Bioconjugate Chemistry最新文献

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":4.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/bcv036i007_1959890","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144631024","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":"","authors":"Gao-Li Xin, Chong Zhang, Jia-Lin Ni, Yong-Kang Li, Yu Sun and Xiu-Xia He*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":4.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.bioconjchem.5c00170","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144631028","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":"","authors":"Jie Zhong, Yuhang Li, Xiaotong Li, Feng Liang, Ran Tao, Shan Qian* and Xinyuan Fan*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":4.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.bioconjchem.5c00293","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144631033","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":"PET Imaging of Thyroid-Stimulating Hormone Receptor (TSHR) in Oncocytic Thyroid Carcinoma for Monitoring TSHR CAR T-Cell Therapy Response.","authors":"Wenhui Fu, Ephraim E Parent, Justyna J Gleba, Joshua A Knight, Saad J Kenderian, John A Copland, Hancheng Cai","doi":"10.1021/acs.bioconjchem.5c00235","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00235","url":null,"abstract":"<p><p>Oncocytic thyroid carcinoma (OTC) is often aggressive and refractory to radioiodine therapy, which is the current standard of care for metastatic thyroid cancer. The thyroid-stimulating hormone receptor (TSHR) regulates thyroid function and metabolism and is highly expressed in the thyroid gland and most thyroid tumors including OTC. Here, we report positron emission tomography (PET) imaging of radiolabeled TSHR antibody for detecting tumoral TSHR expression and monitoring TSHR chimeric antigen receptor (CAR) T-cell therapy response in an OTC mouse model. Radiotracer ⁸⁹Zr-DFO-TSHR-Ab was prepared as previously reported for PET imaging of TSHR expression. Tissue microarray analysis confirmed TSHR expression in both normal thyroid and OTC tumors. A human OTC xenograft model was established by subcutaneous injection of XTC.UC1 cells into NSG mice. PET imaging and biodistribution studies of TSHR expression were subsequently conducted in this model to assess TSHR-expression change before and after TSHR CAR T-cell therapy. TSHR-targeted CAR T-cells were administered intravenously, and longitudinal PET/CT imaging with ⁸⁹Zr-DFO-TSHR-Ab was performed at 24, 72, and 120 h postinjection to monitor tumor response. Eight weeks later, the same mice were rechallenged with XTC.UC1 cells in the contralateral flank to assess long-term therapeutic efficacy and immune memory through serial PET/CT imaging. PET imaging and biodistribution studies demonstrated that this radiotracer effectively detected TSHR-expressing OTC, with reasonable tumor uptake and imaging contrast. Following CAR T-cell therapy, TSHR PET showed significantly decreased tumor uptake, consistent with TSHR-targeted cell immunotherapy response with attenuated TSHR expression. These findings suggest ⁸⁹Zr-DFO-TSHR-Ab enables noninvasive identification of OTC tumors and real-time monitoring of response to TSHR-targeted CAR T-cell therapy.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641232","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":"Exploring the Potentials of Antibody-siRNA Conjugates in Tumor Cell Gene Silencing without Cationic Assistance.","authors":"Yahui Liu, Yanan Quan, Qi Mao, Ruolin Xu, Wanyi Tai","doi":"10.1021/acs.bioconjchem.5c00212","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00212","url":null,"abstract":"<p><p>Antibody-siRNA conjugates (ARCs) are a type of promising drug modalities for cancer therapy. However, initial reports of ARCs present the gene knockdown effect only in limited tissues (e.g., muscles) or tumors of special targets (e.g., TenB2 and BCMA receptors). To expand the scope to more targets, herein we built structurally defined DAR2 ARCs and examined their effect on targeted gene silencing of tumor cells without cationic assistance. We first evaluated the impact of linker structures and Cys-engineered sites on conjugation efficiency, revealing that the ThioMab conjugation of siRNA is favored by the rigid sulfo-SMCC linker coupling at the HC-A118C site. With an additional anion exchange purification process, reactions of this condition can yield a homogeneous ARC product with DAR close to 2 (DAR: 1.9). We found that ARCs, despite a lack of endosome-disrupting ability, can induce effective gene silencing in multiple types of tumor cells by free uptake. The RNAi potency of ARCs is largely affected by siRNA stability and the time interval of uptake. The maximal mRNA knockdown (70-80%) can be achieved on the fourth day after the uptake of ARC bearing the fully modified siRNAs (Adv ESC mode). The delayed silencing activity, together with the restriction to the stable siRNA, indicates that ARC escape from endosomes is a slow and rate-limiting step, suggesting the importance of siRNA stability and resistance to endosomal degradation in ARC activity. In vivo, the anti-HER2 ARC displays a much-compromised circulatory half-life (<i>t</i>_1/2 ∼ 8 h) in mice but can induce gene silencing in HCC1954 xenograft tumors and retard the tumor growth. This study demonstrates the potential of ARCs to treat cancers and other extrahepatic diseases.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144606830","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":"Engineering Fusion Proteins for Nanomedicine-Based Cytokine Therapy.","authors":"Anne de Dreu, Koen de Bruin, Ayla M Hokke, David P Schrijver, Danyel N H Beelen, Lars M Verhalle, Maria C Clavijo Perez, Tom Anbergen, Iris Versteeg, Rianne Maas, Robby C Zwolsman, Cristina Grao-Roldán, Branca Bartelet, Mirre M Trines, Daniek Hoorn, Gijs Ros, Yohana C Toner, Ewelina Kluza, Thijs Beldman, Carlos Pérez-Medina, Mihai G Netea, Maarten Merkx, Roy van der Meel, Willem J M Mulder","doi":"10.1021/acs.bioconjchem.5c00182","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00182","url":null,"abstract":"<p><p>Cytokines play a crucial role in cell communication and immunity, making them interesting potential therapeutics for immune-mediated conditions. However, cytokine therapeutics' clinical translation is hampered by their short blood half-lives and unfavorable biodistribution, resulting in toxicity and poor pharmacokinetics. In this study, we present a strategy to improve cytokines' pharmacokinetic profile by engineering fusions of apolipoproteins and cytokines, which are formulated into apolipoprotein-based nanoparticles (cytokine-aNPs). After establishing chemical and recombinant fusion approaches, we created a small library of diverse proteins, comprising fusions between apolipoprotein A1 or apolipoprotein E with either interleukin 1β, interleukin 2, or interleukin 4. Although chemical conjugation successfully generated biologically active fusion proteins, their yield and purity were insufficient for cytokine-aNP formulation. Using the recombinant method, we expressed and purified the fusion proteins and then incorporated them into cytokine-aNPs. In addition, we show that all cytokine-aNPs remain stable over at least 10 days and are of similar size and shape. We found that the fusion protein's cytokine component remains biologically active after purification and after formulation into cytokine-aNPs. In mice, using zirconium-89 radiolabeling to enable <i>in vivo</i> positron emission tomography imaging, we found that the pharmacokinetic profile of the cytokines incorporated into aNPs changed considerably. As compared to the native cytokines, we found the cytokine-aNPs to predominantly accumulate in the spleen, bone marrow, lymph nodes, and liver. Together, our results demonstrate that we can improve cytokines' <i>in vivo</i> properties using our fusion protein technology and aNP platform, opening up a translational avenue for nanomedicine-based cytokine therapy.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144612040","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":"Clickable and Degradable Polycarbonate Vehicles for mRNA Delivery.","authors":"Christopher J LaSalle, David V Morrissey, Theresa M Reineke","doi":"10.1021/acs.bioconjchem.5c00073","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00073","url":null,"abstract":"<p><p>The development of nucleic acid therapies has enabled access to treatments for several diseases previously thought untreatable, yet effective and safe delivery remains a hurdle. The benefit of synthetic vehicles lies in their modularity in optimizing performance and safety. Herein, we present a novel biodegradable polycarbonate alternative to the nondegradable synthetic and viral vectors often utilized in commercial gene therapies. This PC system leverages ring-opening polymerization of a cyclic carbonate to produce polymers (∼20 kDa) with pendant allyl groups compatible with thiol-ene click post-polymerization modification. The derivatization of the parent polymer enables a direct comparison of the pendant groups without molecular weight and dispersity variables. These pendants include 2-(dimethylamino)ethanethiol hydrochloride (DMA) as the cation and one of three hydrophilic modifiers: mercaptopropanol (OH), thioglycolic acid (COOH), and methoxy polyethylene glycol thiol (PEG), which modulate cellular membrane interaction, charge density, and sheathing properties. This family of vehicles forms stable polymer-mRNA complexes (polyplexes), confirmed via dynamic light scattering and gel electrophoresis. <i>In vitro</i> screening assays showed minimal cytotoxic effects with HEK293T (human embryonic kidney) and A549 (human lung cancer) cells, resulting in a statistically significant viability improvement over the polymer control, JetPEI. Coupling the viability with expression values of EGFP-encoded (enhanced green fluorescent protein) mRNA, <i>in vitro</i> delivery efficiency shows the polycarbonate performance on par with JetPEI in nearly all cases while offering degradation via hydrolysis. Overall, this modular polycarbonate scaffold improves cell viability and maintains performance similar to that of positive controls while featuring modularity and degradability.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144598902","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":"Synthetic Redox-Responsive Nanocomplexes Facilitate Spatially Controlled mRNA Release and Tumor-Selective Expression.","authors":"Sheng Lin, Xia Cheng, Xiyi Chen, Jinxuan He, Wenxiu An, Qiufang Bai, Qixian Chen, Lie Ma, Jianhua Hu, Yue Wang, Xiabin Lan","doi":"10.1021/acs.bioconjchem.5c00264","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00264","url":null,"abstract":"<p><p>The refinement of dynamic molecular mechanisms regulating mRNA release kinetics represents a critical frontier in advancing the synthetic mRNA delivery systems. This study details the synthesis of an intriguing ROS-responsive cationic block copolymer (pM-pBD) via reversible addition-fragmentation chain transfer (RAFT) polymerization, employing biocompatible 2-methacryloyloxyethyl phosphorylcholine (MPC) and charge-reversible (2-acryloyl)ethyl(boronic acid benzyl)diethylammonium bromide (BD) as monomeric precursors. The synthesized copolymer facilitates electrostatic-driven self-assembly with anionic mRNA. Mechanistically, the pBD block exhibits ROS-mediated charge transition, enabling stimulus-dependent molecular decomposition and promoting mRNA payload liberation, thereby establishing spatial regulation of translational activity. Furthermore, intracellular ROS modulation experiments revealed that systemic ascorbic acid administration selectively enriches reactive oxygen species within tumor microenvironments. This redox microenvironment significantly amplifies pM-pBD nanocomplex-mediated mRNA expression by an order of magnitude across multiple carcinogenic cell lines, validating the ROS-responsive characteristics of our rationally designed delivery platform. In vivo studies demonstrated the highest mRNA expression levels in tumors when aided by ascorbic acid adjuvants, despite lower tumor accumulation of mRNA compared to renal and hepatic sequestration post intravenous administration of the pM-pBD nanocomplex. This spatial expression pattern correlates with ascorbic acid-mediated intratumoral ROS accumulation, which promotes cargo release and subsequent protein synthesis of approximately 6.4-fold enhancement. Our approach, integrating redox-responsive polymer design with organ-specific pharmacological modulation, signifies a transformative advancement in targeted nucleic acid delivery. By merging stimulus-responsive materials science with tumor microenvironment biology, this methodology provides a foundation for spatially controlled mRNA expression, presenting an innovative strategy for precision oncology applications.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144598903","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":"Simple and High-Throughput Fluorescence Assay Method for DNA Damage Analysis in Single-Stranded DNA-Encoded Library Synthesis.","authors":"Gyung A Kim, Seungyoon Kang, Myo Naing Win, Min Su Han","doi":"10.1021/acs.bioconjchem.5c00219","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00219","url":null,"abstract":"<p><p>The fluorescent dye-based simple and high-throughput DNA damage assay method was developed for the single-stranded DNA-encoded library (ssDEL) synthesis. The extent of DNA hybridization between single-stranded DNA (ssDNA) and its complementary DNA is influenced by the damage ratio of ssDNA. This damage can be quantified by measuring the change in the fluorescence of PicoGreen, providing valuable insights into the overall ssDNA integrity and facilitating the screening of DNA-compatible conditions for ssDEL synthesis. The assay performance under various conditions, such as pH, temperature, metal ions, and solvents commonly used in ssDEL synthesis, was evaluated, and the results were cross-checked using high-performance liquid chromatography. While certain conditions have been identified as compatible with double-stranded DNA-encoded library synthesis using headpiece DNA, they may still cause considerable DNA damage during ssDEL synthesis due to the low chemical stability of ssDNA. Given its simplicity and speed, this assay can facilitate high-throughput screening of multiple reaction conditions during the early stages of ssDEL synthesis.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590051","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":"Antibody-Free Immunopeptide Nanoconjugates for Brain-Targeted Drug Delivery in Glioblastoma Multiforme.","authors":"Saurabh Sharma, David Lee, Surjendu Maity, Prabhjeet Singh, Jay Chadokiya, Neda Mohaghegh, Alireza Hassani, Hanjun Kim, Ankit Gangarade, Julia Y Ljubimova, Amanda Kirane, Eggehard Holler","doi":"10.1021/acs.bioconjchem.5c00168","DOIUrl":"10.1021/acs.bioconjchem.5c00168","url":null,"abstract":"<p><p>Glioblastoma Multiforme (GBM) represents a significant clinical challenge among central nervous system tumors, with a dismal mean survival rate of less than 8 months, a statistic that has remained largely unchanged for decades (National Brain Society, 2022). The specialized intricate anatomical features of the brain, notably the blood-brain barrier (BBB), pose significant challenges to effective therapeutic interventions, limiting the potential reach of modern advancements in immunotherapy to impact these types of tumors. This study introduces an innovative, actively targeted immunotherapeutic nanoconjugate (P-12/AP-2/NCs) designed to serve as an immunotherapeutic agent capable of traversing the BBB via LRP-1 receptor-mediated transcytosis. P-12/AP-2/NCs exert their immune-modulating effects by inhibiting the PD-1/PD-L1 axis through a small-sized PD-L1/PD-L2 antagonist peptide, Aurigene NP-12 (P-12). P-12/AP-2/NCs are synthesized from completely biodegradable, functionalized high molecular weight β-poly(l-malic acid) (PMLA) polymer conjugated with P-12 and Angiopep-2 (AP-2) to yield P-12/AP-2/NCs. Evaluating nanoconjugates for BBB permeability and 3D tumor model efficacy using an in vitro BBB-Transwell spheroid-based model demonstrated successful crossing of the BBB and internalization in brain 3D tumor environments. In addition, the nanoconjugate mediated T cells' cytotoxicity on 3D tumor region death in a U87 GBM 3D spheroid model. AP-2/P-12/NCs are selectively inhibited in PD1/PDL1 interaction on T cells and the tumor site, increasing inflammatory cytokine secretion and T cell proliferation. In an in vivo murine brain environment, rhodamine fluorophore-labeled AP-2/P-12/NCs displayed significantly increased accumulation in the brain during 2-6 h time intervals postinjection with a prolonged bioavailability over unconjugated peptides. AP-2/P-12/NCs demonstrated a safety profile at both low and high doses based on major organ histopathology evaluations. Our findings introduce a novel, programmable nanoconjugate platform capable of penetrating the BBB for directed delivery of small peptides and significant immune environment modulation without utilizing antibodies, offering promise for treating challenging brain diseases such as glioblastoma multiforme and beyond.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551427","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}