Bioconjugate Chemistry最新文献

{"title":"In Silico-Driven THIOMAB Approach for Stable PROTAC Conjugates by Docking Payloads in Antibody Cavities","authors":"Shiwei Song,&nbsp;Yahui Liu,&nbsp;Jiaqi Liu and Wanyi Tai*,&nbsp;","doi":"10.1021/acs.bioconjchem.4c0058810.1021/acs.bioconjchem.4c00588","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00588https://doi.org/10.1021/acs.bioconjchem.4c00588","url":null,"abstract":"<p >The heterobifunctional proteolysis targeting chimeras (PROTACs) are a class of emerging therapeutic modalities that enable selective degradation of target proteins in cells. As antibody payloads, they offer several advantages compared to conventional chemical toxins, such as catalytic nature, potent and long-lasting activity, and precise selectivity to avoid systemic toxicity. However, the relatively large size and high hydrophobicity of these chimeric payloads may result in challenging the stability of antibodies, which complicates the in vivo performance. In this work, we use the highly hydrophobic GNE-987 as model PROTAC to evaluate a THIOMAB approach for mitigating the conjugate’s hydrophobicity while maintaining the therapeutic potency. We describe an <i>in silico</i> method to select the less hydrophobic site in an antibody and employ the stable tetrapeptide-aminomethoxy linker to conjugate the PROTAC payloads. The resulting degrader-antibody conjugate (J591 DAC) displays antigen-dependent BRD4 degradation and potent cytotoxic activity in PSMA-positive cancer cells. Finally, this DAC, bearing two highly hydrophobic PROTACs, also exhibits a long blood retention and strong antitumor efficacy in mouse models, likely owing to the homogeneous and stable conjugation from the THIOMAB approach. This work provides an example of the design and construction of antibody conjugates with highly hydrophobic payloads.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 5","pages":"960–970 960–970"},"PeriodicalIF":4.0,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144097851","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":"Mitigating Cannabidiol’s Non-Selective Cytotoxicity via Subcellular Organelle Targeting: Exploring Mitochondrial Targeting Potential","authors":"Genglian Liu,&nbsp;Ru Li,&nbsp;Jingwei Gao,&nbsp;Cong Lin,&nbsp;Hongyuan Li,&nbsp;Yinghua Peng*,&nbsp;Hongshuang Wang* and Xiaohui Wang*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c0001210.1021/acs.bioconjchem.5c00012","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00012https://doi.org/10.1021/acs.bioconjchem.5c00012","url":null,"abstract":"<p >Cannabidiol (CBD), a phytocannabinoid from <i>Cannabis sativa</i>, is renowned for its nonpsychoactive properties and therapeutic potential. However, its clinical application is limited by nonselective cytotoxicity, affecting microglia, oligodendrocytes, and other cells. To address this, subcellular organelle-targeting strategies were explored to minimize off-target effects and enhance CBD’s therapeutic index. Three organelle-specific conjugates targeting mitochondria, endoplasmic reticulum, and lysosomes were synthesized. Among these, the mitochondria-targeting triphenylphosphonium (TPP)-modified CBD conjugates demonstrated reduced cytotoxicity and enhanced anti-inflammatory activity. Further optimization identified a four-carbon ether chain linker (<b>CBD-TPP-C4</b>) that increased antineuroinflammatory activity by 3-fold and reduced cytotoxicity by 1.6-fold, compared to unmodified CBD. <b>CBD-TPP-C4</b> also elevated mitochondrial ATP levels in vitro, improved mitochondrial morphology and locomotor function in <i>Caenorhabditis elegans</i>, and potentiated morphine analgesia in mice. These findings highlight subcellular targeting as a promising strategy to enhance CBD’s safety and efficacy, paving the way for improved therapeutic applications.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 5","pages":"980–992 980–992"},"PeriodicalIF":4.0,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144097853","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":"Discovery of a Novel ADC for Multifunctional Theranostics: From Vascular Normalization to Synergistic Therapy","authors":"Yanchen Li,&nbsp;Jin Wang,&nbsp;Tingting Liu,&nbsp;Junyu Zhang,&nbsp;Yuanyuan Shan* and Jie Zhang*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c0011610.1021/acs.bioconjchem.5c00116","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00116https://doi.org/10.1021/acs.bioconjchem.5c00116","url":null,"abstract":"<p >Previous studies have shown the potential of bevacizumab-based ADCs in tumor vascular normalization and chemotherapy synergies. Here, in order to improve the tumor treatment efficiency of ADC and further avoid drug resistance, we introduced the previously discovered photodynamic therapy group PDT into bevacizumab, which has high reactive oxygen generation efficiency and deep tissue penetration ability, and has surprising imaging effect on solid tumors. At the same time, doxorubicin, a chemotherapy drug molecule with strong cytotoxicity, has also been introduced to construct novel multifunctional integrated antibody-drug conjugates, Bevacizumab-DOX-PDT. It is proved that novel ADCs have the antigen–antibody binding ability similar to bevacizumab, while also possess strong antitumor activity and vascular normalization activity. In addition, it also showed great tracer ability for transplanted tumors. In summary, the novel ADC showed a surprising vascular normalization-chemotherapy-photodynamic synergistic therapeutic effect, which further enriched the expansion of vascular normalization in the field of new drug discovery.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 5","pages":"1079–1087 1079–1087"},"PeriodicalIF":4.0,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144097852","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":"Phototheranostic Zinc Porphyrin Nanoparticles Triggered by an 808 nm Laser: NIR-II Fluorescence/Photoacoustic Imaging-Guided Combined Photothermal/Photodynamic/NO Therapy","authors":"Hongyu Chen,&nbsp;Xiaobo Zhao*,&nbsp;Akbar Halimov,&nbsp;Mingkai Fu,&nbsp;Jing Tu,&nbsp;Hui Liu,&nbsp;Huajun Xu* and Jun Liu*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c0008610.1021/acs.bioconjchem.5c00086","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00086https://doi.org/10.1021/acs.bioconjchem.5c00086","url":null,"abstract":"<p >Single-wavelength lasers that trigger intelligently designed multifunctional theranostic nanoplatforms are urgently needed for early cancer diagnosis and imaging-guided therapy. In this study, a novel zinc porphyrin, Por-TR, was fabricated by incorporating thiophene as a donor and introducing electron acceptors on both sides to expand the conjugation. The presence of multiple flexible chains in the molecular structure of Por-TR inhibits π–π stacking, which allows it to form J nanoaggregates when coassembled with DSPE-PEG2000, demonstrating maximum absorption at approximately 808 nm. These Por-TR NPs provide NIR-II fluorescence/PA dual-modal signals for imaging and serve as a combined PTT/PDT therapeutic agent, making them a suitable multifunctional theranostic nanoplatform. To further improve their therapeutic effects, we embedded a thermosensitive NO donor, BNN6, in the Por-TR nanosystem to achieve combined PDT/PTT/NO therapy. Intravenous injection of Por-TR-NO NPs into 4T1 tumor-bearing mice enabled the accurate observation of tumor location via NIR-II fluorescence/PA dual-modal imaging. In vivo therapy results show that the Por-TR-NO NPs exhibited remarkable antitumor efficacy in combined PTT/PDT/NO therapy, which was triggered by an 808 nm laser. Overall, this nanoplatform offers a versatile approach to cancer diagnosis and treatment.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 4","pages":"838–845 838–845"},"PeriodicalIF":4.0,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832624","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":"Mechanistic Characterization of the Potency of THIOMAB Antibody–Drug Conjugates Targeting Staphylococcus aureus and ETbR-Expressing Tumor Cells Using Quantitative LC-MS/MS Analysis of Intracellular Drug Accumulation","authors":"Hilda Hernandez-Barry,&nbsp;Josefa dela Cruz-Chuh,&nbsp;Kimberly K. Kajihara,&nbsp;Jyoti Asundi,&nbsp;Richard Vandlen,&nbsp;Donglu Zhang,&nbsp;Wouter L.W. Hazenbos,&nbsp;Thomas Pillow,&nbsp;Yichin Liu,&nbsp;Cong Wu,&nbsp;Katherine R. Kozak and Kelly M. Loyet*,&nbsp;","doi":"10.1021/acs.bioconjchem.4c0053310.1021/acs.bioconjchem.4c00533","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00533https://doi.org/10.1021/acs.bioconjchem.4c00533","url":null,"abstract":"<p >THIOMAB drug conjugate (TDC) technology provides site-specific conjugation of linker drugs to antibodies, allowing for targeted delivery of the payload. While a direct measurement of TDC cytotoxic potency allows efficient screening and confirmation that new drugs conjugated to antibodies result in proper processing in cells, additional mechanistic characterization is often needed to provide information-rich data to guide further optimization of TDC design. For example, a quantitative understanding of how TDCs are processed intracellularly can help determine which processing step is impacting payload delivery and thereby inform the basis of the TDC efficacy. Here, we measure the cellular accumulation of two different TDC drug payloads: MAPK (mitogen-activated protein kinase) pathway inhibitor targeting ETbR-expressing tumor cells and an antibiotic active against <i>Staphylococcus aureus</i> with an <i>in vitro</i> cell-based drug release LC-MS/MS assay in a 96-well format. This assay allowed us to correlate the cellular potency of each unconjugated molecule with the amount of payload that accumulated inside the cell. In the case of the pathway inhibitor drug, the biochemical characterization of TDC processing by cathepsin B and purified human liver enzyme extract demonstrated a correlation between the efficiency of the linker drug cleavage and intracellular payload accumulation. For the antibody–antibiotic conjugate, kinetic analysis of intracellular free drug retention provided valuable insight into the chemistry modifications needed for an efficient TDC. Taken together, we demonstrated the utility of quantitative LC-MS/MS assays as one tool in guiding the design of more effective TDCs via the mechanistic release characterization of two distinct payloads.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 4","pages":"652–661 652–661"},"PeriodicalIF":4.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832969","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":"Fc Multisite Conjugation and Prolonged Delivery of the Folate-Targeted Drug Conjugate EC140","authors":"Yan Zheng,&nbsp;Hong Cheng,&nbsp;Sibo Jiang and Wanyi Tai*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c0003710.1021/acs.bioconjchem.5c00037","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00037https://doi.org/10.1021/acs.bioconjchem.5c00037","url":null,"abstract":"<p >Small molecule-drug conjugate (SMDC) is a targeted drug delivery technology that develops in parallel with the antibody-drug conjugate. However, the clinical translation of SMDC faces challenges due to its limited circulating half-life in vivo. The drawback in pharmacokinetics is that it restricts the exposure time of SMDC to tumor tissues and ultimately reduces the therapeutic efficacy. In this study, we chemically conjugated a folate-targeted SMDC EC140 to the long-circulating Fc protein at multiple sites, yielding a stable and high-DAR Fc-SMDC conjugate (Fc-EC140). Fc-EC140 can bear approximately 4 molecules of EC140 per Fc protein (drug-antibody ratio = 4.1) and display enhanced potency in folate receptor (FR)-positive tumor cells compared to the SMDC comparator. In addition, Fc-EC140 retains the FcRn-mediated recycling function and displays an extended half-life of 28 h in the mice. In vivo, antitumor experiments demonstrate that intravenous administration of Fc-EC140 (Q7D × 3 at a dose of 15 mg/kg) nearly cures the KB tumors, which is far more effective than the comparator EC140 administrated at equivalent doses. This study presents a new strategy for the targeted delivery of SMDC.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 4","pages":"762–769 762–769"},"PeriodicalIF":4.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832604","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":"Choice of an Optimal Modular Strategy for the Synthesis of DOTA-Containing Heterobivalent Agents Targeting PSMA and GRPr","authors":"Stanislav A. Petrov*,&nbsp;Gleb P. Grigoriev,&nbsp;Grigory A. Orlov,&nbsp;Nikolay Y. Zyk,&nbsp;Yuri K. Grishin,&nbsp;Vitaly A. Roznyatovsky,&nbsp;Maria A. Beloglazkina,&nbsp;Juliana V. Petrova,&nbsp;Aleksei E. Machulkin,&nbsp;Mariia S. Larkina,&nbsp;Anastasia Prach,&nbsp;Ruslan Varvashenya,&nbsp;Vitalina Bodenko,&nbsp;Evgenii Plotnikov,&nbsp;Mekhman S. Yusubov and Elena K. Beloglazkina,&nbsp;","doi":"10.1021/acs.bioconjchem.5c0003310.1021/acs.bioconjchem.5c00033","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00033https://doi.org/10.1021/acs.bioconjchem.5c00033","url":null,"abstract":"<p >Heterodimeric approaches have emerged as a promising method for simultaneously targeting multiple receptors on tumor cells using a single molecule. Simultaneous targeting of the prostate-specific membrane antigen (PSMA) and the gastrin-releasing peptide receptor (GRPr) holds the potential to improve the accuracy of prostate cancer diagnosis. The aim of this study was to develop a convenient and simple modular strategy for the creation of heterobivalent (HBV) conjugates targeting PSMA/GRPr receptors. For this purpose, we developed and compared six alternative routes for the stereoselective synthesis of HBV conjugates designed to deliver the chelating agent DOTA to PSMA/GRPr receptors. The comparison of these alternative synthetic pathways took into account such factors as efficiency, complexity, synthesis, and purification details, as well as yields of the target compounds. Optimal conditions for the stereoselective synthesis of HBV ligands to PSMA and GRPr, which could serve as molecular platforms for the targeted delivery of therapeutic or diagnostic agents to these receptors, were revealed. For synthesized HBV ligand <b>26</b>^<b>x</b> and its HBV conjugate with DOTA <b>27</b>, the complete signal assignment in ¹H, ¹³C, and ¹⁵N NMR spectra was achieved using 2D NMR techniques. Based on these data, comprehensive signal assignments were provided for all final compounds in their NMR spectra. The final HBV conjugate <b>27</b> was labeled with Lu-177, with yields &gt;99%, and the obtained radiotracer was studied in vitro for its binding specificity, with determining of the <i>K</i>_D and <i>B</i>_max using LNCaP (PSMA+) and PC-3 (GRPr+) cell lines.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 4","pages":"748–761 748–761"},"PeriodicalIF":4.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832732","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":"Self-Assembly of Toll-Like Receptor (TLR2/6) Agonist Lipidated Amino Acid or Peptide Conjugates: Distinct Morphologies and Bioactivities","authors":"Valeria Castelletto,&nbsp;Lucas R. de Mello,&nbsp;Juliane Pelin and Ian W Hamley*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c0005110.1021/acs.bioconjchem.5c00051","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00051https://doi.org/10.1021/acs.bioconjchem.5c00051","url":null,"abstract":"<p >Toll-like receptor (TLR) agonists are of interest in immunotherapy and cancer vaccines. The most common agonists of TLR2 are based on Pam₂Cys or Pam₃Cys. In the former, two palmitoyl (Pam) fatty acids are linked to a glycerylcysteine motif by ester linkages. Pam₃Cys is analogous but contains an extra Pam group on the α-amine. Here, we compare the self-assembly in aqueous solution of the parent Pam₂CysOH and Pam₃Cys amino acid conjugates to that of Pam₂CysSK₄ and Pam₃CysSK₄ which are potent TLR2 agonists bearing the CysSK₄ peptide sequence. All four conjugates exhibit a critical aggregation concentration above which self-assembled structures are formed. We find through a combination of small-angle X-ray scattering (SAXS), cryogenic transmission electron microscopy (cryo-TEM), and confocal fluorescence microscopy remarkable differences in self-assembled nanostructures. Pam₂CysOH and Pam₃CysOH both form unilamellar vesicles, although these are larger for the latter compound, an effect ascribed to enhanced membrane rigidity. This is in contrast to previously reported morphologies for Pam₂CysSK₄ and Pam₃CysSK4, which are spherical micelles or predominantly wormlike micelles, respectively [Hamley, I. W.; et al. <i>Toll-like Receptor Agonist Lipopeptides Self-Assemble into Distinct Nanostructures</i>. Chem. Comm. 2014, 50, 15948-15951]. We also examine the effect of introduction in the bulky <i>N</i>-terminal Fmoc [fluorenylmethoxycarbonyl] group on the self-assembly of Fmoc-Pam₂CysOH. This compound also forms vesicles (above a critical aggregation concentration, determined from dye probe fluorescence experiments) in aqueous solution, larger than those for Pam₂CysOH and with a population of perforated/compound vesicles. The carboxyl-coated (and amino-coated for Pam₂CysOH) vesicles demonstrated here represent a promising system for future development toward bionanotechnology applications such as immune therapies. Conjugates Pam₂CysOH, Pam₂CysSK₄, and Pam₃CysSK₄ show good cytocompatibility at low concentrations, and in fact, the cell compatibility extends over a wider concentration range for Pam₂CysOH. The TLR2/6 agonist activity was assessed using an assay that probes secreted alkaline phosphatase (SEAP) in NF-κB-SEAP reporter HEK293 cells expressing human TLR2 and TLR6, and Pam₂CySOH shows significant activity, although not to the extent of Pam₂CysSK4 or Pam₃CysSK₄. Thus, Pam₂CysOH in particular is of interest as a vesicle-forming TLR2/6 agonist and stimulator of immune response.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 4","pages":"792–802 792–802"},"PeriodicalIF":4.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.bioconjchem.5c00051","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832655","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":"Recent Advances in Aggregation-Induced Emission Bioconjugates","authors":"Guiquan Zhang,&nbsp;Daming Zhou,&nbsp;Rong Hu*,&nbsp;Anjun Qin* and Ben Zhong Tang*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c0003610.1021/acs.bioconjchem.5c00036","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00036https://doi.org/10.1021/acs.bioconjchem.5c00036","url":null,"abstract":"<p >Fluorescence imaging technology is playing increasing roles in modern personalized and precision medicine. Thanks to their excellent photophysical properties, organic luminogens featuring aggregation-induced emission (AIE) characteristics (AIEgens) have attracted considerable attention over the past two decades. Because of their superior biocompatibility, ease of processing and functionalization, excellent water solubility, high responsiveness, and exceptional signal-to-noise ratio (SNR) for biotargets, AIE bioconjugates, formed by covalently linking AIEgens with biomolecules, have emerged as an ideal candidate for bioapplications. In this review, we summarize the progress in preparation, properties, and application of AIE bioconjugates in the last five years. Moreover, the challenges and opportunities of AIE bioconjugates are also briefly discussed.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 4","pages":"609–626 609–626"},"PeriodicalIF":4.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832790","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":"Introducing TAPY as a Versatile Alternative to TPP for Selective Mitochondrial Targeting in Cancer Cells","authors":"Jean C. Neto,&nbsp;Federico Lucantoni,&nbsp;Leydy V. González,&nbsp;Eva Falomir,&nbsp;Juan F. Miravet and Francisco Galindo*,&nbsp;","doi":"10.1021/acs.bioconjchem.4c0055410.1021/acs.bioconjchem.4c00554","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00554https://doi.org/10.1021/acs.bioconjchem.4c00554","url":null,"abstract":"<p >The understanding of diseases such as cancer and Alzheimer’s, along with natural aging processes, heavily relies on the study of mitochondrial function. Optical techniques like fluorescence imaging microscopy are pivotal for this purpose, enabling precise mapping of subcellular structures, including mitochondria. In this study, we explored TAPY (triarylpyridinium) cations, a novel family of mitochondrial carriers resembling the well-known triphenylphosphonium cation (TPP). Six TAPY-bodipy (BDP) dyads were prepared and chemically characterized. Confocal Laser Scanning Microscopy (CLSM) studies demonstrated that the systems were delivered selectively to the mitochondria of cancer cells (MCF-7, A549, HT-29). Remarkably, these dyads did not target the mitochondria of normal cells (HEK-293, HMEC-1), suggesting their potential use in distinguishing cancerous cells from healthy ones. A model compound comprised of the same bodipy cargo but attached to TPP was also synthesized and tested. Notably, in preliminary comparative assays with MCF-7 cells, the dyad TAPY(OMe)-BDP outperformed the TPP derivative in mitochondrial imaging, achieving twice the final fluorescence intensity. The potential chemical diversity achievable with TAPY cations is considerable, with many derivatives being accessible starting from readily available commercial products. This implies that, based on the strategy outlined in this study, carefully optimized TAPY derivatives for targeted mitochondrial delivery could potentially be developed in the future as alternatives or complements to TPP, with the present work acting as a proof of concept.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 4","pages":"697–706 697–706"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832574","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}