Bioconjugate Chemistry最新文献

{"title":"Size-Dependent Glioblastoma Targeting by Polymeric Nanoruler with Prolonged Blood Circulation.","authors":"Yukine Ishibashi, Mitsuru Naito, Yusuke Watanuki, Mao Hori, Satomi Ogura, Kaori Taniwaki, Masaru Cho, Ryosuke Komiya, Yuki Mochida, Kanjiro Miyata","doi":"10.1021/acs.bioconjchem.4c00235","DOIUrl":"10.1021/acs.bioconjchem.4c00235","url":null,"abstract":"<p><p>Currently, there is no effective treatment for glioblastoma multiforme (GBM), the most frequent and malignant type of brain tumor. The blood-brain (tumor) barrier (BB(T)B), which is composed of tightly connected endothelial cells and pericytes (with partial vasculature collapse), hampers nanomedicine accumulation in tumor tissues. We aimed to explore the effect of nanomedicine size on passive targeting of GBM. A series of size-tunable poly(ethylene glycol) (PEG)-grafted copolymers (gPEGs) were constructed with hydrodynamic diameters of 8-30 nm. Biodistribution studies using orthotopic brain tumor-bearing mice revealed that gPEG brain tumor accumulation was maximized at 10 nm with ∼14 dose %/g of tumor, which was 19 times higher than that in the normal brain region and 4.2 times higher than that of 30-nm gPEG. Notably, 10-nm gPEG exhibited substantially higher brain tumor accumulation than 11-nm linear PEG owing to the prolonged blood circulation property of gPEGs, which is derived from a densely PEG-packed structure. 10 nm gPEG exhibited deeper penetration into the brain tumor tissue than the larger gPEGs did (>10 nm). This study demonstrates, for the first time, the great potential of a nanomedicine downsizing strategy for passive GBM targeting.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":"1154-1159"},"PeriodicalIF":4.0,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141489875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lignin-Based Nanoparticles for Combination of Tumor Oxidative Stress Amplification and Reactive Oxygen Species Responsive Drug Release.","authors":"Ziwei Zhou, Jin Wang, Xin Xu, Zhuang Wang, Lingchen Mao, Shanhu Zhang, Huanhuan Zhang, Yuqiang Li, Qingsong Yu, Ni Jiang, Guan Zhang, Zhihua Gan, Zhenbo Ning","doi":"10.1021/acs.bioconjchem.4c00261","DOIUrl":"10.1021/acs.bioconjchem.4c00261","url":null,"abstract":"<p><p>In this study, maleic anhydride-modified lignin (LG-M), a ROS-cleavable thioketal (TK) bond, and polyethylene glycol (PEG) were used to synthesize a lignin-based copolymer (LG-M(TK)-PEG). Doxorubicin (DOX) was attached to the ROS-cleavable bond in the LG-M(TK)-PEG for the preparation of the ROS-activatable DOX prodrug (LG-M(TK-DOX)-PEG). Nanoparticles (NPs) with a size of 125.7 ± 3.1 nm were prepared by using LG-M(TK-DOX)-PEG, and they exhibited enhanced uptake by cancer cells compared to free DOX. Notably, the presence of lignin in the nanoparticles could boost ROS production in breast cancer 4T1 cells while showing little effect on L929 normal cells. This selective effect facilitated the specific activation of the DOX prodrug in the tumor microenvironment, resulting in the superior tumor inhibitory effects and enhanced biosafety relative to free DOX. This work demonstrates the potential of the LG-M(TK-DOX)-PEG NPs as an efficient drug delivery system for cancer treatment.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":"1207-1217"},"PeriodicalIF":4.0,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141578229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rational Design of Cyanine-Based Fluorogenic Dimers to Reduce Nonspecific Interactions with Albumin and Lipid Bilayers: Application to Highly Sensitive Imaging of GPCRs in Living Cells.","authors":"Yann Berthomé, Julie Gerber, Fabien Hanser, Stéphanie Riché, Nicolas Humbert, Christel Valencia, Pascal Villa, Julie Karpenko, Océane Florès, Dominique Bonnet","doi":"10.1021/acs.bioconjchem.4c00147","DOIUrl":"10.1021/acs.bioconjchem.4c00147","url":null,"abstract":"<p><p>Fluorogenic dimers with polarity-sensitive folding are powerful probes for live-cell bioimaging. They switch on their fluorescence only after interacting with their targets, thus leading to a high signal-to-noise ratio in wash-free bioimaging. We previously reported the first near-infrared fluorogenic dimers derived from cyanine 5.5 dyes for the optical detection of G protein-coupled receptors. Owing to their hydrophobic character, these dimers are prone to form nonspecific interactions with proteins such as albumin and with the lipid bilayer of the cell membrane resulting in a residual background fluorescence in complex biological media. Herein, we report the rational design of new fluorogenic dimers derived from cyanine 5. By modulating the chemical structure of the cyanine units, we discovered that the two asymmetric cyanine 5.25 dyes were able to form intramolecular H-aggregates and self-quenched in aqueous media. Moreover, the resulting original dimeric probes enabled a significant reduction of the nonspecific interactions with bovine serum albumin and lipid bilayers compared with the first generation of cyanine 5.5 dimers. Finally, the optimized asymmetric fluorogenic dimer was grafted to carbetocin for the specific imaging of the oxytocin receptor under no-wash conditions directly in cell culture media, notably improving the signal-to-background ratio compared with the previous generation of cyanine 5.5 dimers.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":"1182-1189"},"PeriodicalIF":4.0,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141561934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytokine Biopharmaceuticals with \"Activity-on-Demand\" for Cancer Therapy.","authors":"Giulia Rotta, Emanuele Puca, Samuele Cazzamalli, Dario Neri, Sheila Dakhel Plaza","doi":"10.1021/acs.bioconjchem.4c00187","DOIUrl":"10.1021/acs.bioconjchem.4c00187","url":null,"abstract":"<p><p>Cytokines are small proteins that modulate the activity of the immune system. Because of their potent immunomodulatory properties, some recombinant cytokines have undergone clinical development and have gained marketing authorization for the therapy of certain forms of cancer. Recombinant cytokines are typically administered at ultralow doses, as many of them can cause substantial toxicity even at submilligram quantities. In an attempt to increase the therapeutic index, fusion proteins based on tumor-homing antibodies (also called \"immunocytokines\") have been considered, and some products in this class have reached late-stage clinical trials. While antibody-cytokine fusions, which preferentially localize in the neoplastic mass, can activate tumor-resident leukocytes and may be more efficacious than their nontargeted counterparts, such products typically conserve an intact cytokine activity, which may prevent escalation to curative doses. To further improve tolerability, several strategies have been conceived for the development of antibody-cytokine fusions with \"activity-on-demand\", acting on tumors but helping spare normal tissues from undesired toxicity. In this article, we have reviewed some of the most promising strategies, outlining their potential as well as possible limitations.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":"1075-1088"},"PeriodicalIF":4.0,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141416542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Confocal Scanning Protein–Protein Interaction Assay (PPI-CONA) Reveals Exceptional Selectivity and Specificity of CC0651, a Small Molecule Binding Enhancer of the Weak Interaction between the E2 Ubiquitin-Conjugating Enzyme CDC34A and Ubiquitin","authors":"Joanna Koszela,&nbsp;Nhan T. Pham,&nbsp;Steven Shave,&nbsp;Daniel St-Cyr,&nbsp;Derek F. Ceccarelli,&nbsp;Steven Orlicky,&nbsp;Anne Marinier,&nbsp;Frank Sicheri,&nbsp;Mike Tyers and Manfred Auer*,&nbsp;","doi":"10.1021/acs.bioconjchem.4c0034510.1021/acs.bioconjchem.4c00345","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00345https://doi.org/10.1021/acs.bioconjchem.4c00345","url":null,"abstract":"<p >Protein–protein interactions (PPIs) are some of the most challenging target classes in drug discovery. Highly sensitive detection techniques are required for the identification of chemical modulators of PPIs. Here, we introduce PPI confocal nanoscanning (PPI-CONA), a miniaturized, microbead based high-resolution fluorescence imaging assay. We demonstrate the capabilities of PPI-CONA by detecting low affinity ternary complex formation between the human CDC34A ubiquitin-conjugating (E2) enzyme, ubiquitin, and CC0651, a small molecule enhancer of the CDC34A–ubiquitin interaction. We further exemplify PPI-CONA with an E2 enzyme binding study on CC0651 and a CDC34A binding specificity study of a series of CC0651 analogues. Our results indicate that CC0651 is highly selective toward CDC34A. We further demonstrate how PPI-CONA can be applied to screening very low affinity interactions. PPI-CONA holds potential for high-throughput screening for modulators of PPI targets and characterization of their affinity, specificity, and selectivity.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":"35 9","pages":"1441–1449 1441–1449"},"PeriodicalIF":4.0,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.bioconjchem.4c00345","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142237606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A New Age of Drug Delivery: A Comparative Perspective of Ferritin-Drug Conjugates (FDCs) and Antibody-Drug Conjugates (ADCs).","authors":"Juanji Hong, Kang Li, Jiuyang He, Minmin Liang","doi":"10.1021/acs.bioconjchem.4c00254","DOIUrl":"10.1021/acs.bioconjchem.4c00254","url":null,"abstract":"<p><p>Ferritin-drug conjugates (FDCs) and antibody-drug conjugates (ADCs) respectively represent the innovative and traditional mainstream approaches in drug delivery systems, each offering unique advantages and challenges. This viewpoint delves into the evolving landscape of drug delivery technologies, specifically focusing on FDCs and ADCs. Each method exhibits unique advantages and inherent challenges, shaping their roles in therapeutic applications. The article provides a comparative analysis of two delivery systems, FDCs and ADCs, in terms of targeting accuracy, drug loading capacity, and the nature of the payload itself. This comparison offers valuable insights into the distinct advantages and disadvantages associated with each system, enabling a clearer understanding of their potential applications and limitations in therapeutic contexts. This analysis is crucial for optimizing the use of these delivery systems across varying medical contexts, offering a comprehensive overview of their impact on the field of drug delivery.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":"1142-1147"},"PeriodicalIF":4.0,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141915425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and Structure Optimization of Star Copolymers as Tunable Macromolecular Carriers for Minimal Immunogen Vaccine Delivery.","authors":"Gabriela Mixová, Eva Tihlaříková, Yaling Zhu, Lucie Schindler, Ladislav Androvič, Lucie Kracíková, Eliška Hrdá, Bedřich Porsch, Michal Pechar, Christopher M Garliss, David Wilson, Hugh C Welles, Jake Holechek, Qiuyin Ren, Geoffrey M Lynn, Vilém Neděla, Richard Laga","doi":"10.1021/acs.bioconjchem.4c00273","DOIUrl":"10.1021/acs.bioconjchem.4c00273","url":null,"abstract":"<p><p>Minimal immunogen vaccines are being developed to focus antibody responses against otherwise challenging targets, including human immunodeficiency virus (HIV), but multimerization of the minimal peptide immunogen on a carrier platform is required for activity. Star copolymers comprising multiple hydrophilic polymer chains (\"arms\") radiating from a central dendrimer unit (\"core\") were recently reported to be an effective platform for arraying minimal immunogens for inducing antibody responses in mice and primates. However, the impact of different parameters of the star copolymer (e.g., minimal immunogen density and hydrodynamic size) on antibody responses and the optimal synthetic route for controlling those parameters remains to be fully explored. We synthesized a library of star copolymers composed of poly[<i>N</i>-(2-hydroxypropyl)methacrylamide] hydrophilic arms extending from poly(amidoamine) dendrimer cores with the aim of identifying the optimal composition for use as minimal immunogen vaccines. Our results show that the length of the polymer arms has a crucial impact on the star copolymer hydrodynamic size and is precisely tunable over a range of 20-50 nm diameter, while the dendrimer generation affects the maximum number of arms (and therefore minimal immunogens) that can be attached to the surface of the dendrimer. In addition, high-resolution images of selected star copolymer taken by a custom-modified environmental scanning electron microscope enabled the acquisition of high-resolution images, providing new insights into the star copolymer structure. Finally, <i>in vivo</i> studies assessing a star copolymer vaccine comprising an HIV minimal immunogen showed the criticality of polymer arm length in promoting antibody responses and highlighting the importance of composition tunability to yield the desired biological effect.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":"1218-1232"},"PeriodicalIF":4.0,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11342300/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141854140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a Self-Luminescent Living Bioreactor for Enhancing Photodynamic Therapy in Breast Cancer.","authors":"Yanian Xiong, Yingtung Lo, Huizhu Song, Jianzhong Lu","doi":"10.1021/acs.bioconjchem.4c00334","DOIUrl":"10.1021/acs.bioconjchem.4c00334","url":null,"abstract":"<p><p>The penetration ability of visible light (<2 mm) and near-infrared (NIR) light (∼1 cm) remarkably impairs the therapeutic efficacy and clinical applications of photodynamic therapy (PDT). To address the limitation of light penetration depth, a novel self-luminescent bacterium, teLuc.FP-EcN, has been engineered through transfection of a fusion expression plasmid containing the luciferase gene teLuc and bright red fluorescent protein mScarlet-I into <i>Escherichia coli</i> Nissle 1917 (<i>EcN</i>). The engineered teLuc.FP-EcN can specifically target and colonize tumors without significant toxicity to the host. Acting as a continuous internal light source, teLuc.FP-EcN can activate the photosensitizer chlorin e6 (Ce6) to generate reactive oxygen species (ROS) and then effectively destroy tumor tissue from the inside. As a result, a significant reduction in tumor proliferation and extension of the overall survival in mouse tumor models has been observed. Furthermore, teLuc.FP-EcN-boosted PDT amplified its therapeutic effect by activating antitumor immune response, including the conversion of M2 macrophages into pro-inflammatory M1 macrophages, as well as an increase in the proportion of CD3⁺ T cells and a decrease in T-cell exhaustion. In conclusion, teLuc.FP-EcN can be used as an implantable light source for tumor phototherapy, which simultaneously possesses ROS generation and immune regulation.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":"1269-1282"},"PeriodicalIF":4.0,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141904967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microwave-Assisted Synthesis of β-<i>N</i>-Aryl Glycoamphiphiles with Diverse Supramolecular Assemblies and Lectin Accessibility.","authors":"Aïcha Abdallah, Emilie Gillon, Patrice Rannou, Anne Imberty, Sami Halila","doi":"10.1021/acs.bioconjchem.4c00224","DOIUrl":"10.1021/acs.bioconjchem.4c00224","url":null,"abstract":"<p><p>Glycoamphiphiles have attracted considerable interest in a broad range of application fields owing to their solution and bulk-state self-assembly abilities. Despite their importance, the straightforward synthesis of glycoamphiphiles consisting of a hydrophilic carbohydrate linked to a hydrophobic aglycone remains one of the major challenges in glycosciences. Here, a rapid, simple, and efficient synthetic access to chemically stable glycoamphiphiles at physiological pH, namely, <i>N</i>-(β-d-glycosyl)-2-alkylbenzamide, is reported. It leverages the nonreductive amination of unprotected carbohydrates with <i>ortho</i>-substituted aniline derivatives which could be readily obtained by reacting commercially available primary alkylamines with isatoic anhydride. This strategy avoids protection and deprotection of sugar hydroxyl groups and the use of reductive agents, which makes it advantageous in terms of atom and step economy. Moreover, in order to circumvent the cons of classical <i>N</i>-aryl glycosylation, we investigate the use of microwave as a heat source that provides fast, clean, and high-yield β-<i>N</i>-arylation of unprotected carbohydrates. Their self-assembly into water led to multiple morphologies of dynamic supramolecular glycoamphiphiles that were characterized to assess their ability to bind to lectins from pathogenic bacteria. Biophysical interactions probed by isothermal titration microcalorimetry revealed micromolar affinities for most of the synthesized glycoamphiphiles.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":"1200-1206"},"PeriodicalIF":4.0,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141561933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemical Synthesis of Interleukin-6 for Mirror-Image Screening.","authors":"Keisuke Aoki, Kayuu Maeda, Shinsuke Inuki, Hiroaki Ohno, Motohiro Nonaka, Shinya Oishi","doi":"10.1021/acs.bioconjchem.4c00204","DOIUrl":"10.1021/acs.bioconjchem.4c00204","url":null,"abstract":"<p><p>Interleukin-6 (IL-6), a multifunctional cytokine, is an attractive therapeutic target for immunological and inflammatory diseases. We investigated the chemical synthesis of IL-6 and its enantiomer (d-IL-6) using a sequential N-to-C native chemical ligation strategy from six peptide segments. Solubilizing Trt-K₁₀ tags improved the intermediate solubility and served as protecting groups during the metal-free desulfurization to facilitate the synthesis of full-length IL-6 protein. Synthetic l-IL-6 and recombinant IL-6 exhibited nearly identical structural and binding properties. The symmetrical binding property of d-IL-6 was also demonstrated by functional analysis using IL-6-binding peptides. The resulting functional d-IL-6 was employed to screen a phage-displayed antibody fragment library, leading to the identification of several d-IL-6-binding single-domain antibodies. This work will contribute to the development of novel, potent IL-6 inhibitors without the adverse effects of undesired immune activation.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":"1190-1199"},"PeriodicalIF":4.0,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141750465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}