Bioconjugate Chemistry Bioconjugate最新文献

{"title":"Synergistic Polymer Blending Informs Efficient Terpolymer Design and Machine Learning Discerns Performance Trends for pDNA Delivery.","authors":"Michael C Leyden, Felipe Oviedo, Sonashree Saxena, Ramya Kumar, Ngoc Le, Theresa M Reineke","doi":"10.1021/acs.bioconjchem.4c00028","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00028","url":null,"abstract":"<p><p>Cationic polymers offer an alternative to viral vectors in nucleic acid delivery. However, the development of polymer vehicles capable of high transfection efficiency and minimal toxicity has remained elusive, and continued exploration of the vast design space is required. Traditional single polymer syntheses with large monomer bases are very time-intensive, limiting the speed at which new formulations are identified. In this work, we present an experimental method for the quick probing of the design space, utilizing a combinatorial set of 90 polymer blends, derived from 6 statistical copolymers, to deliver pDNA. This workflow facilitated rapid screening of polyplex compositions, successfully tailoring polyplex hydrophobicity, particle size, and payload binding affinity. This workflow identified blended polyplexes with high levels of transfection efficiency and cell viability relative to single copolymer controls and commercial JetPEI, indicating synergistic benefits from copolymer blending. Polyplex composition was coupled with biological outputs to guide the synthesis of single terpolymer vehicles, with high-performing polymers P10 and M20, providing superior transfection of HEK293T cells in serum-free and serum-containing media, respectively. Machine learning coupled with SHapley Additive exPlanations (SHAP) was used to identify polymer/polyplex attributes that most impact transfection efficiency, viability, and overall effective efficiency. Subsequent transfections on ARPE-19 and HDFn cells found that P10 and M20 were surpassed in performance by M10, contrasting with results in HEK293T cells. This cell type dependency reinforced the need to evaluate transfection conditions with multiple cell models to potentially identify moieties more beneficial to delivery in certain tissues. Overall, the workflow employed can be used to expedite the exploration of the polymer design space, bypassing extensive synthesis, and to develop improved polymer delivery vehicles more readily for nucleic acid therapies.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141453617","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":"Recent Advances in Nanoimmunotherapy by Modulating Tumor-Associated Macrophages for Cancer Therapy.","authors":"Jialei Hao, Xinzhi Zhao, Chun Wang, Xianghui Cao, Yang Liu","doi":"10.1021/acs.bioconjchem.4c00242","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00242","url":null,"abstract":"<p><p>Cancer immunotherapy has yielded remarkable results across a variety of tumor types. Nevertheless, the complex and immunosuppressive microenvironment within solid tumors poses significant challenges to established therapies such as immune checkpoint blockade (ICB) and chimeric antigen receptor T-cell (CAR-T) therapy. Within the milieu, tumor-associated macrophages (TAMs) play a significant role by directly suppressing T-cell functionality and fostering an immunosuppressive environment. Effective regulation of TAMs is, therefore, crucial to enhancing the efficacy of immunotherapies. Various therapeutic strategies targeting TAM modulation have emerged, including blocking TAM recruitment, direct elimination, promoting repolarization toward the M1 phenotype, and enhancing phagocytic capacity against tumor cells. The recently introduced CAR macrophage (CAR-M) therapy opens new possibilities for macrophage-based immunotherapy. Compared with CAR-T, CAR-M may demonstrate superior targeting and infiltration capabilities toward solid tumors. This review predominantly delves into the origin and development process of TAMs, their role in promoting tumor growth, and provides a comprehensive overview of immunotherapies targeting TAMs. It underscores the significance of regulating TAMs in bolstering antitumor therapies while discussing the potential and challenges of developing TAMs as targets for immunotherapy.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141448990","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":"Organometallic Oxidative Addition Complexes for <i>S</i>-Arylation of Free Cysteines.","authors":"Hayden R Montgomery, Alexander M Spokoyny, Heather D Maynard","doi":"10.1021/acs.bioconjchem.4c00222","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00222","url":null,"abstract":"<p><p>Development of bioconjugation strategies to efficiently modify biomolecules is of key importance for fundamental and translational scientific studies. Cysteine <i>S</i>-arylation is an approach which is becoming more popular due to generally rapid kinetics and high chemoselectivity, as well as the strong covalently bonded <i>S</i>-aryl linkage created in these processes. Organometallic approaches to cysteine <i>S</i>-arylation have been explored that feature many advantages compared to their more traditional organic counterparts. In this Viewpoint, progress in the use of Au(III) and Pd(II) oxidative addition (OA) complexes for stoichiometric cysteine <i>S</i>-arylation is presented and discussed. A focus is placed on understanding the rapid kinetics of these reactions under mild conditions, as well as the ability to generate biomolecular heterostructures. Potential avenues for further exploration are addressed and usefulness of these methods to the practitioner are emphasized in the discussion.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141445538","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":"Duo-Chol: A Photoconvertible Live Cell Imaging Tool for Tracking Cholesterol.","authors":"June H Ahn, Christopher L Johnny, David M Chenoweth","doi":"10.1021/acs.bioconjchem.4c00207","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00207","url":null,"abstract":"<p><p>Investigating cholesterol trafficking pathways continues to be of significant scientific interest owing to its homeostasis being associated with several debilitating cardiovascular and neurodegenerative diseases including atherosclerosis, Niemann-Pick's disease, Alzheimer's disease, and Parkinson's disease. To further our understanding of cholesterol trafficking, it is imperative to develop new fluorescent probes that possess improved photostability, low efflux, and high spatial and temporal resolution for live-cell imaging. In this study, we developed a photoconvertible fluorescent cholesterol analog, Duo-Chol, enabling the improved spatiotemporal fluorescence imaging of the dynamic localization of cholesterol in live cells. This tool provides a unique and powerful approach to interrogating cholesterol dynamics, addressing the limitations of existing methods, and expanding our ability to probe the biological role of sterols in living cells.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141445537","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":"Lysosome-Targeted and pH-Activatable Phototheranostics for NIR-II Fluorescence Imaging-Guided Nasopharyngeal Carcinoma Phototherapy.","authors":"Zelong Li, Sha Yang, Hao Xiao, Qiang Kang, Na Li, Gui-Long Wu, Senyou Tan, Wenjie Wang, Qian Fu, Xiao Tang, Jun Zhou, Yifei Huang, Guodong Chen, Xiaofeng Tan, Qinglai Yang","doi":"10.1021/acs.bioconjchem.4c00225","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00225","url":null,"abstract":"<p><p>Currently, clinical therapeutic strategies for nasopharyngeal carcinoma (NPC) confront insurmountable dilemmas in which surgical resection is incomplete and chemotherapy/radiotherapy has significant side effects. Phototherapy offers a maneuverable, effective, and noninvasive pattern for NPC therapy. Herein, we developed a lysosome-targeted and pH-responsive nanophototheranostic for near-infrared II (NIR-II) fluorescence imaging-guided photodynamic therapy (PDT) and photothermal therapy (PTT) of NPC. A lysosome-targeted S-D-A-D-S-type NIR-II phototheranostic molecule (IRFEM) is encapsulated within the acid-sensitive amphiphilic DSPE-Hyd-PEG2k to form IRFEM@DHP nanoparticles (NPs). The prepared IRFEM@DHP exhibits a good accumulation in the acidic lysosomes for facilitating the release of IRFEM, which could disrupt lysosomal function by generating an amount of heat and ROS under laser irradiation. Moreover, the guidelines of NIR-II fluorescence enhance the accuracy of PTT/PDT for NPC and avoid damage to normal tissues. Remarkably, IRFEM@DHP enable efficient antitumor effects both <i>in vitro</i> and <i>in vivo</i>, opening up a new avenue for precise NPC theranostics.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141430786","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":"Increasing Signal Intensity of Fluorescent Oligo-Labeled Antibodies to Enable Combination Multiplexing.","authors":"Madeline E McCarthy, Xiaoming Lu, Oluwaferanmi Ogunleye, Danielle R Latham, Megan Abravanel, Daniel Pritko, Jonah R Huggins, Charlotte V Haskell, Nishi D Patel, Zachariah A Pittman, Hugo Sanabria, Marc R Birtwistle","doi":"10.1021/acs.bioconjchem.4c00246","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00246","url":null,"abstract":"<p><p>Full-spectrum flow cytometry has increased antibody-based multiplexing, yet further increases remain potentially impactful. We recently proposed how fluorescence multiplexing using spectral imaging and combinatorics (MuSIC) could do so using tandem dyes and an oligo-based antibody labeling method. In this work, we found that such labeled antibodies had significantly lower signal intensities than conventionally labeled antibodies in human cell experiments. To improve signal intensity, we tested moving the fluorophores from the original external (ext.) 5' or 3' end-labeled orientation to internal (int.) fluorophore modifications. Cell-free spectrophotometer measurements showed a ∼6-fold signal intensity increase of the new int. configuration compared to the previous ext. configuration. Time-resolved fluorescence and fluorescence correlation spectroscopy showed that the ∼3-fold brightness difference is due to static quenching most likely by the oligo or solution in the ext. configuration. Spectral flow cytometry experiments using peripheral blood mononuclear cells show int. MuSIC probe-labeled antibodies (i) retained increased signal intensity while having no significant difference in the estimated % of CD8+ lymphocytes and (ii) labeled with Atto488, Atto647, and Atto488/647 combinations can be demultiplexed in triple-stained samples. The antibody labeling approach is general and can be broadly applied to many biological and diagnostic applications where spectral detection is available.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141416579","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":"https://doi.org/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":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-06-17","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":"Facile Access to Branched Multispecific Proteins.","authors":"Aniekan Okon, Jinyi Yang, JoLynn B Giancola, Oscar J Molina, Jessica Sayers, Keith M Cheah, Yanfeng Li, Eric R Strieter, Ronald T Raines","doi":"10.1021/acs.bioconjchem.4c00162","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00162","url":null,"abstract":"<p><p>Approaches that leverage orthogonal chemical reactions to generate protein-protein conjugates have expanded access to bespoke chimeras. Although the literature is replete with examples of the semisynthesis of bispecific proteins, few methods exist for the semisynthesis of protein conjugates of higher complexity (i.e., greater than two-protein fusions). The recent emergence of trispecific cell engagers for immune cell redirection therapies necessitates the development of chemical methods for the construction of trispecific proteins that would otherwise be inaccessible via natural protein synthesis. Here, we demonstrate that 3-bromo-5-methylene pyrrolone (3Br-5MP) can be used to effect the facile chemical synthesis of trispecific peptides and proteins with exquisite control over the addition of each monomer. The multimeric complexes maintain epitope functionality both in human cells and upon immobilization. We anticipate that facile access to trispecific proteins using this 3Br-5MP will have broad utility in basic science research and will quicken the pace of research to establish novel, multimeric immune cell redirection therapies.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141326992","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":"Rose Bengal Labeled Bovine Serum Albumin for Protein Transport Imaging in Subcutaneous Tissues Using Computed Tomography and Fluorescence Microscopy.","authors":"Mazin H Hakim, Melissa C Brindise, Adib Ahmadzadegan, Kevin P Buno, Antonio C F Dos Santos, Kevin R Cragg, Zhongwang Dou, Michael R Ladisch, Arezoo M Ardekani, Pavlos P Vlachos, Luis Solorio","doi":"10.1021/acs.bioconjchem.4c00240","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00240","url":null,"abstract":"<p><p>Subcutaneous (SC) injection of protein-based therapeutics is a convenient and clinically established drug delivery method. However, progress is needed to increase the bioavailability. Transport of low molecular weight (<i>M</i>_w) biotherapeutics such as insulin and small molecule contrast agents such as lipiodol has been studied using X-ray computed tomography (CT). This analysis, however, does not translate to the investigation of higher <i>M</i>_w therapeutics, such as monoclonal antibodies (mAbs), due to differences in molecular and formulation properties. In this study, an iodinated fluorescein analog rose bengal (RB) was used as a radiopaque and fluorescent label to track the distribution of bovine serum albumin (BSA) compared against unconjugated RB and sodium iodide (NaI) via CT and confocal microscopy following injection into ex vivo porcine SC tissue. Importantly, the high concentration BSA-RB exhibited viscosities more like that of viscous biologics than the small molecule contrast agents, suggesting that the labeled protein may serve as a more suitable formulation for the investigation of injection plumes. Three-dimensional (3D) renderings of the injection plumes showed that the BSA-RB distribution was markedly different from unconjugated RB and NaI, indicating the need for direct visualization of large protein therapeutics using conjugated tags rather than using small molecule tracers. Whereas this proof-of-concept study shows the novel use of RB as a label for tracking BSA distribution, our experimental approach may be applied to high <i>M</i>_w biologics, including mAbs. These studies could provide crucial information about diffusion in SC tissue and the influence of injection parameters on distribution, transport, and downstream bioavailability.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141320092","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":"Late-Stage Desulfurization Enables Rapid and Efficient Solid-Phase Synthesis of Cathepsin-Cleavable Linkers for Antibody-Drug Conjugates.","authors":"Marzieh Ahangarpour, Margaret A Brimble, Iman Kavianinia","doi":"10.1021/acs.bioconjchem.4c00199","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00199","url":null,"abstract":"<p><p>The synthesis of linker-payloads is a critical step in developing antibody-drug conjugates (ADCs), a rapidly advancing therapeutic approach in oncology. The conventional method for synthesizing cathepsin B-labile dipeptide linkers, which are commonly used in ADC development, involves the solution-phase assembly of cathepsin B-sensitive dipeptides, followed by the installation of self-immolative <i>para</i>-aminobenzyl carbonate to facilitate the attachment of potent cytotoxic payloads. However, this approach is often low yield and laborious, especially when extending the peptide chain with components like glutamic acid to improve mouse serum stability or charged amino acids or poly(ethylene glycol) moieties to enhance linker hydrophilicity. Here, we introduce a novel approach utilizing late-stage desulfurization chemistry, enabling safe, facile, and cost-effective access to the cathepsin B-cleavable linker, Val-Ala-PABC-MMAE, on resin for the first time.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141315978","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}