Bioconjugate Chemistry最新文献

{"title":"Modular Synthesis of Anti-HER2 Dual-Drug Antibody-Drug Conjugates Demonstrating Improved Toxicity.","authors":"Christine S Nervig, Megan Rice, Marcello Marelli, R James Christie, Shawn C Owen","doi":"10.1021/acs.bioconjchem.4c00398","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00398","url":null,"abstract":"<p><p>Antibodies have gained clinical success in the last two decades for the targeted delivery of highly toxic small molecule chemotherapeutics. Yet antibody-drug conjugates (ADCs) often fail in the clinic due to the development of resistance. The delivery of two mechanistically distinct small molecule drugs on one antibody is of increasing interest to overcome these challenges with single-drug ADCs. We have developed a modular synthetic strategy for the construction of a library of 19 dual-drug ADCs where drugs are conjugated through unnatural cyclopentadiene-containing amino acids and native cysteine residues on an anti-HER2 trastuzumab scaffold. Importantly, this strategy utilizes the same functional group on the linker-drug construct; this allows for the facile addition of drugs at either conjugation site and enables the evaluation of different drug-to-antibody ratios and combinations of drug pairs. We tested the library on high- and mid-HER2 expressing cell lines and observed increased toxicity in several dual-drug ADCs compared with single-drug constructs. The strategy developed herein provides a method for the facile synthesis, characterization, and evaluation of dual-payload ADCs. Simultaneous delivery of combinations of drugs with distinct mechanisms of action is critical for the next generation of targeted drug delivery.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and Biological Evaluation of Bile Acid-Triclosan Conjugates: A Study on Antibacterial, Antibiofilm, and Molecular Docking.","authors":"Neha V Rathod, Satyendra Mishra","doi":"10.1021/acs.bioconjchem.4c00539","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00539","url":null,"abstract":"<p><p>This work describes the synthesis, characterization, and antibacterial properties of four bile acid-triclosan conjugates. The in vitro antibacterial activity of synthetic bile acid-triclosan conjugates was investigated against a panel of Gram-positive and Gram-negative bacteria. Conjugates <b>3</b> and <b>4</b> show high activity against <i>Escherichia coli</i> (ATCC25922), with IC₅₀ values of 2.94 ± 0.7 and 1.51 ± 0.05 μM, respectively. Conjugate <b>4</b> demonstrated 9 times the activity of triclosan (6.77 μM) and 18 times the potency of kanamycin, a well-known antibiotic. Compound <b>3</b> showed higher potential activity against all evaluated strains, including <i>Bacillus megaterium</i> (IC₅₀: 3.05 ± 0.02), <i>Bacillus amyloquefaciens</i> (IC₅₀: 8.79 ± 0.01), <i>Serratia marcescens</i> (IC₅₀: 6.77 ± 0.4), and <i>E. coli</i> (IC₅₀: 1.51 ± 0.05 μM). These findings indicate that it has broad-spectrum antibacterial activity. Bile acid-triclosan conjugates prevent biofilms by up to 99% at low doses (conjugates <b>4</b>; 4.16 ± 0.8 μM), compared to triclosan. Conjugate <b>5</b> was most potent against <i>B. amyloquefaciens</i> (IC₅₀ = 5.23 ± 0.2 μM), while conjugate <b>4</b> was most effective against <i>B. megaterium</i> (IC₅₀ = 4.16 ± 0.8 μM) in biofilm formation. These conjugates inhibit biofilm formation by limiting the extracellular polymeric substance generation. The in vitro antibacterial study revealed that bile acid-triclosan conjugates were more effective than the parent molecule triclosan at inhibiting bacterial growth and biofilm formation against both Gram-positive and Gram-negative bacteria.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021299","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":"Effect of Lipidation on the Structure, Oligomerization, and Aggregation of Glucagon-like Peptide 1.","authors":"Eva Přáda Brichtová, Irina A Edu, Xinyang Li, Frederik Becher, Ana L Gomes Dos Santos, Sophie E Jackson","doi":"10.1021/acs.bioconjchem.4c00484","DOIUrl":"10.1021/acs.bioconjchem.4c00484","url":null,"abstract":"<p><p>Lipidated analogues of glucagon-like peptide 1 (GLP-1) have gained enormous attention as long-acting peptide therapeutics for type 2 diabetes and also antiobesity treatment. Commercially available therapeutic lipidated GLP-1 analogues, semaglutide and liraglutide, have the great advantage of prolonged half-lives <i>in vivo</i> of hours and days instead of minutes as is the case for native GLP-1. A crucial factor in the development of novel lipidated therapeutic peptides is their physical stability, which greatly influences manufacturing and drug product development. This work provides a systematic study of the solubility, structure, oligomerization, and long-term stability of five different lipidated analogues of GLP-1, varying in the position of the lipidation site and the nature of lipid attachment. The lipidation was found to negatively impact the peptide solubility, in all cases, limiting it to a specific pH range. An increase in the α-helical secondary structure was observed upon lipidation, and the lipidated analogues were found to form larger and more stable oligomeric species compared to nonlipidated GLP-1. Importantly, the distributions and populations of oligomeric species formed were regulated by both the position and the nature of the lipidation. During the 6 days of sample aging, several lipidated analogues formed aggregates with variable morphologies ranging from elongated mature fibrils to amorphous structures. The kinetics of aggregation often showed multiple steps and did not follow a standard nucleation-propagation mechanism. A wide range of behaviors was observed, and while our observations indicate that the formation of a single stable oligomer results in the greatest physical stability, positioning the lipid group toward the N-terminus of the peptide results in extremely rapid amyloid formation. We believe that our study provides important findings for the development of long-acting lipidated analogues of peptide therapeutics.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996179","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":"Quantum Dot Erythropoietin Bioconjugates Enhance EPO-Receptor Clustering on Transfected Human Embryonic Kidney Cells.","authors":"Ryan N Porell, Okhil K Nag, Michael H Stewart, Kimihiro Susumu, Eunkeu Oh, James B Delehanty","doi":"10.1021/acs.bioconjchem.4c00521","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00521","url":null,"abstract":"<p><p>Erythropoietin (EPO)-induced cellular signaling through the EPO receptor (EPOR) is a fundamental pathway for the modulation of cellular behavior and activity. In our previous work, we showed in primary human astrocytes that the multivalent display of EPO on the surface of semiconductor quantum dots (QDs) mediates augmented JAK/STAT signaling, a concomitant 1.8-fold increase in the expression of aquaporin-4 (AQPN-4) channel proteins, and a 2-fold increase in the AQPN-4-mediated water transport activity. Our hypothesis is that this enhanced signaling involves the simultaneous ligation and clustering of EPOR by QD-EPO conjugates. Here, we utilized a human embryonic kidney (HEK 293T/17) cell line transfected with EPOR fused to enhanced green fluorescent protein (eGFP) to visualize EPOR clustering. We demonstrate that QDs displaying five copies of EPO (bearing a C-terminal 6-histidine tract) on the nanoparticle surface induce a 1.8-fold increase in EPOR clustering compared to monomeric EPO at the same concentration. Our findings confirm the critical role played by the multivalent display of EPO in mediating clustering of the EPOR. More generally, these results illustrate the capability of nanoparticle-growth factor bioconjugates to control the activity of cognate receptors and the important role played by multivalent display in the modulation of selective cellular delivery and signaling.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996195","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":"5'-Amino-Formyl-Thieno[3,2-<i>b</i>]thiophene End-Label for On-Strand Synthesis of Far-Red Fluorescent Molecular Rotors and pH-Responsive Probes.","authors":"Ryan E Johnson, Keenan T Regan, Richard A Manderville","doi":"10.1021/acs.bioconjchem.4c00457","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00457","url":null,"abstract":"<p><p>The ability to label synthetic oligonucleotides with fluorescent probes has greatly expanded their nanotechnological applications. To continue this expansion, it is essential to develop approachable, modular, and tunable fluorescent platforms. In this study, we present the synthesis and incorporation of an amino-formyl-thieno[3,2-<i>b</i>]thiophene (AFTh₂) handle at the 5'-position of DNA oligonucleotides. The 5'-AFTh₂ end-label participates in both on-strand Knoevenagel and heterocyclization reactions, yielding far-red hemicyanines and pH-responsive probes with p<i>K</i>_a values in the biological regime. The Knoevenagel products, designated 5'-ATh₂Btz and 5'-ATh₂Ind, demonstrate excitation maxima beyond 640 nm with brightness up to ∼50,000 M^-1 cm^-1. Notably, 5'-ATh₂Btz demonstrates strong topology sensitivity, allowing it to probe transitions from duplex- to single-strand (SS)/G-quadruplex (GQ) topologies with an ∼9-fold increase in fluorescence in the absence of quenchers. In contrast, the heterocyclization product, 5'-ATh₂BIM, displays visible excitation and emission and is weakly fluorescent in basic solution. Upon lowering the pH from ∼8 to 5, this probe undergoes an unprecedented 400-fold light-up. Additionally, attaching 5'-ATh₂BIM to a polymorphic GQ allows for a shift in p<i>K</i>_a by ∼1.5 pH units simply by changing topology. The performance of the probes has been demonstrated in various contexts, including GQs, i-motifs, duplexes, and SS oligonucleotides. Their performance should facilitate the development of new DNA-based sensing platforms.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996101","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":"PEGylation of Dipeptide Linker Improves Therapeutic Index and Pharmacokinetics of Antibody-Drug Conjugates.","authors":"Jing Long, Ting Shao, Yongmei Wang, Tianzhi Chen, Yuning Chen, Yi-Li Chen, Qi Wang, Xiong Yu, Jinghua Yu, Kaifeng He, Han-Bin Lin, Xingxing Diao, Guifeng Wang, Chunhe Wang","doi":"10.1021/acs.bioconjchem.4c00392","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00392","url":null,"abstract":"<p><p>Hydrophobic payloads incorporated into antibody-drug conjugates (ADCs) typically are superior to hydrophilic ones in tumor penetration and \"bystander killing\" upon release from ADCs. However, they are prone to aggregation and accelerated plasma clearance, which lead to reduced efficacies and increased toxicities of ADC molecules. Shielding the hydrophobicity of payloads by incorporating polyethylene glycol (PEG) elements or sugar groups into the ADC linkers has emerged as a viable alternative to directly adopting hydrophilic payloads. In this study, ADC linkers incorporating PEG or sugar groups were synthesized by modifying dipeptide linkers, with hydrophobic monomethyl auristatin E (MMAE) serving as an exemplary hydrophobic payload. All drug-linkers (DLs) were conjugated to RS7, a humanized antibody targeting Trop-2, with drug-to-antibody ratio (DAR) values set at 4 or 8. Among these, the ADC molecule RS7-DL 11, featuring a methyl-PEG₂₄ (mPEG₂₄) moiety as a side chain to the Valine-Lysine-PAB (VK) linker, demonstrated maximum hydrophilicity, biophysical stability, and tumor suppression, along with prolonged half-life and enhanced animal tolerability. In conclusion, through PEGylation of the traditional dipeptide linker, we have demonstrated an optimized ADC conjugation technology that can be employed for conjugating ultrahydrophobic payloads, thus enhancing both the therapeutic index and pharmacokinetics profile.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996192","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":"Correction to \"3D Printed Multifunctional Ti₆Al₄V-Based Hybrid Scaffold for the Management of Osteosarcoma\".","authors":"Bianyun Cai, Leizhen Huang, Jingcheng Wang, Dan Sun, Ce Zhu, Yong Huang, Shujun Li, Zhijun Guo, Limin Liu, Ganjun Feng, Yubao Li, Li Zhang","doi":"10.1021/acs.bioconjchem.4c00585","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00585","url":null,"abstract":"","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996104","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":"Molecular Imaging of Tumor-Infiltrating Lymphocytes in Living Animals Using a Novel mCD3 Fibronectin Scaffold.","authors":"Char Wynter, Arutselvan Natarajan, Clyde John, Kaahini Jain, Ramasamy Paulmurugan","doi":"10.1021/acs.bioconjchem.4c00501","DOIUrl":"10.1021/acs.bioconjchem.4c00501","url":null,"abstract":"&lt;p&gt;&lt;p&gt;The interaction between cancer cells and immune cells in the tumor microenvironment (TME) plays a crucial role in determining tumor growth, metastasis, and response to treatment. Tumor-infiltrating lymphocytes (TILs) in TME could be a predictive marker for treatment response in various therapeutic interventions, including chemotherapy and immunotherapy. Thus, imaging the tumor immune microenvironment is important for selecting the optimal treatment strategies in cancer therapy. The CD3 protein represents a promising target for diagnostic imaging of TILs &lt;i&gt;in vivo&lt;/i&gt; to assess the immune state of the TME. Although many anti-CD3 antibodies have been explored for this application, the nonspecific immune activation by these antibodies limits their applications. To overcome this issue, we engineered a novel fibronectin III domain (FN3) protein binder (mCD3-FN3;11.8 kDa) against mouse CD3 antigen protein using a yeast display library to image TILs homing &lt;i&gt;in vivo&lt;/i&gt; into the TME. We performed &lt;i&gt;in vitro&lt;/i&gt; and &lt;i&gt;in vivo&lt;/i&gt; assays to test the mCD3-FN3 binder purity as well as &lt;i&gt;in vivo&lt;/i&gt; targetability in mouse models of syngeneic tumors. We used near-infrared 800 dye conjugated with mCD3-FN3 (IR800-mCD3-FN3) for &lt;i&gt;in vivo&lt;/i&gt; tracking of TILs &lt;i&gt;via&lt;/i&gt; optical imaging. We used three different syngeneic tumors in mice (mCD3&lt;sup&gt;+&lt;/sup&gt; EL4 tumor in C57BL/6 mice, mCD3&lt;sup&gt;-&lt;/sup&gt; CT26 colon tumor, and mCD3&lt;sup&gt;-&lt;/sup&gt; 4T1 breast tumor in BALB/c mice) for imaging TILs &lt;i&gt;in vivo&lt;/i&gt;. C57BL/6 mice bearing EL4 tumors were separated into two groups (blocking [Blk] and nonblocking [Nblk]; &lt;i&gt;n&lt;/i&gt; = 3 per group) and used for &lt;i&gt;in vivo&lt;/i&gt; imaging. Blocking groups received 200 μg of unlabeled mCD3-FN3 2 h prior to the administration of IR800-mCD3-FN3 binder. Each mouse was administered with 25 μg of the IR800-mCD3-FN3 binder and tracked using an IVIS optical imaging system over time. C57BL/6/EL4 mice were imaged at 4 and 24 h post injection of the IR800-mCD3-FN3 binder, and mouse organs were collected at 24 h after final imaging and used for &lt;i&gt;ex vivo&lt;/i&gt; histological imaging. In CT26 and 4T1 tumor models, TILs in TME were imaged 4, 24, and 48 h after binder injection. The NIR imaging of EL4 tumors showed that IR800-mCD3-FN3 can detect both TILs within the tumor and the tumor cells with a high signal-to-background ratio 24 h after initial binder injection with a total radiant efficiency (mean TRE ± SD) of 6.5 × 10&lt;sup&gt;10&lt;/sup&gt; ± 1.5 × 10&lt;sup&gt;10&lt;/sup&gt; [photons/s]/[μW/cm&lt;sup&gt;2&lt;/sup&gt;]. The animals received preinjection of unlabeled mCD3-FN3(Blk) prior to IR800-mCD3-FN3 binder administration and showed a significant level of fluorescence signal reduction (mean TRE ± SD: 1.6 × 10&lt;sup&gt;10&lt;/sup&gt; ± 4.1 × 10&lt;sup&gt;9&lt;/sup&gt;) in the tumor when compared to the EL4-Nblk tumors (&lt;i&gt;p&lt;/i&gt; = 0.006). The mouse group with CT26 and 4T1 tumors where the probe can only bind to TILs within the tumor showed a specific imaging signal (mean TRE ± SD) of 1.1 × 10&lt;sup&gt;1","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":"104-115"},"PeriodicalIF":4.0,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833207","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":"Iron Oxide Nanoparticles Induce Macrophage Secretion of ATP and HMGB1 to Enhance Irradiation-Led Immunogenic Cell Death.","authors":"Shuyue Zhan, Zhengwei Cao, Jianwen Li, Fanghui Chen, Xinning Lai, Wei Yang, Yong Teng, Zibo Li, Weizhong Zhang, Jin Xie","doi":"10.1021/acs.bioconjchem.4c00488","DOIUrl":"10.1021/acs.bioconjchem.4c00488","url":null,"abstract":"<p><p>ATP (adenosine triphosphate) and HMGB1 (high mobility group box 1 protein) are key players in treatments that induce immunogenic cell death (ICD). However, conventional therapies, including radiotherapy, are often insufficient to induce ICD. In this study, we explore a strategy using nanoparticle-loaded macrophages as a source of ATP and HMGB1 to complement radiation-induced intrinsic and adaptive immune responses. To this end, we tested three inorganic particles, namely, iron oxide nanoparticles (ION), aluminum oxide nanoparticles (AON), and zinc oxide nanoparticles (ZON), <i>in vitro</i> with bone marrow-derived dendritic cells (BMDCs) and then <i>in vivo</i> in syngeneic tumor models. Our results showed that ION was the most effective of the three nanoparticles in promoting the secretion of ATP and HMGB1 from macrophages without negatively affecting macrophage survival. Secretions from ION-loaded macrophages can activate BMDCs. Intratumoral injection of ION-loaded macrophages significantly enhanced tumor infiltration and activation of dendritic cells and cytotoxic T cells. Moreover, exogenous ION macrophages can enhance the efficacy of radiotherapy. In addition, direct injection of ION can also enhance the efficacy of radiotherapy, which is attributed to ION uptake by and stimulation of endogenous macrophages. Instead of directly targeting cancer cells, our strategy targets macrophages and uses them as a secretory source of ATP and HMGB1 to enhance radiation-induced ICD. Our research introduces a new nanoparticle-based immunomodulatory approach that may have applications in radiotherapy and beyond.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":"80-91"},"PeriodicalIF":4.0,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740999/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142826515","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":"FAP-Targeted Fluorescent Imaging Agents to Study Cancer-Associated Fibroblasts In Vivo.","authors":"Riley J Deutsch-Williams, Kelton A Schleyer, Riddha Das, Jasmine E Carrothers, Rainer H Kohler, Claudio Vinegoni, Ralph Weissleder","doi":"10.1021/acs.bioconjchem.4c00426","DOIUrl":"10.1021/acs.bioconjchem.4c00426","url":null,"abstract":"<p><p>Cancer-associated fibroblasts (CAFs) expressing fibroblast activation protein alpha (FAP) are abundant in tumor microenvironments and represent an emerging target for PET cancer imaging. While different quinolone-based small molecule agents have been developed for whole-body imaging, there is a scarcity of well-validated fluorescent small molecule imaging agents to better study these cells in vivo. Here, we report the synthesis and characterization of a series of fluorescent FAP imaging agents based on the common quinolone azide inhibitor. Our data show excellent performance of some synthesized FAP Targeting Fluorescent probes (FTFs) for both topical application and intravenous delivery to label CAF populations in solid tumors. These results suggest that FTF can be used to study CAF biology and therapeutic targeting in vivo.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":"44-53"},"PeriodicalIF":4.0,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816650","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}