Molecular Pharmaceutics最新文献_第5页

Optimization of Immunogenic Cell Death in Triple-Negative Breast Cancer with Virus-like Particle-Based Photothermal Therapy.

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2025-03-06 DOI: 10.1021/acs.molpharmaceut.4c01059

Ryanne N Ehrman, Nancy Tran, Ikeda Trashi, Orikeda Trashi, Thomas S Howlett, Ziqi Wang, Sneha Kumari, Alyssa C Chiev, Jeremiah J Gassensmith

{"title":"Optimization of Immunogenic Cell Death in Triple-Negative Breast Cancer with Virus-like Particle-Based Photothermal Therapy.","authors":"Ryanne N Ehrman, Nancy Tran, Ikeda Trashi, Orikeda Trashi, Thomas S Howlett, Ziqi Wang, Sneha Kumari, Alyssa C Chiev, Jeremiah J Gassensmith","doi":"10.1021/acs.molpharmaceut.4c01059","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01059","url":null,"abstract":"Photothermal therapy (PTT) uses near-infrared (NIR) light and a photothermal agent (PTA) to generate heat to kill tumor cells. PTT is an attractive therapy for highly metastatic tumors─such as triple-negative breast cancer (TNBC)─because PTT is a potent activator of immunogenic cell death (ICD). ICD is characterized by the production of damage-associated molecular patterns (DAMPs) that help the immune system recognize cancer cells as \"nonself.\" This generates an immune response against the tumor cells and helps to combat both primary and metastatic tumors. However, an unknown thermal window remains in which ICD is most prevalent. Here, we conjugate an NIR-absorbing dye to the surface of bacteriophage Qβ to generate a viral-based PTA. Additionally, we demonstrate that mild PTT (<45 °C) is not enough to cause significant apoptosis in the murine TNBC model. In comparison, hot PTT (>60 °C) effectively eliminates cancer cells but is less likely to induce ICD. An optimal temperature range is moderate PTT (50-60 °C), where effective cell killing and ICD occur. We show an increased surface expression of DAMPs within this range, along with an increased ratio of pro- to anti-inflammatory cytokines by dendritic cells.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565510","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}

引用次数: 0

The pH-Dependent Microspecies Dissociations in the Trade-Off of Solubility and Permeability of Vitamin B2 Eutectic Solids.

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2025-03-05 DOI: 10.1021/acs.molpharmaceut.4c01518

Archita Goswami, Bipul Sarma

引用次数: 0

Probing the Effect of Fluorine on Hydrogen Bonding Interactions in a Pharmaceutical Hydrate Using Advanced Solid-State NMR.

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2025-03-05 DOI: 10.1021/acs.molpharmaceut.4c01055

Chaithanya Hareendran, T G Ajithkumar

引用次数: 0

Lipid Nanoparticles and PEG: Time Frame of Immune Checkpoint Blockade Can Be Controlled by Adjusting the Rate of Cellular Uptake of Nanoparticles.

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2025-03-04 DOI: 10.1021/acs.molpharmaceut.4c01039

Andrew S Choi, Taylor J Moon, Anubhuti Bhalotia, Aarthi Rajan, Laolu Ogunnaike, Diarmuid W Hutchinson, Inga Hwang, Aaditya Gokhale, Justin N Kim, Timothy Ma, Efstathios Karathanasis

{"title":"Lipid Nanoparticles and PEG: Time Frame of Immune Checkpoint Blockade Can Be Controlled by Adjusting the Rate of Cellular Uptake of Nanoparticles.","authors":"Andrew S Choi, Taylor J Moon, Anubhuti Bhalotia, Aarthi Rajan, Laolu Ogunnaike, Diarmuid W Hutchinson, Inga Hwang, Aaditya Gokhale, Justin N Kim, Timothy Ma, Efstathios Karathanasis","doi":"10.1021/acs.molpharmaceut.4c01039","DOIUrl":"10.1021/acs.molpharmaceut.4c01039","url":null,"abstract":"The engineerability of lipid nanoparticles (LNPs) and their ability to deliver nucleic acids make LNPs attractive tools for cancer immunotherapy. LNP-based gene delivery can be employed for various approaches in cancer immunotherapy, including encoding tumor-associated antigens and silencing of negative immune checkpoint proteins. For example, LNPs carrying small interfering RNAs can offer several advantages, including sustained and durable inhibition of an immune checkpoint protein. Due to their tunable design, modifying the lipid composition of LNPs can regulate the rate of their uptake by immune cells and the rate of gene silencing. Controlling the kinetics of LNP uptake provides additional flexibility and strategies to generate appropriate immunomodulation in the tumor microenvironment. Here, we evaluated the effects of polyethylene glycol (PEG) content ranging from 0.5 to 6 mol % on the cellular uptake of LNPs by immune cells and gene silencing of PD-L1 after intratumoral administration. We evaluated the cellular uptake and PD-L1 blockade in vitro in cell studies and in vivo using the YUMM1.7 melanoma tumor model. Cell studies showed that the rate of cell uptake was inversely correlated to an increasing mol % of PEG in a linear relationship. In the in vivo studies, 0.5% PEG LNP initiated an immediate effect in the tumor with a significant decrease in the PD-L1 expression of immune cells observed within 24 h. In comparison, the gene silencing effect of 6% PEG LNP was delayed, with a significant decrease of PD-L1 expression in immune cell subsets being observed 72 h after administration. Notably, performance of the 6% PEG LNP at 72 h was comparable to that of the 0.5% PEG LNP at 24 h. Overall, this study suggests that PEG modifications and intratumoral administration of LNPs can be a promising strategy for an effective antitumor immune response.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539362","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}

引用次数: 0

A Site-Specific MiniAp4-Trastuzumab Conjugate Prevents Brain Metastasis.

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2025-03-03 Epub Date: 2025-02-10 DOI: 10.1021/acs.molpharmaceut.4c01091

Mariam Masmudi-Martín, Benjamí Oller-Salvia, María Perea, Meritxell Teixidó, Manuel Valiente, Ernest Giralt, Macarena Sánchez-Navarro

{"title":"A Site-Specific MiniAp4-Trastuzumab Conjugate Prevents Brain Metastasis.","authors":"Mariam Masmudi-Martín, Benjamí Oller-Salvia, María Perea, Meritxell Teixidó, Manuel Valiente, Ernest Giralt, Macarena Sánchez-Navarro","doi":"10.1021/acs.molpharmaceut.4c01091","DOIUrl":"10.1021/acs.molpharmaceut.4c01091","url":null,"abstract":"Monoclonal antibodies (mAbs) are changing cancer treatments. However, the presence of the blood-brain barrier (BBB) and the blood-tumor barrier (BTB) limits the use of mAbs to treat brain cancer or brain metastasis. Molecules that hijack endogenous transport mechanisms on the brain endothelium (brain shuttles) have been shown to increase the transport of large molecules and nanoparticles across the BBB. Among these shuttles, protease-resistant peptides such as MiniAp-4 are particularly efficient. Here, we report the synthesis, characterization, and evaluation of site-specific mAb-brainshuttle antibody conjugates (ASC) based on the anti-HER2 mAb trastuzumab (Tz) and four molecules of MiniAp-4. The ASCs preserve the binding and cell cycle arrest capacity of Tz. MiniAp-4 ASC displays enhanced transport across an in vitro BBB cellular model with respect to Tz and Tz conjugated to Angiopep-2, the brain shuttle that has advanced the most in clinical trials. More importantly, evaluation of Tz-MiniAp4 in a murine brain metastasis model demonstrated that the protease-resistant peptide showed preferential transport across the BBB/BTB, displaying a marked therapeutic effect and protecting against metastasis development. The technology described herein could be applied to any antibody of interest to treat central nervous system-related diseases. MiniAp-4 enhances the brain transport of the monoclonal antibody trastuzumab, preventing brain metastasis.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"1384-1395"},"PeriodicalIF":4.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Endogenous Iron(II) Self-Enriched Fenton Nanocatalyst via FTH1 Activity Inhibition and Iron(III) Reduction for Amplified Cancer Ferroptosis Therapy.

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2025-03-03 Epub Date: 2025-02-06 DOI: 10.1021/acs.molpharmaceut.4c01292

Ying Chen, Qin Ma, Jun Zhang, Jianhang Li, Yu'e Wang, Yongchao Yao, Yang Ding, Xin Dai, Xinghong Luo, Linjing Wu, Ling Tao, Xiangchun Shen

{"title":"Endogenous Iron(II) Self-Enriched Fenton Nanocatalyst via FTH1 Activity Inhibition and Iron(III) Reduction for Amplified Cancer Ferroptosis Therapy.","authors":"Ying Chen, Qin Ma, Jun Zhang, Jianhang Li, Yu'e Wang, Yongchao Yao, Yang Ding, Xin Dai, Xinghong Luo, Linjing Wu, Ling Tao, Xiangchun Shen","doi":"10.1021/acs.molpharmaceut.4c01292","DOIUrl":"10.1021/acs.molpharmaceut.4c01292","url":null,"abstract":"Due to the increased expression of iron storage proteins in cancer cells, utilizing the endogenous iron-catalyzed Fenton reaction for cancer ferroptosis therapy has recently emerged as a prominent research focus. However, endogenous iron primarily exists within ferroxidase FTH1 in the Fe (III)-bound state, hindering the effective catalysis of the Fenton reaction. Herein, an endogenous iron(II) self-enriched Fenton nanocatalyst (BAI@cLANCs) is fabricated by encapsulating the FTH1 inhibitor baicalin (BAI) in cross-linked lipoic acid nanocarriers (cLANCs) to amplify endogenous ferroptosis. Once internalized, BAI@cLANCs are disrupted by glutathione (GSH) in tumor cells to release BAI, which inhibits FTH1 activity and hinders Fe2+ oxidation. Meanwhile, cLANCs degrade into dihydrolipoic acid (DHLA), which reduces Fe3+ to Fe2+, synergically enriching endogenous Fe2+. Simultaneously, both BAI and DHLA stimulate H2O2 production and facilitate the Fenton reaction to produce abundant ·OH, thereby triggering lipid peroxidation and inducing tumor ferroptosis. Moreover, the reduction of Fe3+ to Fe2+ depletes GSH, facilitating ·OH production and inactivating glutathione peroxidase-4, ultimately amplifying tumor ferroptosis. Overall, this work highlights the potential of an endogenous iron(II) self-enriched Fenton nanocatalyst for cancer ferroptosis therapy, providing a paradigm for amplifying endogenous ferroptosis by inhibiting FTH1 activity and reducing iron(III) to enrich endogenous iron(II).","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"1568-1583"},"PeriodicalIF":4.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363262","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}

引用次数: 0

From Unwanted Annoyances to Oral Delivery Saviors: The Rollercoaster Journey of Amorphous Drugs.

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2025-03-03 DOI: 10.1021/acs.molpharmaceut.5c00013

Lynne S Taylor, George Zografi

引用次数: 0

Investigating the Interaction between Excipients and Monoclonal Antibodies PGT121 and N49P9.6-FR-LS: A Comprehensive Analysis.

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2025-03-03 DOI: 10.1021/acs.molpharmaceut.4c00973

Xun Li, Asuka A Orr, Mohammad M Sajadi, Anthony L DeVico, Daniel J Deredge, Alexander D MacKerell, Stephen W Hoag

{"title":"Investigating the Interaction between Excipients and Monoclonal Antibodies PGT121 and N49P9.6-FR-LS: A Comprehensive Analysis.","authors":"Xun Li, Asuka A Orr, Mohammad M Sajadi, Anthony L DeVico, Daniel J Deredge, Alexander D MacKerell, Stephen W Hoag","doi":"10.1021/acs.molpharmaceut.4c00973","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00973","url":null,"abstract":"N49P9.6-FR-LS and PGT121 are promising antibodies with significant therapeutic potential against HIV infection, but they are prone to precipitation at concentrations greater than 12 to 13 mg/mL. This study evaluates the influence of six excipients─arginine, alanine, sucrose, trehalose, methionine, and glutamate─on the biophysical stability of antibodies. We employed a comprehensive approach, combining computational mAb-excipient interaction analysis via the site-identification by ligand competitive saturation (SILCS) method with extensive experimental characterization. Our experimental matrix included viscosity measurements across temperature gradients, particle size distribution, zeta potential, pH value, and solution appearance, alongside a short-term stability product study at 30 °C and 65% relative humidity, with assessments at t0 (initial), t1 (14 days), and t2 (28 days). Results indicated that sucrose, arginine, alanine, and trehalose provided varying degrees of stabilization for both antibodies. Conversely, glutamate destabilized PGT121 but stabilized N49P9.6-FR-LS, while methionine had a negative effect on N49P9.6-FR-LS but a positive one on PGT121. SILCS-Biologics analysis suggested that stabilization by these excipients is linked to their ability to occupy regions involved in self-protein interactions. Debye-Hückel-Henry charge calculations further indicated that neutral excipients like sucrose and trehalose could alter mAb charges by affecting buffer binding, influencing aggregation propensity. These findings offer valuable insights for optimizing antibody formulations, ensuring enhanced product stability and therapeutic efficacy for HIV treatment.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539360","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}

引用次数: 0

In Vitro Drug Release and Ex Vivo Dermal Drug Permeation Studies of Selected Commercial Benzoyl Peroxide Topical Formulations: Correlation Between Human and Porcine Skin Models.

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2025-03-03 Epub Date: 2025-02-03 DOI: 10.1021/acs.molpharmaceut.4c01058

Murilo de Souza Brighenti, Lilian Rosário da Silva Montanheri, Marcelo Dutra Duque, Newton Andreo-Filho, Patricia Santos Lopes, Maria Teresa Junqueira Garcia, Lorraine Mackenzie, Vânia Rodrigues Leite-Silva

{"title":"In Vitro Drug Release and Ex Vivo Dermal Drug Permeation Studies of Selected Commercial Benzoyl Peroxide Topical Formulations: Correlation Between Human and Porcine Skin Models.","authors":"Murilo de Souza Brighenti, Lilian Rosário da Silva Montanheri, Marcelo Dutra Duque, Newton Andreo-Filho, Patricia Santos Lopes, Maria Teresa Junqueira Garcia, Lorraine Mackenzie, Vânia Rodrigues Leite-Silva","doi":"10.1021/acs.molpharmaceut.4c01058","DOIUrl":"10.1021/acs.molpharmaceut.4c01058","url":null,"abstract":"In vitro release testing (IVRT) serves as a crucial tool to assess the quality, physicochemical behavior, and performance of semisolid formulations already available on the market. In vitro skin permeation studies (IVPT) are widely used to evaluate the safety and efficacy profiles of topical drugs, utilizing biological membranes prepared from ex vivo human and porcine skin tissues. This study aimed to develop and validate a discriminative IVRT method to evaluate various marketed topical benzoyl peroxide formulations. Additionally, IVPT was employed to assess skin permeation and retention profiles of these formulations, comparing porcine skin results with those obtained by using ex vivo human skin tissues. Physicochemical differences among the evaluated benzoyl peroxide formulations were identified, with the poloxamer-based formulation exhibiting a higher release rate. IVPT using both porcine and human skin differentiated retention and skin permeation profiles, with the poloxamer-based formulation demonstrating greater skin retention capacity compared to the other formulations evaluated. Similar conclusions on benzoyl peroxide retention and cutaneous permeation were drawn from both porcine and human skin IVPT tests, confirming the correlation between the two models.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"1365-1372"},"PeriodicalIF":4.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143121785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mucin Mimics and Impacts the Function of Polymeric Inhibitors in Stabilizing Drug Supersaturation.

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2025-03-03 Epub Date: 2025-02-20 DOI: 10.1021/acs.molpharmaceut.4c01102

Victus Kordorwu, Steven Castleberry, Steve Lustig, Rebecca L Carrier

{"title":"Mucin Mimics and Impacts the Function of Polymeric Inhibitors in Stabilizing Drug Supersaturation.","authors":"Victus Kordorwu, Steven Castleberry, Steve Lustig, Rebecca L Carrier","doi":"10.1021/acs.molpharmaceut.4c01102","DOIUrl":"10.1021/acs.molpharmaceut.4c01102","url":null,"abstract":"Many drugs entering clinical trials today are poorly water-soluble and rely on supersaturating formulations, such as amorphous solid dispersions (ASD) to enhance their bioavailability. The in vivo performance of these formulations is often investigated through biorelevant dissolution testing using simulated intestinal fluid. Often overlooked in biorelevant dissolution is the presence of mucus within the intestinal environment and its possible role in affecting the formulation performance. In this study, the impact of mucins, the main structural glycoproteins of mucus, on the precipitation of two model compounds, carvedilol and nifedipine, from supersaturated solutions was investigated. The presence of mucin within the supersaturated environment was demonstrated to significantly alter the rate of drug precipitation in vitro. The impact of mucin on precipitation was then compared to commercially available polymer precipitation inhibitors hydroxypropyl methylcellulose (HPMC) and Kollidon VA 64, which are commonly used in ASD formulations. Surprisingly, when present at the same concentration (0.2% (w/v)), mucin reduces drug precipitation to an extent comparable to that of polymer precipitation inhibitors. Additionally, we observed that the presence of mucin in the supersaturated environment altered the precipitation inhibitory effects of HPMC and Kollidon VA64, suggesting that mucin could play an important and complicated role in formulation performance in the intestine.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"1396-1407"},"PeriodicalIF":4.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0