable insight into the mechanisms underlying the protective effects of hydrogen against AD and support the development of hydrogen-based therapies for slowing or preventing disease progression.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"23 11","pages":"5288–5304"},"PeriodicalIF":4.9,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149306013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Formulations at the Nanoscale: Multi-dimensional Electron Diffraction of Long-Acting Injectable, Cabotegravir","authors":"Helen W. Leung,&nbsp;Royston C. B. Copley,&nbsp;Stephanie Lam,&nbsp;Luca Russo,&nbsp;Simon Fairclough,&nbsp;Duncan N. Johnstone,&nbsp;Paul A. Midgley","doi":"10.1021/acs.molpharmaceut.6c00365","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.6c00365","url":null,"abstract":"<p>Long-acting injectables (LAIs) are pharmaceutical formulations designed for slow, sustained release of medication, allowing for less frequent dosing and improved adherence. Cabotegravir-LA is an intramuscular injectable form of the antiretroviral drug cabotegravir (GSK1265744) for Human Immunodeficiency Virus prevention, in which nanocrystallites of cabotegravir are suspended in an aqueous solution. Particle size plays a major role in determining the rate of drug release; in Cabotegravir-LA, cabotegravir crystals are nano-milled to achieve the desired median particle size. In this work, we apply multi-dimensional electron diffraction to an LAI formulation of cabotegravir. Firstly, we use 3D electron diffraction to solve the structure of cabotegravir from a microcrystal, demonstrating its structure within the formulation is consistent with the single-crystal X-ray diffraction structure. Secondly, 3D electron diffraction is combined with high-angle annular dark field imaging to relate the shape of cabotegravir particles to its crystal structure. We compare these experimental observations to crystal growth and morphology models. Finally, we use 4D-scanning transmission electron microscopy to observe dislocations in the crystals. These insights could, in future, enable further optimization of the product formulation by engineering nanoscale structural and microstructural features.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"23 11","pages":"5318–5326"},"PeriodicalIF":4.9,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149305638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing TB Therapy with Precision: Immunomodulatory Nanoparticles Co-Delivering Rifampicin and Vitamin D3 for Macrophage-Targeted Treatment","authors":"Leon J. Khoza,&nbsp;Pradeep Kumar,&nbsp;Admire Dube,&nbsp;Bhavna G. Gordhan,&nbsp;Bavesh D. Kana,&nbsp;Yahya E. Choonara","doi":"10.1021/acs.molpharmaceut.6c00601","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.6c00601","url":null,"abstract":"<p>Tuberculosis (TB) remains a leading cause of death worldwide, with over 6.2 million cases and nearly 2 million deaths annually. Despite available chemotherapies, significant challenges persist, including prolonged treatment, poor compliance, and the rise of multidrug-resistant (MDR) strains. This study developed a biocompatible, multifunctional drug-delivery system using 1,3-β-glucan-functionalized chitosan-polycaprolactone nanoparticles (1,3-β-Glu-CS-PCL) for co-delivery of Rifampicin (RIF) and Vitamin D3 (VITD3) to alveolar macrophages. Reactive oxygen species (ROS) generation was enhanced by Glu-CS-PCL-RIF (1.5- to 1.8-fold) and Glu-CS-PCL-VITD3 (1.7-fold higher than non-functionalized nanoparticles). Glu-CS-PCL-VITD3 also stimulated TNF-α secretion (1.8-fold increase), indicating a shift in the immune response towards macrophage activation. Minimum inhibitory concentration (MIC) studies showed superior bactericidal activity of Glu-CS-PCL-RIF against a drug-susceptible laboratory strain and clinically resistant isolates of <em>Mycobacterium tuberculosis</em> (Mtb), with a MIC of 0.00149 μg/mL, 2-fold lower than that of standard RIF. The combination of RIF and VITD3 demonstrated significant potency against drug-resistant TB with an effective dose 4x lower than standard treatment. Intracellular killing studies in THP-1 macrophages revealed that CS-PCL-RIF significantly reduced Mtb CFU counts (while containing approximately 15 times less RIF than the standard 50 μg/mL treatment). Glu-CS-PCL-VITD3 showed a notable reduction in CFUs compared to non-functionalized counterparts, illustrating the impact of 1,3-β-glucan functionalization. In conclusion, these multifunctional nanoparticles demonstrate strong potential for targeted anti-TB therapy by combining immunomodulation with enhanced antibacterial efficacy for future clinical applications.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"23 11","pages":"5502–5519"},"PeriodicalIF":4.9,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149305714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Monoclonal Antibody Coformulations Reveal Three Interaction Patterns Governing Stability","authors":"Lateefat A. Kalejaye,&nbsp;Mitali Shah,&nbsp;Austin Gallegos,&nbsp;Neil Mody,&nbsp;Pin-Kuang Lai","doi":"10.1021/acs.molpharmaceut.6c00768","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.6c00768","url":null,"abstract":"<p>Coformulated monoclonal antibodies (mAbs) offer a promising next-generation therapeutic strategy by combining multiple antibodies in a single drug product to enhance efficacy and improve patient compliance. However, ensuring the quality and stability of individual components in combination remains a key challenge. Here, we systematically characterized ten IgG1 mAbs (eight low-viscosity and two high-viscosity mAbs at 150 mg/mL) and all 45 possible 1:1 binary coformulations. Viscosity measurements revealed three distinct cross-interaction patterns: (1) minimal cross-interaction, where coformulation viscosity fell between those of the parental mAbs; (2) attractive cross-interaction, characterized by viscosity above both parental mAbs; and (3) repulsive cross-interaction, characterized by viscosity below both parental mAbs. Among the two high-viscosity mAbs, one exhibited reduced viscosity when coformulated with low-viscosity mAbs, whereas the other exhibited increased viscosity. Diffusion interaction parameter (<span>⁠<span></span><math><msub><mi>k</mi><mi>D</mi></msub></math>⁠</span>) measurements showed partial correspondence with the observed interaction patterns, although <span><span></span><math><msub><mi>k</mi><mi>D</mi></msub></math></span> did not consistently align with the viscosity trends across all coformulation pairs. In parallel, conformational stability was assessed using thermal unfolding parameters, including onset temperature (<span>⁠<span></span><math><msub><mi>T</mi><mrow><mi>o</mi><mi>n</mi><mi>s</mi><mi>e</mi><mi>t</mi></mrow></msub></math>⁠</span>) and the first unfolding transition temperature (<span>⁠<span></span><math><msub><mi>T</mi><mrow><mi>m</mi><mn>1</mn></mrow></msub></math>⁠</span>). Most coformulations exhibited thermal unfolding parameters intermediate between those of their parental mAbs, often shifting toward the less conformationally stable parent, indicating that conformational stability was generally retained following coformulation. This study represents one of the most comprehensive investigations of antibody coformulations to date and, to our knowledge, is the first to report repulsive interactions, particularly in the context of high-concentration viscosity. These findings highlight fundamental protein−protein interaction patterns that govern antibody coformulations, expand the knowledge base for the development of stable next-generation antibody combination therapies, and provide a rich experimental dataset to guide future computational modeling of mAb−mAb coformulation behavior.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"23 11","pages":"5642–5656"},"PeriodicalIF":4.9,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149305774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Roles of Bioassay Subject Matter Experts in Developing Potency Methods and Managing Chemistry, Manufacturing, and Controls Deliverables","authors":"Maroun J. Beyrouthy","doi":"10.1021/acs.molpharmaceut.6c01004","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.6c01004","url":null,"abstract":"<p>Bioassay subject matter experts (SMEs) play an increasingly important role in chemistry, manufacturing, and controls (CM&amp;C) organizations as biologic therapeutics become more complex. This review describes how bioassay SMEs support potency method development and CM&amp;C deliverables from early discovery through commercialization. As therapeutic modalities progress, bioassay control strategies have become more sophisticated, evolving from using simple binding assays to multi-attribute, orthogonal testing approaches. The review summarizes the SME’s expanding contributions to assay design, optimization, method transfer, phase-appropriate qualification and validation, lot release, stability testing, comparability, and regulatory submissions. A case study on ADC potency assay cell-line selection illustrates how biochemical and biological factors affect assay specificity and impurity discrimination. The review also addresses key scientific, technical, and cross-functional challenges, including assay variability and the need for effective leadership across analytical, regulatory, and quality functions. As biologic modalities continue to diversify, interdisciplinary bioassay SME training will be critical to support regulatory-compliant potency strategies.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"23 11","pages":"5242–5249"},"PeriodicalIF":4.9,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149305973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibitory Effect and Mechanism of Paclitaxel-Loaded Magnetic Iron Oxide Nanomicrobubbles Combined with Ultrasound Therapy on Breast Cancer Xenografts in Nude Mice","authors":"Weiyang Lv,&nbsp;Zihan Wang,&nbsp;Chunxin Huang,&nbsp;Xing Li,&nbsp;Lianjie Bai,&nbsp;Xiaotong Wang,&nbsp;Huilin Liu,&nbsp;Yunna Song,&nbsp;Bowen Liu,&nbsp;Xiaomei Ning","doi":"10.1021/acs.molpharmaceut.5c01920","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c01920","url":null,"abstract":"<p>This study aimed to investigate the therapeutic efficacy and underlying mechanisms of paclitaxel (PTX)-loaded magnetic iron oxide nanomicrobubbles (PTX@Fe₃O₄ NMBs) combined with ultrasound therapy in breast cancer xenograft models. The PTX@Fe₃O₄ NMBs were synthesised using a modified microfluidic approach and characterised for size, stability and drug loading. Female BALB/c nude mice bearing MCF-7 xenografts were randomly divided into five groups: control, free PTX (TPL), blank NMBs with ultrasound (TPL + US), targeted NMBs with ultrasound (TLUM + US) and combination therapy with ultrasound (FA-TLUM + US). Tumour growth was monitored for 21 days. Contrast-enhanced ultrasound imaging was performed to evaluate tumour perfusion. Apoptotic mechanisms were assessed through quantitative real-time polymerase chain reaction (PCR) and Western blotting. The PTX@Fe₃O₄ NMBs showed a mean diameter of 186 ± 15 nm, a polydispersity index value of 0.118, a zeta potential of −21.3 ± 2.1 mV, drug encapsulation of 85.4% ± 3.2% and loading capacity of 8.6% ± 0.4% (w/w), with ≤5% drug leakage over 14 days at 4°C. The FA-TLUM + US group achieved the highest tumour growth inhibition rate of 78.6%, significantly superior to other treatment groups (<em>p</em> &lt; 0.001). Contrast-enhanced ultrasound imaging demonstrated enhanced signal intensity and prolonged retention time in targeted NMB groups. Quantitative PCR analysis revealed significant upregulation of pro-apoptotic genes (Bax increased 5.0-fold, caspase-3 increased 4.2-fold) and downregulation of anti-apoptotic genes (Bcl-2 decreased by 76%, survivin decreased by 72%) in the combination therapy group. The PTX@Fe₃O₄ NMBs combined with ultrasound therapy demonstrated potent antitumour efficacy through enhanced drug delivery and activation of mitochondrial apoptotic pathways, representing a promising theranostic platform for breast cancer treatment.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"23 11","pages":"5250–5260"},"PeriodicalIF":4.9,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149306018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prediction of Plasma Concentration−Time Profiles in Mice from Chemical Structure Using a Kinetically Constrained Hybrid Neural ODE","authors":"Yuki Doi,&nbsp;Harutoshi Kato,&nbsp;Fumiyoshi Yamashita","doi":"10.1021/acs.molpharmaceut.6c00453","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.6c00453","url":null,"abstract":"<p>Predicting plasma concentration−time profiles directly from chemical structure remains intrinsically challenging in early drug discovery. Existing approaches typically fall into two paradigms: mechanistic reconstruction via predicted PK parameters, which is constrained by the assumed model structure, and direct data-driven prediction of concentrations, which often suffers from instability and poor temporal coherence under sparse and irregular sampling. Here, we present a kinetically constrained hybrid Neural ordinary differential equation (KCH-NODE) framework for structure-to-PK prediction that bridges these limitations. KCH-NODE anchors predictions to a shared, learnable two-compartment typical trajectory while modeling compound-specific PK behavior as continuous-time deviations governed by a Neural ODE. This hybrid design generates flexible yet pharmacokinetically coherent trajectories, even under sparse observations. Trained on mouse intravenous (IV) and oral (PO) PK data from 1159 compounds across 30 projects, KCH-NODE generally provided more accurate predictions than a purely data-driven Neural ODE in both compound-level and scaffold-based cross-validation (median RMSE 0.374 and 0.388 for IV; 0.564 and 0.570 for PO) and in a temporally held-out evaluation (223 compounds; median RMSE 0.637 for IV and 0.731 for PO), with a smaller loss of accuracy on the temporal split. Predictive accuracy for oral administration nevertheless remained limited on the temporal test set for both methods. Integrated Gradients supported mechanistically consistent feature contributions, and structural similarity to the model-development dataset together with ensemble disagreement provided complementary indicators of prediction reliability. These results indicate that kinetically constrained hybrid Neural ODEs offer an effective and interpretable framework for structure-to-PK profile prediction.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"23 11","pages":"5385–5398"},"PeriodicalIF":4.9,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149305709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of a 64Cu-Labeled Heterobivalent Bicyclic Peptide (Nectin-4/Albumin) for Targeting of Tumor-Associated Nectin-4","authors":"Tobias Krönke,&nbsp;Johanna Mauersberger,&nbsp;Martin Ullrich,&nbsp;Markus Laube,&nbsp;Reik Löser,&nbsp;Florian Brandt,&nbsp;Klaus Kopka,&nbsp;Sven Stadlbauer,&nbsp;Jens Pietzsch,&nbsp;Robert Wodtke","doi":"10.1021/acs.molpharmaceut.6c00928","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.6c00928","url":null,"abstract":"&lt;p&gt;The cell adhesion protein Nectin-4 has been proven as an effective target for therapeutic approaches in bladder cancer. In addition, the interest as a target protein for targeted radionuclide theranostic approaches is growing. While several promising radioligands for imaging purposes have been described in recent years, therapeutic radioligands are largely missing so far, which is mainly reasoned by a comparatively low uptake into the tumor tissue accompanied by a fast washout kinetic of the radioligand. In this study, we investigated how the introduction of an albumin-binding unit into our previously developed ligand &lt;strong&gt;NECT-224&lt;/strong&gt;, which is structurally derived from the bicyclic toxin conjugate &lt;strong&gt;BT8009&lt;/strong&gt;, can improve the integral tumor uptake. The resulting heterobivalent ligand &lt;strong&gt;NECT-308&lt;/strong&gt; was successfully synthesized via solid-phase peptide synthesis. Nectin-4-selective binding was confirmed by surface plasmon resonance interaction analysis. The radiopharmacological characterization of &lt;strong&gt;[&lt;/strong&gt;&lt;sup&gt;&lt;strong&gt;64&lt;/strong&gt;&lt;/sup&gt;&lt;strong&gt;Cu]Cu-NECT-308&lt;/strong&gt; in vitro revealed an albumin-binding affinity of 25 μM and an apparent binding affinity to cellular Nectin-4 of 14 nM as assessed by an ultrafiltration assay using human serum albumin and saturation binding analysis using intact HT-1376 cells (urothelial carcinoma cell line), respectively. PET imaging studies in HT-1376 tumor-bearing mice highlighted an almost fourfold higher integral tumor uptake of &lt;strong&gt;[&lt;/strong&gt;&lt;sup&gt;&lt;strong&gt;64&lt;/strong&gt;&lt;/sup&gt;&lt;strong&gt;Cu]Cu-NECT-308&lt;/strong&gt; over 24 h compared to &lt;strong&gt;[&lt;/strong&gt;&lt;sup&gt;&lt;strong&gt;64&lt;/strong&gt;&lt;/sup&gt;&lt;strong&gt;Cu]Cu-NECT-224&lt;/strong&gt;. As expected, this was accompanied by an increased activity retention in the blood circulation and also by an increased kidney uptake. Control experiments with either a radioligand that exhibits a comparable binding affinity to albumin but bears no Nectin-4-targeting unit or by blocking the binding of &lt;strong&gt;[&lt;/strong&gt;&lt;sup&gt;&lt;strong&gt;64&lt;/strong&gt;&lt;/sup&gt;&lt;strong&gt;Cu]Cu-NECT-308&lt;/strong&gt; to tumor-associated Nectin-4 revealed that the increase in tumor uptake is mainly attributed to Nectin-4-independent mechanisms. The implications of this finding, in particular regarding the clinical translation of such heterobivalent radioligands, are discussed in detail. The radiopharmacological characterization of &lt;strong&gt;[&lt;/strong&gt;&lt;sup&gt;&lt;strong&gt;64&lt;/strong&gt;&lt;/sup&gt;&lt;strong&gt;Cu]Cu-NECT-308&lt;/strong&gt; was complemented by dosimetric calculations for &lt;strong&gt;[&lt;/strong&gt;&lt;sup&gt;&lt;strong&gt;64/67&lt;/strong&gt;&lt;/sup&gt;&lt;strong&gt;Cu]Cu-NECT-224&lt;/strong&gt; and &lt;strong&gt;[&lt;/strong&gt;&lt;sup&gt;&lt;strong&gt;64/67&lt;/strong&gt;&lt;/sup&gt;&lt;strong&gt;Cu]Cu-NECT-308&lt;/strong&gt; in mice and humans, which indicated that the kidneys are the dose-limiting organs. Overall, our results reveal that further structural optimizations of the Nectin-4-directed bicyclic peptide scaffold are necessary to achieve a higher and longer Nectin-4-dependent tumor uptake as well as","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"23 11","pages":"5833–5847"},"PeriodicalIF":4.9,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149306026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PIP3 and EGFR Dual Targeting for the Development of a Polypeptide Complex Drug Aimed at the Specific Delivery and Therapy of Anaplastic Thyroid Carcinoma","authors":"Zehra-Cagla Kahvecioglu,&nbsp;Rachel Baillif,&nbsp;Alison Daubry,&nbsp;Ami Gloria Toulehohoun,&nbsp;Charlotte Rogien,&nbsp;Merveil Steve Sotche,&nbsp;Amandine Nachtergael,&nbsp;Pierre Duez,&nbsp;Denis Nonclercq,&nbsp;Myriam Remmelink,&nbsp;Sophie Laurent,&nbsp;Sven Saussez,&nbsp;Carmen Burtea","doi":"10.1021/acs.molpharmaceut.6c00569","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.6c00569","url":null,"abstract":"<p>Anaplastic thyroid carcinoma (ATC) is rare but highly aggressive with a median survival of only four months post-diagnosis. Current treatments offer limited survival benefits, highlighting the urgent need for novel targeted therapies. One of the hallmarks of ATC is the dysregulation of key signaling cascades, particularly the PI3K/AKT/mTOR (PAM) pathway. EGFR overexpression and aberrant PAM signaling are major contributors to ATC aggressiveness. We developed a therapeutic peptide (TP) that disrupts PIP3-dependent protein interactions, thereby inhibiting AKT activation with the final goal of triggering apoptosis. To enhance specificity and reduce systemic toxicity, a vectoring peptide (VP) was designed to bind the EGFR. Both peptides were chemically linked to form a peptide complex (PC). EGFR and AKT expression were assessed in ATC cell lines 8505c and Cal-62. Apoptosis was evaluated via Annexin V flow cytometry and activated caspase 3 immunofluorescent detection. The therapeutic efficacy of PC was assessed in athymic nude mice bearing Cal-62 or 8505c tumors. ATC cells showed elevated AKT activation, with nuclear localization. PC induced significantly greater apoptosis than TP alone. In vivo, PC treatment remarkably reduced the tumor size and enhanced apoptosis. Toxicological analyses showed no morphological damage in major organs attributable to PC. Overall, histology and plasma biomarkers confirmed low systemic toxicity. CYP450 screening suggested a potential interaction with PC, although its nature (e.g., substrate or competitive, allosteric, or mixed inhibitor) remains to be elucidated. This EGFR/PIP3-targeted PC demonstrates potent antitumor activity and limited toxicity in ATC models by inhibiting the PAM pathway.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"23 11","pages":"5450–5475"},"PeriodicalIF":4.9,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149305975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding the Influence of Polyvinyl Alcohol on the Functionalization and Cellular Uptake of Poly(lactic-co-glycolic) Acid Nanoparticles","authors":"Fatima Hameedat,&nbsp;Rasika Daware,&nbsp;Ilaria Onori,&nbsp;Jozef Adamcik,&nbsp;Amelie Bazzoni,&nbsp;Federica De Lorenzi,&nbsp;José Augusto Berrocal,&nbsp;Barbara Rothen-Rutishauser,&nbsp;Alke Fink,&nbsp;Twan Lammers,&nbsp;Flávia Sousa","doi":"10.1021/acs.molpharmaceut.6c00389","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.6c00389","url":null,"abstract":"<p>Poly(lactic-<em>co</em>-glycolic acid) (PLGA) nanoparticles (NPs) are widely investigated drug delivery systems, yet efficient surface functionalization remains challenging. Here, we demonstrate that residual polyvinyl alcohol (PVA), commonly used as a stabilizer during nanoparticle preparation, remains strongly associated with the surface of PLGA NPs and influences their surface properties, functionalization efficiency, and cellular uptake. To investigate this effect, we compared a traditional water-in-oil-in-water (w/o/w) double-emulsion solvent evaporation method with an optimized formulation strategy in which PVA was confined to the internal aqueous phase. The optimized formulation reduced the calculated surface PVA density from 60.68 to 0.83 mg/m² while requiring only a single purification step. Furthermore, epidermal growth factor (EGF)-functionalized nanoparticles prepared using the optimized method exhibited higher ligand association efficiency and up to 35-fold greater cellular uptake in A549 cells after 24 h compared with nanoparticles prepared using the traditional method. Importantly, both formulations maintained comparable physicochemical stability over 15 days and enabled efficient biomolecule association. Collectively, these findings demonstrate that PVA strongly influences nanoparticle surface characteristics, functionalization efficiency, and cellular interactions, highlighting the importance of surface engineering in the design of functionalized PLGA nanoparticle delivery systems.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"23 11","pages":"5341–5351"},"PeriodicalIF":4.9,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149305979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}