Molecular Pharmaceutics最新文献

{"title":"Mechanochemical Engineering of High-Dose Inhalable Antibiotic Powders for Lower Respiratory Tract Infections","authors":"Xiaojie Sun,&nbsp;Albert Bolhuis,&nbsp;Matthew D. Jones,&nbsp;William J. Ganley,&nbsp;Nikoletta Fotaki,&nbsp;Marina Navas Bachiller,&nbsp;Bernardo Castro-Dominguez","doi":"10.1021/acs.molpharmaceut.6c00936","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.6c00936","url":null,"abstract":"<p>Lower respiratory tract infections require high local antibiotic concentrations in the lung, yet current dry powder inhaler (DPI) technologies are poorly suited to delivering high drug payloads while maintaining particle stability, dispersibility, and antimicrobial function. Here, we report a novel solvent-minimized mechanochemical strategy for the design of high-dose inhalable antibiotic powders based on ciprofloxacin−maleic acid (CIP−MA) salt formation. CIP−MA was prepared by oscillatory ball milling and co-processed with <span>l</span>-leucine (L-Leu), polyvinylpyrrolidone 10,000 (PVP), or D-mannitol (D-Man) using a design of experiment approach to tune the milling frequency, processing time, and excipient loading. The process generated crystalline, thermally stable powders with respirable particle sizes, controllable morphology, and reduced hygroscopicity compared with raw ciprofloxacin. Excipient selection provided distinct formulation functions. L-Leu improved dispersibility and achieved the highest proportion of particles with geometric diameter below 5 μm (89%) and fine particle fraction &lt; 5 μm (∼37%) measured using a next-generation impactor at a 200 mg dose in the Orbital^TM high-dose DPI. However, PVP and D-Man favored improved device emptying and altered dissolution behavior. All CIP−MA formulations retained antimicrobial potency, with minimum inhibitory concentrations comparable to raw ciprofloxacin and approximately 95% reduction in viable <em>Pseudomonas aeruginosa</em> biofilm. Importantly, the formulations showed accelerated dissolution under pulmonary-relevant flow-through conditions, releasing 70−80% of ciprofloxacin within 30 min, compared with the slower dissolution of raw ciprofloxacin. These findings establish oscillatory ball milling as a lower solvent use, tunable solid-state approach that integrates salt formation, preservation of crystallininty, particle engineering, high-dose aerosol delivery, and biological performance for next-generation inhalable antibiotic formulations.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"23 11","pages":"5863–5878"},"PeriodicalIF":4.9,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149305632","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":"Design and Evaluation of Colon-Specific Epinastine Prodrugs as Potent Anti-Colitis Agents Acting via the Activation of the Nrf2−HO-1 Pathway","authors":"Changyu Kang,&nbsp;Jaejeong Kim,&nbsp;Yunjin Jung","doi":"10.1021/acs.molpharmaceut.6c00817","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.6c00817","url":null,"abstract":"<p>The antihistamine epinastine (EPNT) is used to treat allergic and atopic diseases. To reposition EPNT as a therapeutic agent for inflammatory bowel disease (IBD), EPNT was conjugated with colon-specific promoieties: 5-aminosalicylic acid (5-ASA), aspartic acid (Asp)-conjugated 5-ASA, and glutamic acid (Glu)-conjugated 5-ASA via azo bonds to yield EPNT-azo-salicylic acid (EAS), Asp-conjugated EAS (EAS-Asp), and Glu-conjugated EAS (EAS-Glu), respectively. These EPNT derivatives exhibited lower distribution coefficients and reduced transport across Caco-2 cell monolayers. While remaining stable in the upper intestinal environment, the EPNT derivatives were converted to EPNT in the cecal contents with an efficiency comparable to that of the current anti-IBD azo prodrug, sulfasalazine (SSZ). Moreover, orally administered EPNT derivatives resulted in a higher delivery of EPNT to the cecum than oral EPNT alone. The colon-specific performance of the EPNT derivatives followed the order EAS-Asp ≈ EAS-Glu &gt; EAS. In a dinitrobenzenesulfonic acid-induced rat colitis model, the EPNT derivatives were more effective in mitigating colonic damage and inflammation than EPNT and SSZ, with anti-colitis efficacy corresponding to their colon-targeting performance. Oral EPNT derivatives increased the levels of nuclear factor erythroid 2−related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) proteins, likely via the activation of adenosine monophosphate-activated protein kinase (AMPK) in inflamed colonic tissues. Furthermore, co-treatment with zinc protoporphyrin, an HO-1 inhibitor, markedly reduced the anti-colitis effect of EAS-Glu. Finally, oral administration of EPNT derivatives significantly reduced the systemic absorption of EPNT. In conclusion, colon-targeted EPNT may enhance the therapeutic efficacy and safety of EPNT when repositioned as an anti-IBD drug, with the AMPK−Nrf2−HO-1 pathway contributing to its anti-colitis mechanism.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"23 11","pages":"5735–5749"},"PeriodicalIF":4.9,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149305667","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":"Near UV Photo-Degradation of IgG1-Fc Promoted by His and Fe(III): Probing the Role of the Metal-Binding Pocket by Site-Directed Mutagenesis","authors":"Maribel Espinoza Ballesteros,&nbsp;Marcela Solis Rodriguez,&nbsp;Steve Seibold,&nbsp;Kevin P. Battaile,&nbsp;Scott Lovell,&nbsp;Thomas J. Tolbert,&nbsp;Christian Schöneich","doi":"10.1021/acs.molpharmaceut.6c00605","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.6c00605","url":null,"abstract":"<p>Light exposure of therapeutic proteins can affect chemical and physical stability and compromise safety and efficacy. In order to develop stable pharmaceutical formulations without undesired side effects, it is essential to understand both product formation and reaction mechanisms which lead to light-induced protein degradation. We recently reported that visible and near UV light induce site-specific fragmentation and photo-conversion of a heavy chain Thr residue in IgG1-Fc, full length IgG1 and IgG1-based fusion proteins formulated in Fe(III)-containing histidine buffer. These post-translational modifications manifest differently in each modality, with the photo-conversion of Thr to Ala being more prominent in IgG1-Fc. Mechanistically, these photo-degradation pathways occur within a Fe(III)-binding pocket present in the CH2 domain. Here, we investigate the role of individual metal-binding residues located in the Fe(III)-binding pocket in the photo-degradation of IgG1-Fc. The single mutants of Asp²⁵ to Ala, Thr³² to Ala, and Glu³⁴ to Gln in IgG1-Fc completely prevent the site-specific photo-degradation of Thr³², while the mutation of Pro³³ to Ala had only a relatively small effect. A comparison of crystal structures reveals that the replacement of Pro³³ by Ala does not significantly affect the structure of the Fe(III)-binding pocket. Our results indicate that a single amino acid mutation can prevent the Fe(III)-catalyzed photo-degradation, suggesting that single point mutations may be a future pathway towards photo-stable pharmaceutical formulations.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"23 11","pages":"5489–5501"},"PeriodicalIF":4.9,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149305669","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":"An Efficient Workflow to Access Cocrystal Eutectics across a Wide Solubility Range and Evaluate Determinants of Cocrystal Solubility","authors":"Sanika Jadhav,&nbsp;Lewis L. Stevens","doi":"10.1021/acs.molpharmaceut.6c00848","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.6c00848","url":null,"abstract":"<p>Pharmaceutical cocrystals offer a promising strategy to improve the performance of solubility-limited drug candidates, but determining the total equilibrium cocrystal solubility (<em>S</em>_CC,T) remains challenging for highly soluble and potentially highly desirable cocrystals prone to solution-mediated phase transformations. This work establishes a material-efficient approach to access eutectic compositions and to determine <em>S</em>_CC,T across cocrystals with a broad range of coformer solubilities, using only drug and coformer solubility information and targeted experiments, avoiding resource-intensive trial-and-error experiments. Ten naringenin cocrystals, spanning a wide range of coformer-to-drug solubility ratios (<em>S</em>_CF,T/<em>S</em>_D,T), were evaluated in biorelevant media. For five highly soluble and kinetically unstable cocrystals (<em>S</em>_CF,T/<em>S</em>_D,T &gt; 5000), eutectic compositions were successfully achieved using a predissolving coformer strategy, enabling the determination of key cocrystal solution parameters, mainly the apparent solubility product, cocrystal solubility, and solution stability. The coformer concentration required to reach the eutectic point was cocrystal-dependent and strongly correlated with <em>S</em>_CF,T/<em>S</em>_D,T (<em>R</em>² = 0.955), enabling an a priori estimation of the eutectic point and minimizing the experimental burden and API consumption. Across the resulting broad range in S_CC,T, only a modest log−log correlation with <em>S</em>_CF,T/<em>S</em>_D,T was observed, indicating coformer solubility alone is an insufficient predictor of cocrystal solubility. Exploratory multivariate analyses showed coformer solubility, lattice energetics, coformer lipophilicity, and drug-coformer intermolecular interactions collectively provided improved descriptive performance over coformer solubility alone. Overall, this work provides a practical and efficient approach for rationally accessing eutectic conditions and determining cocrystal solubility with limited material across cocrystals with diverse solubilities. This study lays the groundwork to expand the <em>S</em>_CC,T database and better establish coformer−cocrystal performance relationships to anticipate cocrystal solution performance and support the rational selection of coformers for pharmaceutical cocrystal design.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"23 11","pages":"5808–5820"},"PeriodicalIF":4.9,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149305708","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":"In Vitro−In Silico Screening for Assessing Variability in Food Effects for Different Solid Forms of a Free Base Drug","authors":"Niloufar Salehi,&nbsp;William Omar Mendoza Morales,&nbsp;Gislaine Kuminek,&nbsp;Karina Vazquez,&nbsp;David C. Sperry","doi":"10.1021/acs.molpharmaceut.6c01028","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.6c01028","url":null,"abstract":"<p>Understanding and predicting food effects for weakly basic, poorly soluble drugs remain a major challenge in oral drug development. Posaconazole (PSZ), a highly lipophilic antifungal agent, exhibits pronounced fasted-fed variability when administered as the free base. In this work, we developed an integrated in vitro-in silico screening strategy to evaluate the impact of physiological variability on the dissolution and predicted absorption of PSZ and its 4-aminobenzoic acid cocrystal form, PSZ-4ABA. Using a two-stage dissolution framework, key gastrointestinal parameters, including pH, bile salt concentration, buffer capacity, gastric residence time, and gastric-to-intestinal volume ratio, were systematically varied within physiologically relevant ranges to assess their influence on drug solubility, supersaturation, and precipitation risk. PSZ-4ABA consistently demonstrated higher apparent solubility and reduced sensitivity to physiological fluctuations compared to the free base, particularly under fasted conditions, where PSZ exhibited greater precipitation risk. Normalized AUC values derived from dissolution profiles revealed that the cocrystal form substantially attenuates variability across fed and fasted states. Physiologically based biopharmaceutics modeling (PBBM), built by incorporating the solubility-pH profile of the free form and cocrystal, further supported these findings. Overall, this study highlights the utility of combining biorelevant dissolution testing with PBBM to identify solid forms with reduced food-effect liability and to anticipate variability arising from gastrointestinal physiology.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"23 11","pages":"5891–5904"},"PeriodicalIF":4.9,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149305713","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":"PET Imaging of Dual GLP-1R and GIPR Targeting with [18F]AlF-NOTA-Asp2-Tirzepatide","authors":"Kadeer Tudi,&nbsp;Zhisheng Jie,&nbsp;Zihao Chen,&nbsp;Weijiang Liao,&nbsp;Yi Liu,&nbsp;Ganghua Tang","doi":"10.1021/acs.molpharmaceut.6c00761","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.6c00761","url":null,"abstract":"<p>Tirzepatide is a clinical dual GLP-1R and GIPR agonist for type 2 diabetes and obesity, and non-invasive approaches to assess its in vivo biodistribution and systemic toxicity in living animals remain limited. Both receptors also serve as potential targets for neuroendocrine tumor imaging, and dual-target PET probes for simultaneous GLP-1R and GIPR detection are still lacking. Herein, we developed a novel PET probe [¹⁸F]AlF-NOTA-Asp₂-tirzepatide via structural modification of tirzepatide. This probe successfully visualized the in vivo distribution of tirzepatide, which was primarily eliminated through the renal system. The C₂₀ fatty diacid moiety caused elevated uptake in the heart, liver and blood due to enhanced albumin binding. In vitro assays verified its reliable GLP-1R and moderate GIPR binding affinity. Persistent tumor accumulation was observed in INS-1 and A549-GIPR xenografts, allowing effective tumor visualization. In summary, [¹⁸F]AlF-NOTA-Asp₂-tirzepatide features facile radiolabeling and enables the clear visualization of tirzepatide in vivo, along with favorable dual-targeting performance, while excessive non-target uptake still needs to be optimized for further clinical translation.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"23 11","pages":"5620–5629"},"PeriodicalIF":4.9,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149305744","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":"Development and Preclinical Evaluation of [68Ga]Ga-DOTA-L3: A Novel PET Tracer for Quantitative Imaging of Carbonic Anhydrase IX","authors":"Jie Li,&nbsp;Yuhui Luo,&nbsp;Chengyu Luo,&nbsp;Zixin Yang,&nbsp;Fei Luo,&nbsp;Huajian Gu,&nbsp;Fei Chen,&nbsp;Zongxi He,&nbsp;Suping Li","doi":"10.1021/acs.molpharmaceut.6c00836","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.6c00836","url":null,"abstract":"<p>Carbonic anhydrase IX (CA IX) is a key biomarker for tumor hypoxia and a promising target for molecular imaging. In this study, we developed [⁶⁸Ga]Ga-DOTA-L3, a novel small-molecule CA IX-targeted PET tracer. The radiolabeling was optimized to consistently achieve a radiochemical purity of &gt;98% (10 μg precursor, 90 °C, pH 4.5, 10 min), with excellent stability in saline and FBS up to 240 min. In vivo studies demonstrated rapid blood clearance and predominant renal excretion. Surface plasmon resonance analysis demonstrated high-affinity binding of the DOTA-L3 precursor toward CA IX (K_d = 7.60 ± 0.37 nM) with highest affinity observed for CA IX among the tested isoforms. MicroPET/CT imaging (30−240 min p.i.) showed robust tumor accumulation in OSRC-2 (SUV_mean = 1.47 ± 0.21) and HT-29 (SUV_mean = 1.03 ± 0.12) xenografts, while minimal uptake was observed in CA IX-low FTC-238 tumors (SUV_mean = 0.21 ± 0.05) at 60 min p.i. PET-derived tumor uptake showed a strong linear correlation with CA IX expression levels (R² = 0.976, P &lt; 0.001) across the three tumor models. High tumor-to-muscle and tumor-to-blood ratios further confirm favorable imaging contrast (T/M = 27.53 ± 1.89 and T/B = 24.61 ± 2.35 at 240 min p.i. for OSRC-2 model). These results support [⁶⁸Ga]Ga-DOTA-L3 as a promising candidate for non-invasive assessment of CA IX-associated hypoxia and as a scaffold for future theranostic development.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"23 11","pages":"5787–5798"},"PeriodicalIF":4.9,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149305946","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":"Organelle-Function-Modulated In Situ Assembling Peptide Systems for Intracellular Drug Delivery","authors":"Zhiyu Han,&nbsp;Hong Ju,&nbsp;Tongtong Chen,&nbsp;Dongmei Xi,&nbsp;Yanqiu Song","doi":"10.1021/acs.molpharmaceut.6c00723","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.6c00723","url":null,"abstract":"<p>In situ peptide assembly has emerged as a promising strategy for constructing bioactive materials that can dynamically respond to complex intracellular environments, offering improved spatiotemporal control, functional precision, and biocompatibility compared with conventional drug delivery systems. By integrating organelle-specific targeting with stimuli-responsive assembly, these systems enable localized therapeutic activation and precise modulation of intracellular organelle functions. This review summarizes recent advances in organelle-function-modulated in situ assembling peptide systems for intracellular drug delivery, with a particular focus on peptide assemblies targeting lysosomes, endoplasmic reticulum, Golgi apparatus, nucleus, and mitochondria. The fundamental design principles underlying these systems, including organelle targeting, microenvironment-responsive activation, programmable peptide assembly, functional regulation, and metabolic safety, are first discussed. Representative examples are then highlighted according to their therapeutic mechanisms, illustrating two distinct strategies: peptide assembly functioning directly as the therapeutic modality and peptide assembly serving as a carrier for therapeutic payloads. Emerging multi-organelle targeting approaches are also discussed to demonstrate how coordinated regulation of intracellular organelles may improve therapeutic efficacy. Finally, this review critically summarizes the current challenges associated with mechanistic understanding, in situ assembly characterization, biological safety, and clinical translation, and outlines future opportunities for the rational design of next-generation organelle-targeted peptide biomaterials. Overall, organelle-function-modulated in situ assembling peptide systems represent a versatile platform for precision intracellular therapeutics, although further advances in mechanistic studies, translational design, and in vivo validation will be essential for their future biomedical applications.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"23 11","pages":"5216–5241"},"PeriodicalIF":4.9,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149305948","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":"Conformation and Hydrodynamics of Spherical High-Density Lipoprotein and Its Specific Adsorption onto Different Membrane Surfaces","authors":"Gu Kim,&nbsp;Hwankyu Lee","doi":"10.1021/acs.molpharmaceut.6c00616","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.6c00616","url":null,"abstract":"<p>Spherical high-density lipoproteins (LpA-I HDL), consisting of apolipoprotein A-I (apoA-I), 1-palmitoyl-2-oleoyl-<em>glycero</em>-3-phosphocholine (POPC), cholesterol, triglyceride, and cholesteryl ester, adsorbed onto various lipid bilayers are simulated using all-atom models. First, LpA-I particles with different molar ratios are equilibrated in water, during which three apoA-I molecules adsorb onto the lipid particle by twisting their helical domains, consistent with the experimentally proposed trefoil model, which is further supported by hydrodynamic sizes and shapes, lysine cross-links, helicities, and component distributions of LpA-I particles. Intermolecular and intramolecular cross-links are distinguished, with specific lysine pairs remaining closely associated and contributing to the maintenance of the trefoil model. In particular, higher POPC content promotes the formation of many more hydrogen bonds with apoA-I, weakening intermolecular hydrogen bonds between apoA-I proteins and thus reducing apoA-I helicity. Binding free-energy calculations from umbrella sampling show strong adsorption of LpA-I onto bilayers composed of anionic lipids or zwitterionic lipids with relatively small amine headgroups, consistent with experiments. This adsorption is attributed to hydrogen-bonding interactions mediated by electrostatic forces between bilayer headgroups and apoA-I, especially within its C-terminal region, which also modulate the helicity of amphipathic apoA-I. These findings help explain experimental observations and proposed models regarding the conformation and hydrodynamics of spherical LpA-I HDL particles, as well as their protein corona formation on specific liposomes.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"23 11","pages":"5520–5537"},"PeriodicalIF":4.9,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149306021","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":"Glutathione-Responsive Nano-Prodrug Mediates Synergistic Photothermal Chemotherapy for Tumor Inhibition","authors":"Yu Jiang,&nbsp;Chen Guo,&nbsp;Zhenkun Sun,&nbsp;Kaixin Du,&nbsp;Yinbin Liang,&nbsp;Junwei Zhuang,&nbsp;Aqsa Sarfraz,&nbsp;Yang Sun,&nbsp;Jianyong Liu,&nbsp;Qinying Liu","doi":"10.1021/acs.molpharmaceut.6c00801","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.6c00801","url":null,"abstract":"<p>Photothermal therapy (PTT) offers the advantages of noninvasiveness and high selectivity, while chemotherapy shows potent antitumor activity. However, their standalone applications are limited by insufficient photothermal ablation efficacy and chemotherapeutic resistance, respectively. To address these challenges, we developed a novel boron dipyrromethene (BODIPY)-based scaffold featuring “barrier-free” rotators and an intramolecular charge-transfer (ICT) effect to enhance photothermal performance. Two chlorambucil (CLB) molecules were conjugated to the scaffold via a glutathione (GSH)-sensitive disulfide linker. The resulting prodrug was further encapsulated by an amphiphilic mPEG-b-PCL copolymer to construct a nanoplatform that integrates efficient photothermal therapy with tumor microenvironment-responsive drug release. Both in vitro and in vivo studies confirmed selective tumor accumulation through the enhanced permeability and retention (EPR) effect, significant tumor growth inhibition upon laser irradiation, and low systemic toxicity. This work provides a promising strategy for effective and safe combination photothermal chemotherapy.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"23 11","pages":"5691–5703"},"PeriodicalIF":4.9,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149306045","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}