Bioconjugate Chemistry最新文献_第4页

Cationic Peptide Conjugation Enhances Intratumoral Retention and Antitumor Efficacy of Immune Checkpoint Blockade Antibodies 阳离子肽偶联增强免疫检查点阻断抗体瘤内滞留和抗肿瘤效果。

IF 3.9 2区化学

Bioconjugate Chemistry Pub Date : 2025-09-03 DOI: 10.1021/acs.bioconjchem.5c00257

Rashmi P Mohanty, Yuting Pan, Mae M Lewis, Melissa R. Soto, Esther Y Maier, Riyad F Alzhrani and Debadyuti Ghosh*,

{"title":"Cationic Peptide Conjugation Enhances Intratumoral Retention and Antitumor Efficacy of Immune Checkpoint Blockade Antibodies","authors":"Rashmi P Mohanty, Yuting Pan, Mae M Lewis, Melissa R. Soto, Esther Y Maier, Riyad F Alzhrani and Debadyuti Ghosh*, ","doi":"10.1021/acs.bioconjchem.5c00257","DOIUrl":"10.1021/acs.bioconjchem.5c00257","url":null,"abstract":"The tumor extracellular matrix (ECM) forms a net negatively charged network that interacts with and hinders the transport of molecules, partly based on electrostatic interactions. The focus on drug delivery in solid tumors has traditionally been on developing neutral charge coatings to minimize interactions with the ECM for improved transport. In contrast to prior work, we recently found a cationic peptide that interacted electrostatically with the negatively charged components of the ECM, resulting in enhanced uptake and retention of nanoparticles in the tumor ECM and tumor tissue. Based on this previous study, here, we hypothesize that the electrostatically driven interactions of the cationic peptide will improve the binding and retention of immune checkpoint blockade antibodies (ICBs), ultimately enhancing their antitumor immunogenic responses. We prepared peptide-antibody conjugates by conjugating the cationic peptide to anti-Cytotoxic T-Lymphocyte Antigen 4 (α-CTLA4) and anti-Programmed cell Death Ligand-1 (α-PD-L1) ICBs using copper-free click chemistry. We confirmed an average of 1–2 peptides per antibody. The cationic peptide electrostatically interacted with the net negatively charged tumor ECM and improved the binding of the antibodies to the tumor ECM without affecting their ability to recognize their antigens. Modifying the antibodies with cationic peptides reduced the systemic exposure of the antibodies and did not induce treatment-related toxicities. The conjugation of ICBs with cationic peptides improved their retention in the tumor microenvironment, resulting in improved antitumor efficacy compared to unconjugated ICBs. These results suggest that leveraging simple electrostatic interactions between cationic peptide anchors and the tumor microenvironment can ultimately improve the antitumor efficacy of immune checkpoint blockade antibodies.","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 9","pages":"1987–2001"},"PeriodicalIF":3.9,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935644","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}

引用次数: 0

Dual Stimuli-Responsive Gemcitabine-Conjugated Alginate-Chitosan Nanoparticles for Triple-Negative Breast Cancer Therapy: A Smart Approach 双刺激反应吉西他滨偶联海藻酸壳聚糖纳米颗粒用于三阴性乳腺癌治疗：一种聪明的方法。

IF 3.9 2区化学

Bioconjugate Chemistry Pub Date : 2025-09-01 DOI: 10.1021/acs.bioconjchem.5c00334

Tarun Patel, Ambati Himaja, Swati Biswas and Balaram Ghosh*,

{"title":"Dual Stimuli-Responsive Gemcitabine-Conjugated Alginate-Chitosan Nanoparticles for Triple-Negative Breast Cancer Therapy: A Smart Approach","authors":"Tarun Patel, Ambati Himaja, Swati Biswas and Balaram Ghosh*, ","doi":"10.1021/acs.bioconjchem.5c00334","DOIUrl":"10.1021/acs.bioconjchem.5c00334","url":null,"abstract":"Among the available chemotherapeutic agents, gemcitabine (GEM) has demonstrated significant efficacy against various cancers. Nevertheless, its clinical application is restricted due to its poor pharmacokinetic properties, highlighting the need for improved drug delivery strategies. Here, Dual stimuli-responsive hybrid polymeric nanoparticles conjugating GEM have been developed using a chitosan alginate biopolymer. The polymers anchored GEM via hydrazone and disulfide linkers, enabling dual stimuli-responsive drug release in tumors by leveraging pH variations and elevated glutathione (GSH) levels. This innovative nanoplatform enhances GEM systemic exposure, stability, and therapeutic efficacy while minimizing systemic toxicity. The Alg/Chi-GEM nanoparticles (NPs) were comprehensively characterized for their physicochemical properties via 1H NMR, infrared spectroscopy, GPC, DSC, and particle size analysis, along with stimuli-responsive drug release and hemolysis studies to confirm their robustness. The therapeutic potential of the nanoplatform was rigorously assessed in various breast cancer cell lines, including 4T1, MCF-7, and MDA-MB-231 cells, where the NPs demonstrated superior cellular uptake, enhanced cytotoxicity, and efficient apoptosis induction through DNA fragmentation, ROS generation, mitochondrial depolarization, and G2/M phase arrest. In vivo studies using 4T1-Luc tumor-bearing mice further validated their antitumor efficacy, showing significant tumor growth inhibition at a 10 mg/kg GEM equivalent dose with reduced toxicity compared to free GEM. These findings indicated that Alg/Chi-GEM NPs, as a next-generation nanomedicine, offer a safer, more effective approach to overcoming gemcitabine resistance and enhancing breast cancer therapy.","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 9","pages":"2037–2053"},"PeriodicalIF":3.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.bioconjchem.5c00334","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935648","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}

引用次数: 0

pH/GSH Dual-Responsive Copolyprodrug for Tumor-Specific Chemo/Ferroptosis Combination Therapy pH/GSH双反应共聚药物用于肿瘤特异性化疗/铁下垂联合治疗。

IF 3.9 2区化学

Bioconjugate Chemistry Pub Date : 2025-08-28 DOI: 10.1021/acs.bioconjchem.5c00240

Xiaomei Zhao, and , Peng Liu*,

{"title":"pH/GSH Dual-Responsive Copolyprodrug for Tumor-Specific Chemo/Ferroptosis Combination Therapy","authors":"Xiaomei Zhao,  and , Peng Liu*, ","doi":"10.1021/acs.bioconjchem.5c00240","DOIUrl":"10.1021/acs.bioconjchem.5c00240","url":null,"abstract":"The efficacy of conventional chemotherapy is often limited by tumor heterogeneity, multidrug resistance, and off-target toxicity. Via a nonapoptotic, iron-dependent cell death mechanism, ferroptosis has emerged as a promising complement to chemotherapy. To achieve tumor-selective and synergistic treatment, pH/GSH dual-responsive amphiphilic copolyprodrug P(DOXss-Fc)-PEG was designed with high drug content (63.9% for DOX and 17.2% for FcDH), by polycondensation of disulfide-linked doxorubicin dimer (DOXss) and ferrocene dicarbohydrazide (FcDH), with DOX-PEG2000 as end-capping group. The self-assembled P(DOXss-Fc)-PEG-NP nanoparticles exhibited uniform spherical morphology around 95 nm, favorable stability, and minimal premature drug leakage under normal physiological condition, while efficient intracellular release of DOX, accompanied by GSH depletion and Fc-mediated Fenton reactions to enhance ferroptosis in the acidic and high-GSH tumor-like conditions. In vitro assays demonstrated efficient internalization by HepG2 cells, nuclear accumulation of DOX, and markedly reduced cytotoxicity toward normal L02 cells. Compared with free DOX, the nanoparticles exhibited enhanced antitumor activity with a lower IC50 (9.11 vs 10.61 μg/mL) and a combination index (CI) of 0.95, indicating a synergistic therapeutic effect.","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 9","pages":"1970–1979"},"PeriodicalIF":3.9,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935584","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}

引用次数: 0

Biophysical and Biochemical Characterization of PEGylated High-Molecular-Weight Relaxed and Tense Quaternary State Polymerized Human Hemoglobin 聚乙二醇化高分子量放松和紧张季态聚合人血红蛋白的生物物理和生化表征。

IF 3.9 2区化学

Bioconjugate Chemistry Pub Date : 2025-08-26 DOI: 10.1021/acs.bioconjchem.5c00311

Mohd Asim Khan, Griffin J. Beyer, Tanmay Salvi and Andre F. Palmer*,

{"title":"Biophysical and Biochemical Characterization of PEGylated High-Molecular-Weight Relaxed and Tense Quaternary State Polymerized Human Hemoglobin","authors":"Mohd Asim Khan, Griffin J. Beyer, Tanmay Salvi and Andre F. Palmer*, ","doi":"10.1021/acs.bioconjchem.5c00311","DOIUrl":"10.1021/acs.bioconjchem.5c00311","url":null,"abstract":"This study investigates the biophysical properties of PEGylated hemoglobin-based oxygen carriers (HBOCs), including PEGylated human hemoglobin (hHb) and tense (T) and relaxed (R) quaternary state polymerized human hemoglobins (PolyhHbs), to potentially improve their safety and efficacy as red blood cell substitutes. PEGylation slightly increased autoxidation in all variants compared to their precursors (hHb and T- and R-state PolyhHb). PEG-hHb showed elevated heme release, while PEGylated PolyhHbs retained a similar heme release compared to their precursors. The thermal stability of PEGylated variants was maintained compared to their precursors, indicating a preserved structural integrity. PEG-T-state PolyhHb maintained a low oxygen affinity (P50: 46.6 mmHg) and PEG-R-state PolyhHb showed a high affinity (P50: 1.9 mmHg) similar to their precursors, reflecting quaternary structural effects. Oxygen offloading kinetics were quaternary structure-dependent and unaffected by PEGylation. The Bohr effect was significantly reduced in PEG-hHb, T-state PolyhHb, and PEG-T-state PolyhHb compared to hHb. Catalase activity remained consistent post-PEGylation, and both PEG-T- and R-state PolyhHbs exhibited reduced haptoglobin binding compared to that of their precursors, suggesting prolonged circulation potential. Resistance to H2O2-induced oxidation was also preserved. Overall, PEGylation modulated key HBOC properties, positioning PEG-T-state polyhHb as a promising candidate for further HBOC development.","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 9","pages":"2020–2036"},"PeriodicalIF":3.9,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.bioconjchem.5c00311","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935620","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}

引用次数: 0

Van Leusen Imidazole Synthesis for One-Bead-One-Compound DNA-Encoded Libraries Van Leusen咪唑单粒单化合物dna编码文库的合成

IF 3.9 2区化学

Bioconjugate Chemistry Pub Date : 2025-08-23 DOI: 10.1021/acs.bioconjchem.5c00317

Yihui Xie, Mengtian Huang, Yanfen Jiang, Xiaoming Miao, Haopei Wang, Qi Zhang, Dongcheng Dai*, Xiangzhi Zeng, Qingmin Yang, Wenji Su, Alexander L. Satz* and Letian Kuai,

引用次数: 0

A Cell-Surface-Targeted Fluorogenic Probe for Detection of Sulfatase 2 Activity 细胞表面荧光探针检测硫酸酯酶2活性。

IF 3.9 2区化学

Bioconjugate Chemistry Pub Date : 2025-08-23 DOI: 10.1021/acs.bioconjchem.5c00251

Yi Ding, Toshiyuki Kowada, Toshitaka Matsui, Norihiko Sasaki* and Shin Mizukami*,

引用次数: 0

[2.2.1]Heterobicyclic Bromovinyl Sulfones for Thiol-Triggered Strategies in Linker Chemistry: Aza- vs Oxa-Norbornadienic Systems [2.2.1]偶氮偶氮与氧-降冰片二烯体系的偶氮偶氮偶氮偶氮偶氮偶氮偶氮偶氮偶氮偶氮偶氮偶氮偶氮偶氮偶氮。

IF 3.9 2区化学

Bioconjugate Chemistry Pub Date : 2025-08-22 DOI: 10.1021/acs.bioconjchem.5c00371

Marina Carranza, Ana T. Carmona*, Celia Maya, Enrique Gil de Montes, Aldrin V. Vasco, Gonçalo J. L. Bernardes and Antonio J. Moreno-Vargas*,

{"title":"[2.2.1]Heterobicyclic Bromovinyl Sulfones for Thiol-Triggered Strategies in Linker Chemistry: Aza- vs Oxa-Norbornadienic Systems","authors":"Marina Carranza, Ana T. Carmona*, Celia Maya, Enrique Gil de Montes, Aldrin V. Vasco, Gonçalo J. L. Bernardes and Antonio J. Moreno-Vargas*, ","doi":"10.1021/acs.bioconjchem.5c00371","DOIUrl":"10.1021/acs.bioconjchem.5c00371","url":null,"abstract":"Azanorbornadienes (ANDs) containing a bromovinyl sulfone are able to accept a first thiol and, in a further stage, fragment upon reaction with a second thiol. This fragmentation has been studied in a collection of differently substituted ANDs. The substitution pattern of the AND influences the rate of the first thiolation and, specially, the further fragmentation. N-pyramidalization of selected ANDs was demonstrated via X-ray diffraction. This structural feature attenuates the resonance effect of N-substituents in the further reactivity of ANDs. A comparison with related oxanorbornadienes is also reported. The installation of a fluorogenic AND onto a single domain Antibody against PD-L1 (PD-L1 sdAb) resulted in a conjugate capable of releasing the corresponding fluorogenic pyrrole in the presence of glutathione (GSH) under physiological conditions. Overall, these scaffolds demonstrate potential to be implemented as new drug delivery systems.","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 9","pages":"2079–2089"},"PeriodicalIF":3.9,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.bioconjchem.5c00371","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935670","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}

引用次数: 0

Resin-Supported Site-Specific Antibody Conjugation Method Leads to Antibody-Drug Conjugates with Retained Efficacy and Improved Stability 树脂支持的位点特异性抗体偶联方法使抗体-药物偶联具有保留的效力和提高的稳定性。

IF 3.9 2区化学

Bioconjugate Chemistry Pub Date : 2025-08-21 DOI: 10.1021/acs.bioconjchem.5c00224

Mohan Reddy Mullapudi, Fanny Xu, Samantha R. Benjamin, Katherine J. Leong, Alexandra Maria Psaras, Mohammad Asikur Rahman, Tao Zhang, Tracy A. Brooks and L. Nathan Tumey*,

{"title":"Resin-Supported Site-Specific Antibody Conjugation Method Leads to Antibody-Drug Conjugates with Retained Efficacy and Improved Stability","authors":"Mohan Reddy Mullapudi, Fanny Xu, Samantha R. Benjamin, Katherine J. Leong, Alexandra Maria Psaras, Mohammad Asikur Rahman, Tao Zhang, Tracy A. Brooks and L. Nathan Tumey*, ","doi":"10.1021/acs.bioconjchem.5c00224","DOIUrl":"10.1021/acs.bioconjchem.5c00224","url":null,"abstract":"Herein, we describe an optimized method for the generation of “thiolated Q295” site-specific antibody-drug conjugates (ADCs) with drug-to-antibody ratio (DAR) 2 from nonengineered IgG1 antibodies. Traditional ADCs take advantage of the 4 intrachain disulfide residues as the sites of attachment. While operationally simple to prepare, ADCs that rely on attachment to these endogenous cysteine residues suffer from heterogeneity arising from stochastic mixtures of differently loaded species. Our team recently reported a site-specific thiolation method targeting the conserved Q295 residue in deglycosylated antibodies. This approach involves deglycosylation of Q297 (using PNGase F) to eliminate steric hindrance from the N-glycan, followed by introducing a thiol-containing small molecule, cysteamine, at Q295, using microbial transglutaminase (mTGase). Our original method employed a global reduction/reoxidation to liberate the Q295 thiol for conjugation. However, this process was challenging due to competing reoxidation of the newly introduced Q295 thiol. In order to overcome this issue, we systematically explored various reducing agents and conditions, ultimately resulting in a new process that avoids the need for reduction/reoxidation. This resin-supported method, which is suitable for high-throughput synthesis, relies on the selective reduction of the engineered disulfide by sterically hindered phosphine, monosulfonated triphenylphosphine (TPPMS). Relying on this optimized methodology, we studied a small set of tubulysin ADCs showing that the resulting Q295-conjugated ADCs have favorable biophysical and biological properties as compared to traditional stochastic conjugation.","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 9","pages":"1956–1969"},"PeriodicalIF":3.9,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935676","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}

引用次数: 0

Expression of Concern for “Enhanced Cell Killing by Paclitaxel-Loaded Recombinant Protein Micelles Bearing Integrin-Binding and Cell-Penetrating Peptides” 表达对“携带整合素结合和细胞穿透肽的紫杉醇负载重组蛋白胶束增强细胞杀伤”的关注

IF 3.9 2区化学

Bioconjugate Chemistry Pub Date : 2025-08-20 DOI: 10.1021/acs.bioconjchem.5c00324

Chen Gao, Vera Guan-Yee Lee and Daniel A. Hammer*,

引用次数: 0

FlexTORCH: An Improved Flexible Fluorophore–Linker–Quencher Molecule Enlightening ADC Research FlexTORCH：一种改进的柔性荧光团连接猝灭分子，对ADC研究有启发。

IF 3.9 2区化学

Bioconjugate Chemistry Pub Date : 2025-08-19 DOI: 10.1021/acs.bioconjchem.5c00135

Tim Neumann, Katrin Schreiber, Min Shan, Nicolas Rasche, Stephan Dickgiesser, Stefan Hecht, Jan Anderl, Harald Kolmar, Birgit Piater* and Stanley Sweeney-Lasch*,

{"title":"FlexTORCH: An Improved Flexible Fluorophore–Linker–Quencher Molecule Enlightening ADC Research","authors":"Tim Neumann, Katrin Schreiber, Min Shan, Nicolas Rasche, Stephan Dickgiesser, Stefan Hecht, Jan Anderl, Harald Kolmar, Birgit Piater* and Stanley Sweeney-Lasch*, ","doi":"10.1021/acs.bioconjchem.5c00135","DOIUrl":"10.1021/acs.bioconjchem.5c00135","url":null,"abstract":"Antibody–drug conjugates (ADCs) are an emerging class of molecules for cancer therapy. An ADC consists of an antibody that is attached to a toxic payload via a linker molecule. Once the ADC is internalized into the cancer cell, the payload is released inside the cell, which leads to tumor cell death. Most approved ADC molecules make use of enzymatically cleavable linker structures. The kinetics of antibody internalization, linker cleavage, and payload release are evident for the mode of action of ADCs in vitro and in vivo. We have previously described the generation of the tool molecule TORCH (Turn On after Release by Cathepsin) for studying ADC kinetics by analyzing increasing fluorescence. The molecular TORCH is a fluorophore–quencher molecule that is separated by a valin–citrullin (VC) linker. The VC linker is cleaved by the protease cathepsin B. We previously demonstrated the in vitro proof of principle with the molecular TORCH. These studies strongly facilitated ADC research and the analysis of internalization and release kinetics. Here, we show an improved design of the TORCH molecule, also named flexTORCH, overcoming challenges in synthesis, conjugation, and flexibility of design. The flexTORCH molecule enables modular and flexible assembling. For this, different TORCH linker–quencher modules and the fluorophore were equipped with functional groups for orthogonal click chemistry. This study shows the feasibility of flexTORCH synthesis, its stepwise conjugation to trastuzumab, and the in vitro proof of principle. For showcasing the flexibility of the flexTORCH, four different constructs were produced, including VC-PABC (para-aminobenzyl carbamate), ß-glucuronide-PABC, AAN-PABC, and AAN linker that represent recognition patterns for cathepsin B, ß-glucuronidase, and legumain.","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 9","pages":"1943–1955"},"PeriodicalIF":3.9,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144870252","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}

引用次数: 0