Molecular Pharmaceutics最新文献

筛选
英文 中文
Bohemian Rhapsody of Future Drug Delivery Systems: Rational Changes Necessary for the Next Revolution. 未来给药系统的波希米亚狂想曲:下一次革命所需的理性变革。
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2024-07-12 DOI: 10.1021/acs.molpharmaceut.4c00550
Kinam Park, Andrew Otte, Tonglei Li
{"title":"Bohemian Rhapsody of Future Drug Delivery Systems: Rational Changes Necessary for the Next Revolution.","authors":"Kinam Park, Andrew Otte, Tonglei Li","doi":"10.1021/acs.molpharmaceut.4c00550","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00550","url":null,"abstract":"<p><p>Controlled drug delivery technology has matured for more than 70 years, starting from a twice-a-day oral formulation to 6 month long-acting injectable formulations. Further technological advances require superior formulations to treat various diseases more efficiently. Developing future formulations with practical innovations for treating existing and new diseases necessitates our continued efforts to overcome at least three main hurdles. They include (i) drug delivery with reduced side effects, (ii) long-term treatment of chronic diseases, and (iii) the overcoming of biological barriers. Such efforts start with the improved ability to accurately test drug delivery efficacy using proper controls. Future development can be aided by artificial intelligence if used properly. The next revolution of drug delivery systems will be augmented if implementation is given equal weight as discovery. Such a process can be accelerated with the systemic revamp of the research funding structure and cultivating a new generation of scientists who can think differently.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141597944","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
Translocation of Antimicrobial Peptides across Model Membranes: The Role of Peptide Chain Length. 抗菌肽在模型膜上的转运:肽链长度的作用
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2024-07-12 DOI: 10.1021/acs.molpharmaceut.4c00450
Amanda E Skog, Nicolò Paracini, Yuri Gerelli, Marie Skepö
{"title":"Translocation of Antimicrobial Peptides across Model Membranes: The Role of Peptide Chain Length.","authors":"Amanda E Skog, Nicolò Paracini, Yuri Gerelli, Marie Skepö","doi":"10.1021/acs.molpharmaceut.4c00450","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00450","url":null,"abstract":"<p><p>Cushioned lipid bilayers are structures consisting of a lipid bilayer supported on a solid substrate with an intervening layer of soft material. They offer possibilities for studying the behavior and interactions of biological membranes more accurately under physiological conditions. In this work, we continue our studies of cushion formation induced by histatin 5 (<sup>24</sup>Hst5), focusing on the effect of the length of the peptide chain. <sup>24</sup>Hst5 is a short, positively charged, intrinsically disordered saliva peptide, and here, both a shorter (<sup>14</sup>Hst5) and a longer (<sup>48</sup>Hst5) peptide variant were evaluated. Experimental surface active techniques were combined with coarse-grained Monte Carlo simulations to obtain information about these peptides. Results show that at 10 mM NaCl, both the shorter and the longer peptide variants behave like <sup>24</sup>Hst5 and a cushion below the bilayer is formed. At 150 mM NaCl, however, no interaction is observed for <sup>24</sup>Hst5. On the contrary, a cushion is formed both in the case of <sup>14</sup>Hst5 and <sup>48</sup>Hst5, and in the latter, an additional thick, diffuse, and highly hydrated layer of peptide and lipid molecules is formed, on top of the bilayer. Similar trends were observed from the simulations, which allowed us to hypothesize that positively charged patches of the amino acids lysine and arginine in all three peptides are essential for them to interact with and translocate over the bilayer. We therefore hypothesize that electrostatic interactions are important for the interaction between the solid-supported lipid bilayers and the peptide depending on the linear charge density through the primary sequence and the positively charged patches in the sequence. The understanding of how, why, and when the cushion is formed opens up the possibility for this system to be used in the research and development of new drugs and pharmaceuticals.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141589003","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
PET Imaging of Differentiated Thyroid Cancer with TSHR-Targeted [89Zr]Zr-TR1402. 用 TSHR 靶向 [89Zr]Zr-TR1402 对分化型甲状腺癌进行 PET 成像。
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2024-07-08 DOI: 10.1021/acs.molpharmaceut.4c00224
Grayson R Gimblet, Hailey A Houson, Jason Whitt, Pratheek Reddy, John Al Copland, Saad S Kenderian, Mariusz W Szkudlinski, Renata Jaskula-Sztul, Suzanne E Lapi
{"title":"PET Imaging of Differentiated Thyroid Cancer with TSHR-Targeted [<sup>89</sup>Zr]Zr-TR1402.","authors":"Grayson R Gimblet, Hailey A Houson, Jason Whitt, Pratheek Reddy, John Al Copland, Saad S Kenderian, Mariusz W Szkudlinski, Renata Jaskula-Sztul, Suzanne E Lapi","doi":"10.1021/acs.molpharmaceut.4c00224","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00224","url":null,"abstract":"<p><p>Thyroid cancer is the most common endocrine cancer, with differentiated thyroid cancers (DTCs) accounting for 95% of diagnoses. While most DTC patients are diagnosed and treated with radioiodine (RAI), up to 20% of DTC patients become RAI refractory (RAI-R). RAI-R patients have significantly reduced survival rates compared to patients who remain RAI-avid. This study explores [<sup>89</sup>Zr]Zr-TR1402 as a thyroid-stimulating hormone receptor (TSHR)-targeted PET radiopharmaceutical for DTC. [<sup>89</sup>Zr]Zr-TR1402 was synthesized with a molar activity of 25.9 MBq/nmol by conjugating recombinant human TSH (rhTSH) analogue TR1402 to chelator p-SCN-Bn-deferoxamine (DFO) in a molar ratio of 3:1 (DFO/TR1402) and radiolabeling with <sup>89</sup>Zr (<i>t</i><sub>1/2</sub> = 78.4 h, β<sup>+</sup> = 22.7%). As TSHR is absent in commonly available DTC-derived cell lines, TSHR was reintroduced via stable transduction by delivering a lentivirus containing the full-length coding region of the human TSHR gene. Receptor-mediated uptake of [<sup>89</sup>Zr]Zr-TR1402 was evaluated <i>in vitro</i> in stably transduced TSHR+ and wild-type TSHR- DTC cell lines. <i>In vivo</i> PET imaging was performed on Days 1-3 postinjection in male and female athymic nude mice bearing TSHR+ and TSHR- xenografts, along with <i>ex vivo</i> biodistribution on Day 3 postinjection. <i>In vitro</i> uptake of 1 nM [<sup>89</sup>Zr]Zr-TR1402 was significantly higher in TSHR+ THJ529T (<i>P</i> < 0.0001) and FTC133 (<i>P</i> < 0.01) cells than in TSHR- THJ529T and FTC133 cells. This uptake was shown to be specific in both TSHR+ THJ529T (<i>P</i> < 0.0001) and TSHR+ FTC133 (<i>P</i> < 0.0001) cells by blocking uptake with 250 nm DFO-TR1402. <i>In vivo</i> PET imaging showed accumulation of [<sup>89</sup>Zr]Zr-TR1402 in TSHR+ tumors, which was the highest on Day 1. In the male FTC133 xenograft model, <i>ex vivo</i> biodistribution confirmed a significant difference (<i>P</i> < 0.001) in uptake between FTC133+ (1.3 ± 0.1%ID/g) and FTC133- (0.8 ± 0.1%ID/g) tumors. A significant difference (<i>P</i> < 0.05) in uptake was also seen in the male THJ529T xenograft model between THJ529T+ (1.8 ± 0.6%ID/g) and THJ529T- (0.8 ± 0.4%ID/g) tumors. The <i>in vitro</i> and <i>in vivo</i> accumulation of [<sup>89</sup>Zr]Zr-TR1402 in TSHR-expressing DTC cell lines support the continued preclinical optimization of this approach.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141557451","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
Effect of Ibuprofen as an Albumin Binder on Melanoma-Targeting Properties of 177Lu-Labeled Ibuprofen-Conjugated Alpha-Melanocyte-Stimulating Hormone Peptides. 布洛芬作为白蛋白粘合剂对 177Lu 标记的布洛芬共轭α-黑色素细胞刺激素肽的黑色素瘤靶向特性的影响
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2024-07-07 DOI: 10.1021/acs.molpharmaceut.4c00369
Zheng Qiao, Jingli Xu, Fabio Gallazzi, Darrell R Fisher, Rene Gonzalez, Jennifer Kwak, Yubin Miao
{"title":"Effect of Ibuprofen as an Albumin Binder on Melanoma-Targeting Properties of <sup>177</sup>Lu-Labeled Ibuprofen-Conjugated Alpha-Melanocyte-Stimulating Hormone Peptides.","authors":"Zheng Qiao, Jingli Xu, Fabio Gallazzi, Darrell R Fisher, Rene Gonzalez, Jennifer Kwak, Yubin Miao","doi":"10.1021/acs.molpharmaceut.4c00369","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00369","url":null,"abstract":"<p><p>The purpose of this study was to examine how the introduction of ibuprofen (IBU) affected tumor-targeting and biodistribution properties of <sup>177</sup>Lu-labeled IBU-conjugated alpha-melanocyte-stimulating hormone peptides. The IBU was used as an albumin binder and conjugated to the DOTA-Lys moiety without or with a linker to yield DOTA-Lys(IBU)-GG-Nle-CycMSH<sub>hex</sub> {1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-Lys(IBU)-Gly-Gly-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH<sub>2</sub>}, DOTA-Lys(Asp-IBU)-GGNle-CycMSH<sub>hex</sub>, DOTA-Lys(Asn-IBU)-GGNle-CycMSH<sub>hex</sub>, and DOTA-Lys(Dab-IBU)-GGNle-CycMSH<sub>hex</sub> peptides. Their melanocortin-receptor 1 (MC1R) binding affinities were determined on B16/F10 melanoma cells first. Then the biodistribution of <sup>177</sup>Lu-labeled peptides was determined on B16/F10 melanoma-bearing C57 mice at 2 h postinjection to choose the lead peptide for further examination. The full biodistribution and melanoma imaging properties of <sup>177</sup>Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSH<sub>hex</sub> were further evaluated using B16/F10 melanoma-bearing C57 mice. DOTA-Lys(IBU)-GG-Nle-CycMSH<sub>hex</sub>, DOTA-Lys(Asp-IBU)-GGNle-CycMSH<sub>hex</sub>, DOTA-Lys(Asn-IBU)-GGNle-CycMSH<sub>hex</sub>, and DOTA-Lys(Dab-IBU)-GGNle-CycMSH<sub>hex</sub> displayed the IC<sub>50</sub> values of 1.41 ± 0.37, 1.52 ± 0.08, 0.03 ± 0.01, and 0.58 ± 0.06 nM on B16/F10 melanoma cells, respectively. <sup>177</sup>Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSH<sub>hex</sub> exhibited the lowest liver and kidney uptake among all four designed <sup>177</sup>Lu peptides. Therefore, <sup>177</sup>Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSH<sub>hex</sub> was further evaluated for its full biodistribution and melanoma imaging properties. The B16/F10 melanoma uptake of <sup>177</sup>Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSH<sub>hex</sub> was 19.5 ± 3.12, 24.12 ± 3.35, 23.85 ± 2.08, and 10.80 ± 2.89% ID/g at 0.5, 2, 4, and 24 h postinjection, respectively. Moreover, <sup>177</sup>Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSH<sub>hex</sub> could clearly visualize the B16/F10 melanoma lesions at 2 h postinjection. The conjugation of IBU with or without a linker to GGNle-CycMSH<sub>hex</sub> affected the MC1R binding affinities of the designed peptides. The charge of the linker played a key role in the liver and kidney uptake of <sup>177</sup>Lu-Asp-IBU, <sup>177</sup>Lu-Asn-IBU, and <sup>177</sup>Lu-Dab-IBU. <sup>177</sup>Lu-Asp-IBU exhibited higher tumor/liver and tumor/kidney uptake ratios than those of <sup>177</sup>Lu-Asn-IBU and <sup>177</sup>Lu-Dab-IBU, underscoring its potential evaluation for melanoma therapy in the future.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141553614","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
Photodynamic Therapy Synergizes CD47 Blockade Strategy for Enhanced Antitumor Therapy. 光动力疗法协同 CD47 阻断策略,增强抗肿瘤治疗。
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2024-07-03 DOI: 10.1021/acs.molpharmaceut.4c00254
Zhaoming Fu, Minghui Feng, Jinxian Wu, Bo Liu, Jiajia Fu, Wen Song
{"title":"Photodynamic Therapy Synergizes CD47 Blockade Strategy for Enhanced Antitumor Therapy.","authors":"Zhaoming Fu, Minghui Feng, Jinxian Wu, Bo Liu, Jiajia Fu, Wen Song","doi":"10.1021/acs.molpharmaceut.4c00254","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00254","url":null,"abstract":"<p><p>The antitumor strategies based on innate immunity activation have become favored by researchers in recent years. In particular, strategies targeting antiphagocytic signaling blockade to enhance phagocytosis have been widely reported. For example, the addition of prophagocytic signals such as calreticulin could make the strategy significantly more effective. In this study, an antitumor strategy that combines photodynamic therapy (PDT) with CD47 blockade has been reported. This approach promotes the maturation of dendritic cells and the presentation of tumor antigens by PDT-mediated tumor immunogenic cell death, as well as the enhancement of cytotoxic T lymphocyte infiltration in tumor areas and the phagocytic activity of phagocytes. Furthermore, the downregulation and blockage of CD47 protein could further promote phagocytic activity, strengthen the innate immune system, and ultimately elevate the antitumor efficacy and inhibit tumor metastasis.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141496367","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
More Than a Gut Feeling─A Combination of Physiologically Driven Dissolution and Pharmacokinetic Modeling as a Tool for Understanding Human Gastric Motility. 不仅仅是直觉--将生理学驱动的溶解与药物动力学模型相结合,作为了解人体胃动力的工具。
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2024-07-03 DOI: 10.1021/acs.molpharmaceut.4c00117
Michał Romański, Marcela Staniszewska, Justyna Dobosz, Daria Myslitska, Jadwiga Paszkowska, Bartosz Kołodziej, Svitlana Romanova, Grzegorz Banach, Grzegorz Garbacz, Inese Sarcevica, Yeamin Huh, Vivek Purohit, Mark McAllister, Suet M Wong, Dorota Danielak
{"title":"More Than a Gut Feeling─A Combination of Physiologically Driven Dissolution and Pharmacokinetic Modeling as a Tool for Understanding Human Gastric Motility.","authors":"Michał Romański, Marcela Staniszewska, Justyna Dobosz, Daria Myslitska, Jadwiga Paszkowska, Bartosz Kołodziej, Svitlana Romanova, Grzegorz Banach, Grzegorz Garbacz, Inese Sarcevica, Yeamin Huh, Vivek Purohit, Mark McAllister, Suet M Wong, Dorota Danielak","doi":"10.1021/acs.molpharmaceut.4c00117","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00117","url":null,"abstract":"<p><p><i>In vivo</i> studies of formulation performance with <i>in vitro</i> and/or <i>in silico</i> simulations are often limited by significant gaps in our knowledge of the interaction between administered dosage forms and the human gastrointestinal tract. This work presents a novel approach for the investigation of gastric motility influence on dosage form performance, by combining biopredictive dissolution tests in an innovative <i>PhysioCell</i> apparatus with mechanistic physiology-based pharmacokinetic modeling. The methodology was based on the pharmacokinetic data from a large (<i>n</i> = 118) cohort of healthy volunteers who ingested a capsule containing a highly soluble and rapidly absorbed drug under fasted conditions. The developed dissolution tests included biorelevant media, varied fluid flows, and mechanical stress events of physiological timing and intensity. The dissolution results were used as inputs for pharmacokinetic modeling that led to the deduction of five patterns of gastric motility and their prevalence in the studied population. As these patterns significantly influenced the observed pharmacokinetic profiles, the proposed methodology is potentially useful to other <i>in vitro</i>-<i>in vivo</i> predictions involving immediate-release oral dosage forms.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141490000","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
Hydroxypropyl Cellulose-Based Orally Dissolving Film Loaded with Insoluble Dexamethasone for Treatment of Oral Ulcers. 含不溶性地塞米松的羟丙基纤维素口腔溶解膜用于治疗口腔溃疡
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2024-07-03 DOI: 10.1021/acs.molpharmaceut.4c00391
Xinyu Cao, Bingyu Wu, Jiayi Chen, Zhikuan Liu, Yang Yang, Shanshan Li, Hongyan Zhu, Lixing Xu, Haiqing Huang
{"title":"Hydroxypropyl Cellulose-Based Orally Dissolving Film Loaded with Insoluble Dexamethasone for Treatment of Oral Ulcers.","authors":"Xinyu Cao, Bingyu Wu, Jiayi Chen, Zhikuan Liu, Yang Yang, Shanshan Li, Hongyan Zhu, Lixing Xu, Haiqing Huang","doi":"10.1021/acs.molpharmaceut.4c00391","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00391","url":null,"abstract":"<p><p>Oral ulcers present as recurrent and spontaneous lesions, often causing intolerable burning pain that significantly disrupts patients' daily lives and compromises their quality of life. In addressing this clinical challenge, oral dissolving films (ODFs) have emerged as promising pharmaceutical formulations for oral ulcer management due to their rapid onset of action, ease of administration, and portability. In this study, ODFs containing the insoluble drug dexamethasone (Dex) were formulated for the treatment of oral ulcers in rabbits using a solvent casting method with ethanol as the solvent. To optimize the composition of the ODFs, a Box-Behnken Design (BBD) experiment was employed to investigate the effects of varying concentrations of hydroxypropyl cellulose (HPC), low-substituted hydroxypropyl cellulose (L-HPC), and plasticizer (glycerol) on key parameters, such as disintegration time, tensile strength, and peel-off efficiency of the films. Subsequently, the film properties of the Dex-loaded ODFs (ODF@Dex) were thoroughly assessed, revealing favorable attributes, including homogeneity, mechanical strength, and solubility. Notably, the use of ethanol as the solvent in the ODF preparation facilitated the homogeneous distribution of insoluble drugs within the film matrix, thereby enhancing their solubility and dissolution rate. Leveraging the potent pharmacological activity of Dex, ODF@Dex was further evaluated for its efficacy in promoting ulcer healing and mitigating the expression of inflammatory factors both in vitro and in vivo. The findings demonstrated that the ODF@Dex exerted significant antiulcer effects by modulating the PI3K/Akt signaling pathway, thus contributing to ulcer resolution. In conclusion, our study underscores the potential of HPC-based ODFs formulated with ethanol as a solvent as a promising platform for delivering insoluble drugs, offering a viable strategy for the clinical management of oral ulcers.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141489999","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
Small-Angle X-ray Scattering as a Powerful Tool for Phase and Crystallinity Assessment of Monoclonal Antibody Crystallites in Support of Batch Crystallization. 小角 X 射线散射是评估单克隆抗体结晶的相位和结晶度以支持批量结晶的有力工具。
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2024-07-03 DOI: 10.1021/acs.molpharmaceut.4c00418
Patrick Larpent, Lorenzo Codan, Jameson R Bothe, Luca Iuzzolino, Suzette Pabit, Sudipta Gupta, Thierry Fischmann, Yongchao Su, Paul Reichert, Dirk Stueber, Aaron Cote
{"title":"Small-Angle X-ray Scattering as a Powerful Tool for Phase and Crystallinity Assessment of Monoclonal Antibody Crystallites in Support of Batch Crystallization.","authors":"Patrick Larpent, Lorenzo Codan, Jameson R Bothe, Luca Iuzzolino, Suzette Pabit, Sudipta Gupta, Thierry Fischmann, Yongchao Su, Paul Reichert, Dirk Stueber, Aaron Cote","doi":"10.1021/acs.molpharmaceut.4c00418","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00418","url":null,"abstract":"<p><p>Crystalline suspensions of monoclonal antibodies (mAbs) have great potential to improve drug substance isolation and purification on a large scale and to be used for drug delivery via high-concentration formulations. Crystalline mAb suspensions are expected to have enhanced chemical and physical properties relative to mAb solutions delivered intravenously, making them attractive candidates for subcutaneous delivery. In contrast to small molecules, the development of protein crystalline suspensions is not a widely used approach in the pharmaceutical industry. This is mainly due to the challenges in finding crystalline hits and the suboptimal physical properties of the resulting crystallites when hits are found. Modern advances in instrumentation and increased knowledge of mAb crystallization have, however, resulted in higher probabilities of discovering crystal forms and improving their particle properties and characterization. In this regard, physical, analytical characterization plays a central role in the initial steps of understanding and later optimizing the crystallization of mAbs and requires careful selection of the appropriate tools. This contribution describes a novel crystal structure of the antibody pembrolizumab and demonstrates the usefulness of small-angle X-ray scattering (SAXS) for characterizing its crystalline suspensions. It illustrates the advantages of SAXS when used to (i) confirm crystallinity and crystal phase of crystallites produced in batch mode; (ii) confirm crystallinity under various conditions and detect variations in crystal phases, enabling fine-tuning of the crystallizations for phase control across multiple batches; (iii) monitor the physical response and stability of the crystallites in suspension with regard to filtration and washing; and (iv) monitor the physical stability of the crystallites upon drying. Overall, this work highlights how SAXS is an essential tool for mAb crystallization characterization.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141490014","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
Development and Validation of Novel Z-360-Based Macromolecules for the Active Targeting of CCK2-R. 开发和验证基于 Z-360 的新型大分子,用于主动靶向 CCK2-R。
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2024-07-03 DOI: 10.1021/acs.molpharmaceut.4c00124
Elisa Vettorato, Marco Verona, Greta Bellio, Stefania Croci, Riccardo Filadi, Alessandra Bisio, Eugenia Spessot, Alberto Andrighetto, Devid Maniglio, Mattia Asti, Giovanni Marzaro, Francesca Mastrotto
{"title":"Development and Validation of Novel Z-360-Based Macromolecules for the Active Targeting of CCK2-R.","authors":"Elisa Vettorato, Marco Verona, Greta Bellio, Stefania Croci, Riccardo Filadi, Alessandra Bisio, Eugenia Spessot, Alberto Andrighetto, Devid Maniglio, Mattia Asti, Giovanni Marzaro, Francesca Mastrotto","doi":"10.1021/acs.molpharmaceut.4c00124","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00124","url":null,"abstract":"<p><p>The cholecystokinin type 2 receptor (CCK2-R) represents an ideal target for cancer therapy since it is overexpressed in several tumors and is associated with poor prognosis. Nastorazepide (Z-360), a selective CCK2-R antagonist, has been widely investigated as a CCK2-R ligand for targeted therapy; however, its high hydrophobicity may represent a limit to cell selectivity and optimal in vivo biodistribution. Here, we present three new fluorescent Z-360 derivatives (<b>IP-002</b><sub><b>G</b></sub><b>-Rho, IP-002</b><sub><b>L</b></sub><b>-Rho, and IP-002</b><sub><b>M</b></sub><b>-Rho</b>) in which nastorazepide was linked, through spacers bearing different saccharides (glucose (G), lactose (L), and maltotriose (M)), to sulforhodamine B. A fourth compound (<b>IP-002</b><sub><b>H</b></sub><b>-Rho</b>) with no pendant sugar was also synthesized as a control. Through two-dimensional (2D) and three-dimensional (3D) in vitro studies, we evaluated the compound association with and selectivity for CCK2-R-overexpressing cells (A431-CCK2-R<sup>+</sup>) vs CCK2-R-underexpressing cells (A431 WT). 2D in vitro studies highlighted a progressive increase of IP-002<sub><i>x</i></sub>-Rho association with A431-CCK2-R<sup>+</sup> cells according to the linker hydrophilicity, that is, maltotriose > lactose > glucose > hydrogen, with <b>IP-002</b><sub><b>M</b></sub><b>-Rho</b> showing a 2.4- and a 1.36-fold higher uptake than <b>IP-002</b><sub><b>G</b></sub><b>-Rho</b> and <b>IP-002</b><sub><b>L</b></sub><b>-Rho</b>, respectively. Unexpectedly, <b>IP-002</b><sub><b>H</b></sub><b>-Rho</b> showed a similar cell association to that of <b>IP-002</b><sub><b>L</b></sub><b>-Rho</b> but with no difference between the two tested cell lines. On the contrary, association with A431-CCK2-R<sup>+</sup> cells as compared to the A431 WT was found to be 1.08-, 1.14-, and 1.37-fold higher for <b>IP-002</b><sub><b>G</b></sub><b>-Rho</b>, <b>IP-002</b><sub><b>L</b></sub><b>-Rho</b>, and <b>IP-002</b><sub><b>M</b></sub><b>-Rho</b>, respectively, proving <b>IP-002</b><sub><b>M</b></sub><b>-Rho</b> to be the best-performing compound, as also confirmed by competition studies. Trafficking studies on A431-CCK2-R<sup>+</sup> cells incubated with <b>IP-002</b><sub><b>M</b></sub><b>-Rho</b> suggested the coexistence of receptor-mediated endocytosis and simple diffusion. On the contrary, a high and selective uptake of <b>IP-002</b><sub><b>M</b></sub><b>-Rho</b> by A431-CCK2-R<sup>+</sup> cells only was observed on 3D scaffolds embedded with cells, underlining the importance of 3D models in in vitro preliminary evaluation.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141496366","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
Advancing mRNA Therapeutics: The Role and Future of Nanoparticle Delivery Systems. 推进 mRNA 治疗:纳米颗粒传输系统的作用和未来。
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2024-07-02 DOI: 10.1021/acs.molpharmaceut.4c00276
Jiaxuan Li, Yuning Zhang, Yong-Guang Yang, Tianmeng Sun
{"title":"Advancing mRNA Therapeutics: The Role and Future of Nanoparticle Delivery Systems.","authors":"Jiaxuan Li, Yuning Zhang, Yong-Guang Yang, Tianmeng Sun","doi":"10.1021/acs.molpharmaceut.4c00276","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00276","url":null,"abstract":"<p><p>The coronavirus (COVID-19) pandemic has underscored the critical role of mRNA-based vaccines as powerful, adaptable, readily manufacturable, and safe methodologies for prophylaxis. mRNA-based treatments are emerging as a hopeful avenue for a plethora of conditions, encompassing infectious diseases, cancer, autoimmune diseases, genetic diseases, and rare disorders. Nonetheless, the in vivo delivery of mRNA faces challenges due to its instability, suboptimal delivery, and potential for triggering undesired immune reactions. In this context, the development of effective drug delivery systems, particularly nanoparticles (NPs), is paramount. Tailored with biophysical and chemical properties and susceptible to surface customization, these NPs have demonstrated enhanced mRNA delivery in vivo and led to the approval of several NPs-based formulations for clinical use. Despite these advancements, the necessity for developing a refined, targeted NP delivery system remains imperative. This review comprehensively surveys the biological, translational, and clinical progress in NPs-mediated mRNA therapeutics for both the prevention and treatment of diverse diseases. By addressing critical factors for enhancing existing methodologies, it aims to inform the future development of precise and efficacious mRNA-based therapeutic interventions.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141489998","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
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
请完成安全验证×
相关产品
×
本文献相关产品
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信