Pub Date : 2024-07-03DOI: 10.1021/acs.bioconjchem.4c0023510.1021/acs.bioconjchem.4c00235
Yukine Ishibashi, Mitsuru Naito*, Yusuke Watanuki, Mao Hori, Satomi Ogura, Kaori Taniwaki, Masaru Cho, Ryosuke Komiya, Yuki Mochida and Kanjiro Miyata*,
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.
{"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 and Kanjiro Miyata*, ","doi":"10.1021/acs.bioconjchem.4c0023510.1021/acs.bioconjchem.4c00235","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00235https://doi.org/10.1021/acs.bioconjchem.4c00235","url":null,"abstract":"<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":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142011105","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}
Pub Date : 2024-07-02DOI: 10.1021/acs.bioconjchem.4c0021410.1021/acs.bioconjchem.4c00214
Lei Li, Rui Cao, Kaixin Chen, Chunrong Qu, Kun Qian, Jia Lin, Renda Li, Chaoquan Lai, Xiao Wang, Zijian Han, Zhijian Xu, Liping Zhou, Shaoli Song*, Weiliang Zhu* and Zhen Cheng*,
Fibroblast activation protein (FAP) has recently gained significant attention as a promising tumor biomarker for both diagnosis and therapeutic applications. A series of radiopharmaceuticals based on fibroblast activation protein inhibitors (FAPIs) have been developed and translated into the clinic. Though some of them such as radiolabeled FAPI-04 probes have achieved favorable in vivo imaging performance, further improvement is still highly desired for obtaining radiopharmaceuticals with a high theranostics potential. In this study, we innovatively designed an FAPI ligand SMIC-3002 by changing the core quinoline motif of FAPI-04 to the quinolinium scaffold. The engineered molecule was further radiolabeled with 68Ga to generate a positron emission tomography (PET) probe, [68Ga]Ga-SMIC-3002, which was then evaluated in vitro and in vivo. [68Ga]Ga-SMIC-3002 demonstrated high in vitro stability, nanomolar affinity for FAP (8 nM for protein, 23 nM for U87MG cells), and specific uptake in FAP-expressing tumors, with a tumor/muscle ratio of 19.1 and a tumor uptake of 1.48 ± 0.03 ID/g% at 0.5 h in U87MG tumor-bearing mice. In summary, the quinolinium scaffold can be successfully used for the development of the FAP-targeted tracer. [68Ga]Ga-SMIC-3002 not only shows high potential for clinical translation but also offers insights into designing a new generation of FAPI tracers.
{"title":"Development of an FAP-Targeted PET Probe Based on a Novel Quinolinium Molecular Scaffold","authors":"Lei Li, Rui Cao, Kaixin Chen, Chunrong Qu, Kun Qian, Jia Lin, Renda Li, Chaoquan Lai, Xiao Wang, Zijian Han, Zhijian Xu, Liping Zhou, Shaoli Song*, Weiliang Zhu* and Zhen Cheng*, ","doi":"10.1021/acs.bioconjchem.4c0021410.1021/acs.bioconjchem.4c00214","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00214https://doi.org/10.1021/acs.bioconjchem.4c00214","url":null,"abstract":"<p >Fibroblast activation protein (FAP) has recently gained significant attention as a promising tumor biomarker for both diagnosis and therapeutic applications. A series of radiopharmaceuticals based on fibroblast activation protein inhibitors (FAPIs) have been developed and translated into the clinic. Though some of them such as radiolabeled FAPI-04 probes have achieved favorable in vivo imaging performance, further improvement is still highly desired for obtaining radiopharmaceuticals with a high theranostics potential. In this study, we innovatively designed an FAPI ligand SMIC-3002 by changing the core quinoline motif of FAPI-04 to the quinolinium scaffold. The engineered molecule was further radiolabeled with <sup>68</sup>Ga to generate a positron emission tomography (PET) probe, [<sup>68</sup>Ga]Ga-SMIC-3002, which was then evaluated in vitro and in vivo. [<sup>68</sup>Ga]Ga-SMIC-3002 demonstrated high in vitro stability, nanomolar affinity for FAP (8 nM for protein, 23 nM for U87MG cells), and specific uptake in FAP-expressing tumors, with a tumor/muscle ratio of 19.1 and a tumor uptake of 1.48 ± 0.03 ID/g% at 0.5 h in U87MG tumor-bearing mice. In summary, the quinolinium scaffold can be successfully used for the development of the FAP-targeted tracer. [<sup>68</sup>Ga]Ga-SMIC-3002 not only shows high potential for clinical translation but also offers insights into designing a new generation of FAPI tracers.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142237618","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}
The chemical synthesis of homogeneously ubiquitylated histones is a powerful approach to decipher histone ubiquitylation-dependent epigenetic regulation. Among the various methods, α-halogen ketone-mediated conjugation chemistry has recently been an attractive strategy to generate single-monoubiquitylated histones for biochemical and structural studies. Herein, we report the use of this strategy to prepare not only dual- and even triple-monoubiquitylated histones but also diubiquitin-modified histones. We were surprised to find that the synthetic efficiencies of multi-monoubiquitylated histones were comparable to those of single-monoubiquitylated ones, suggesting that this strategy is highly tolerant to the number of ubiquitin monomers installed onto histones. The facile generation of a series of single-, dual-, and triple-monoubiquitylated H3 proteins enabled us to evaluate the influence of ubiquitylation patterns on the binding of DNA methyltransferase 1 (DNMT1) to nucleosomes. Our study highlights the potential of site-specific conjugation chemistry to generate chemically defined histones for epigenetic studies.
化学合成均一泛素化组蛋白是破译组蛋白泛素化依赖性表观遗传调控的有力方法。在各种方法中,α-卤代酮介导的共轭化学是近来生成单泛素化组蛋白用于生化和结构研究的一种有吸引力的策略。在此,我们报告了利用这种策略不仅制备了双单泛素化组蛋白,甚至还制备了三单泛素化组蛋白以及二泛素修饰组蛋白的情况。我们惊奇地发现,多泛素单体化组蛋白的合成效率与单泛素单体化组蛋白的合成效率相当,这表明这种策略对组蛋白上泛素单体的数量具有很高的容忍度。一系列单泛素化、双泛素化和三泛素化 H3 蛋白的简便生成使我们能够评估泛素化模式对 DNA 甲基转移酶 1(DNMT1)与核小体结合的影响。我们的研究凸显了位点特异性共轭化学生成化学定义组蛋白用于表观遗传学研究的潜力。
{"title":"Efficient Chemical Synthesis of Multi-Monoubiquitylated and Diubiquitylated Histones by the α-Halogen Ketone-Mediated Strategy","authors":"Shuai Peng, Xin Liu, Chengpiao Lu, Haibo Wang, Xiaotong Liu, Qingyue Gong, Huizhong Tao, Hongrui Xu, Changlin Tian*, Guoqiang Xu* and Jia-Bin Li*, ","doi":"10.1021/acs.bioconjchem.4c00130","DOIUrl":"10.1021/acs.bioconjchem.4c00130","url":null,"abstract":"<p >The chemical synthesis of homogeneously ubiquitylated histones is a powerful approach to decipher histone ubiquitylation-dependent epigenetic regulation. Among the various methods, α-halogen ketone-mediated conjugation chemistry has recently been an attractive strategy to generate single-monoubiquitylated histones for biochemical and structural studies. Herein, we report the use of this strategy to prepare not only dual- and even triple-monoubiquitylated histones but also diubiquitin-modified histones. We were surprised to find that the synthetic efficiencies of multi-monoubiquitylated histones were comparable to those of single-monoubiquitylated ones, suggesting that this strategy is highly tolerant to the number of ubiquitin monomers installed onto histones. The facile generation of a series of single-, dual-, and triple-monoubiquitylated H3 proteins enabled us to evaluate the influence of ubiquitylation patterns on the binding of DNA methyltransferase 1 (DNMT1) to nucleosomes. Our study highlights the potential of site-specific conjugation chemistry to generate chemically defined histones for epigenetic studies.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141489874","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}
Pub Date : 2024-07-01DOI: 10.1021/acs.bioconjchem.4c00196
Maud D. M. E. Linssen, Yu-Ting Lin, Sebastian A. H. van den Wildenberg, Marrit M. E. Tholen, Arthur M. de Jong and Menno W. J. Prins*,
Biosensors based on immobilized antibodies require molecular strategies that (i) couple the antibodies in a stable fashion while maintaining the conformation and functionality, (ii) give outward orientation of the paratope regions of the antibodies for good accessibility to analyte molecules in the biofluid, and (iii) surround the antibodies by antibiofouling molecules. Here, we demonstrate a method to achieve oriented coupling of antibodies to an antifouling poly(l-lysine)-grafted-poly(ethylene glycol) (PLL-g-PEG) substrate, using glycan remodeling to create antibody–DNA conjugates. The coupling, orientation, and functionality of the antibodies were studied using two analysis methods with single-molecule resolution, namely single-molecule localization microscopy and continuous biosensing by particle motion. The biosensing functionality of the glycan-remodeled antibodies was demonstrated in a sandwich immunosensor for procalcitonin. The results show that glycan-remodeled antibodies enable oriented immobilization and biosensing functionality with low nonspecific binding on antifouling polymer substrates.
{"title":"Oriented Antibody Coupling to an Antifouling Polymer Using Glycan Remodeling for Biosensing by Particle Motion","authors":"Maud D. M. E. Linssen, Yu-Ting Lin, Sebastian A. H. van den Wildenberg, Marrit M. E. Tholen, Arthur M. de Jong and Menno W. J. Prins*, ","doi":"10.1021/acs.bioconjchem.4c00196","DOIUrl":"10.1021/acs.bioconjchem.4c00196","url":null,"abstract":"<p >Biosensors based on immobilized antibodies require molecular strategies that (i) couple the antibodies in a stable fashion while maintaining the conformation and functionality, (ii) give outward orientation of the paratope regions of the antibodies for good accessibility to analyte molecules in the biofluid, and (iii) surround the antibodies by antibiofouling molecules. Here, we demonstrate a method to achieve oriented coupling of antibodies to an antifouling poly(<span>l</span>-lysine)-<i>grafted</i>-poly(ethylene glycol) (PLL-<i>g</i>-PEG) substrate, using glycan remodeling to create antibody–DNA conjugates. The coupling, orientation, and functionality of the antibodies were studied using two analysis methods with single-molecule resolution, namely single-molecule localization microscopy and continuous biosensing by particle motion. The biosensing functionality of the glycan-remodeled antibodies was demonstrated in a sandwich immunosensor for procalcitonin. The results show that glycan-remodeled antibodies enable oriented immobilization and biosensing functionality with low nonspecific binding on antifouling polymer substrates.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.bioconjchem.4c00196","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141464305","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}
Membrane tension is an important physical parameter of describing cellular homeostasis, and it is widely used in the study of cellular processes involving membrane deformation and reorganization, such as cell migration, cell spreading, and cell division. Despite the importance of membrane tension, direct measurement remains difficult. In this work, we developed a ratiometric fluorescent probe sensitive to membrane tension by adjusting the carbon chain structure based on polarity-sensitive fluorophores. The probe is sensitive to changes in membrane tension after cells were subjected to physical or chemical stimuli, such as osmotic shock, lipid peroxidation, and mechanical stress. When the polarity of the plasma membrane increases (the green/red ratio decreases) and the membrane tension increases, the relative magnitude of the membrane tension can be quantitatively calculated by fluorescence ratio imaging. Thus, the probe proved to be an efficient and sensitive membrane tension probe.
{"title":"Ratiometric Fluorescence Probes for In Situ Imaging of Membrane Tension in Live Cells","authors":"Hai-Yan Wen, Yusi Hu, You-Yang Duo, Liang Zhao, Zhi-Gang Wang* and Shu-Lin Liu*, ","doi":"10.1021/acs.bioconjchem.4c00101","DOIUrl":"10.1021/acs.bioconjchem.4c00101","url":null,"abstract":"<p >Membrane tension is an important physical parameter of describing cellular homeostasis, and it is widely used in the study of cellular processes involving membrane deformation and reorganization, such as cell migration, cell spreading, and cell division. Despite the importance of membrane tension, direct measurement remains difficult. In this work, we developed a ratiometric fluorescent probe sensitive to membrane tension by adjusting the carbon chain structure based on polarity-sensitive fluorophores. The probe is sensitive to changes in membrane tension after cells were subjected to physical or chemical stimuli, such as osmotic shock, lipid peroxidation, and mechanical stress. When the polarity of the plasma membrane increases (the green/red ratio decreases) and the membrane tension increases, the relative magnitude of the membrane tension can be quantitatively calculated by fluorescence ratio imaging. Thus, the probe proved to be an efficient and sensitive membrane tension probe.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141464306","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}
Pub Date : 2024-06-26DOI: 10.1021/acs.bioconjchem.4c00028
Michael C. Leyden, Felipe Oviedo, Sonashree Saxena, Ramya Kumar, Ngoc Le and Theresa M. Reineke*,
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.
{"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 and Theresa M. Reineke*, ","doi":"10.1021/acs.bioconjchem.4c00028","DOIUrl":"10.1021/acs.bioconjchem.4c00028","url":null,"abstract":"<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}
Pub Date : 2024-06-26DOI: 10.1021/acs.bioconjchem.4c00242
Jialei Hao, Xinzhi Zhao, Chun Wang, Xianghui Cao and Yang Liu*,
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.
癌症免疫疗法已在多种肿瘤类型中取得了显著效果。然而,实体瘤内复杂的免疫抑制微环境给免疫检查点阻断(ICB)和嵌合抗原受体 T 细胞(CAR-T)疗法等既有疗法带来了巨大挑战。在这种环境中,肿瘤相关巨噬细胞(TAMs)通过直接抑制 T 细胞功能和营造免疫抑制环境发挥着重要作用。因此,有效调节 TAMs 对提高免疫疗法的疗效至关重要。针对 TAM 调节的各种治疗策略已经出现,包括阻断 TAM 招募、直接清除、促进向 M1 表型的再极化,以及增强对肿瘤细胞的吞噬能力。最近推出的 CAR 巨噬细胞(CAR-M)疗法为基于巨噬细胞的免疫疗法提供了新的可能性。与CAR-T疗法相比,CAR-M疗法对实体瘤的靶向性和浸润能力更强。这篇综述主要探讨了TAMs的起源和发展过程、它们在促进肿瘤生长中的作用,并全面概述了针对TAMs的免疫疗法。它强调了调节 TAMs 对加强抗肿瘤疗法的重要意义,同时讨论了将 TAMs 开发为免疫疗法靶点的潜力和挑战。
{"title":"Recent Advances in Nanoimmunotherapy by Modulating Tumor-Associated Macrophages for Cancer Therapy","authors":"Jialei Hao, Xinzhi Zhao, Chun Wang, Xianghui Cao and Yang Liu*, ","doi":"10.1021/acs.bioconjchem.4c00242","DOIUrl":"10.1021/acs.bioconjchem.4c00242","url":null,"abstract":"<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}
Pub Date : 2024-06-24DOI: 10.1021/acs.bioconjchem.4c00222
Hayden R. Montgomery, Alexander M. Spokoyny* and Heather D. Maynard*,
Development of bioconjugation strategies to efficiently modify biomolecules is of key importance for fundamental and translational scientific studies. Cysteine S-arylation is an approach which is becoming more popular due to generally rapid kinetics and high chemoselectivity, as well as the strong covalently bonded S-aryl linkage created in these processes. Organometallic approaches to cysteine S-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 S-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.
{"title":"Organometallic Oxidative Addition Complexes for S-Arylation of Free Cysteines","authors":"Hayden R. Montgomery, Alexander M. Spokoyny* and Heather D. Maynard*, ","doi":"10.1021/acs.bioconjchem.4c00222","DOIUrl":"10.1021/acs.bioconjchem.4c00222","url":null,"abstract":"<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}
Pub Date : 2024-06-24DOI: 10.1021/acs.bioconjchem.4c00207
June H. Ahn, Christopher L. Johnny and David M. Chenoweth*,
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.
{"title":"Duo-Chol: A Photoconvertible Live Cell Imaging Tool for Tracking Cholesterol","authors":"June H. Ahn, Christopher L. Johnny and David M. Chenoweth*, ","doi":"10.1021/acs.bioconjchem.4c00207","DOIUrl":"10.1021/acs.bioconjchem.4c00207","url":null,"abstract":"<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}
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 in vitro and in vivo, opening up a new avenue for precise NPC theranostics.
{"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* and Qinglai Yang*, ","doi":"10.1021/acs.bioconjchem.4c00225","DOIUrl":"10.1021/acs.bioconjchem.4c00225","url":null,"abstract":"<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}