Bioconjugate Chemistry最新文献

{"title":"Heterovalent Click Reactions on DNA Origami.","authors":"Grant A Knappe, Jeffrey Gorman, Andrew N Bigley, Steven P Harvey, Mark Bathe","doi":"10.1021/acs.bioconjchem.4c00552","DOIUrl":"10.1021/acs.bioconjchem.4c00552","url":null,"abstract":"<p><p>Nucleic acid nanoparticles (NANPs) fabricated by using the DNA origami method have broad utility in materials science and bioengineering. Their site-specific, heterovalent functionalization with secondary molecules such as proteins or fluorophores is a unique feature of this technology that drives its utility. Currently, however, there are few chemistries that enable fast, efficient covalent functionalization of NANPs with a broad conjugate scope and heterovalency. To address this need, we introduce synthetic methods to access inverse electron-demand Diels-Alder chemistry on NANPs. We demonstrate a broad conjugate scope, characterize application-relevant kinetics, and integrate this new chemistry with strain-promoted azide-alkyne cycloaddition chemistry to enable heterovalent click reactions on NANPs. We applied these chemistries to formulate a prototypical chemical countermeasure against chemical nerve agents. We envision this additional chemistry finding broad utility in the synthetic toolkit accessible to the nucleic acid nanotechnology community.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":"476-485"},"PeriodicalIF":4.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555305","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":"Improved Pendant-Bearing Glucose-Neopentyl Glycols for Membrane Protein Stability","authors":"Taeyeol Youn,&nbsp;Ganghee Kim,&nbsp;Parameswaran Hariharan,&nbsp;Xianglan Li,&nbsp;Waqar Ahmed,&nbsp;Bernadette Byrne,&nbsp;Xiangyu Liu,&nbsp;Lan Guan and Pil Seok Chae*,&nbsp;","doi":"10.1021/acs.bioconjchem.4c0055610.1021/acs.bioconjchem.4c00556","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00556https://doi.org/10.1021/acs.bioconjchem.4c00556","url":null,"abstract":"<p >Membrane proteins are biologically and pharmaceutically significant, and determining their 3D structures requires a membrane-mimetic system to maintain protein stability. Detergent micelles are widely used as membrane mimetics; however, their dynamic structures often lead to the denaturation and aggregation of encapsulated membrane proteins. To address the limitations of classical detergents in stabilizing membrane proteins, we previously reported a class of glucose-neopentyl glycols (GNGs) and their pendant-bearing versions (P-GNGs), several of which proved more effective than DDM in stabilizing membrane proteins. In this study, we synthesized additional GNG derivatives by varying the lengths of the pendant (P-GNGs), and by introducing hemifluorinated pendants to the GNG scaffold (fluorinated pendant-bearing GNGs or FP-GNGs). The synthetic flexibility of the GNG chemical architecture allowed us to create a diverse range of derivatives, essential for the effective optimization of detergent properties. When tested with two model membrane proteins (a transporter and a G-protein coupled receptor (GPCR)), most of the new (F)P-GNGs demonstrated superior stabilization of these membrane proteins compared to DDM, the original GNG (OGNG)), and a previously developed P-GNG (i.e., GNG-3,14). Notably, several P-GNGs synthesized in this study were as effective as or even better than lauryl maltose neopentyl glycol (LMNG) in stabilizing a human GPCR, beta2 adrenergic receptor (β2AR). Enhanced protein stability was particularly observed for the P-GNGs with a butyl (C4) or pentyl (C5) pendant, indicating that these pendant sizes are optimal for membrane protein stability. The volumes of these pendants appear to minimize the empty spaces in the micelle interiors, thereby enhancing detergent-detergent interactions in micelles complexed with the membrane proteins. Additionally, we identified one FP-GNG that was more efficient at extracting the transporter and more effective at stabilizing the GPCR than DDM. Thus, the current study demonstrates that both chain length and number of fluorine atoms in the pendants of the P-GNGs were crucial determinants for membrane protein stability. We not only developed a few (F)P-GNGs that are significantly more effective than maltoside detergents (LMNG/DDM) for protein extraction and stability but we also provided an effective strategy for detergent design through the utilization of partially fluorinated pendants of varying length.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 4","pages":"707–717 707–717"},"PeriodicalIF":4.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832637","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 Determinants of Affinity and Isoform Selectivity in Protein─Small Molecule Hybrid Inhibitors of Carbonic Anhydrase.","authors":"Sarah W Torres, Crystal Lan, Abbigael Harthorn, Zachary Schmitz, Paul L Blanchard, Jon Collins, Benjamin J Hackel","doi":"10.1021/acs.bioconjchem.5c00006","DOIUrl":"10.1021/acs.bioconjchem.5c00006","url":null,"abstract":"<p><p>Multiple studies have demonstrated the benefit of engineering hybrid ligands that combine the unique benefits of small molecules and proteins or peptides. However, the molecular complexity of hybrid ligands generates a parameter space so large it cannot be exhaustively explored. We systematically evaluated the impact of one molecular design element, conjugation site, on the discovery of functional protein-small molecule hybrids (PriSMs). We utilized a library of yeast-displayed fibronectin domain variants with amino acid and loop length diversity in the paratope and a single cysteine at one of 18 possible conjugation sites. The protein variants were coupled with maleimide-functionalized acetazolamide and sorted via competitive flow cytometry to discover potent and selective inhibitors of three isoforms of carbonic anhydrase. Deep sequencing of the resultant populations of functional PriSMs revealed an isoform-dependent distribution of conjugation site preferences. The top PriSMs showed potency and selectivity gains up to 23- and 100-fold (in this case, for CA-II vs CA-XII, with a 43-fold selectivity gain for CA-II vs CA-IX) relative to PEG₂-acetazolamide alone. The presented study expands our fundamental understanding of the role of conjugation site in PriSM function and informs future PriSM engineering efforts by highlighting the benefit of conjugation site diversity in PriSM libraries.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":"549-562"},"PeriodicalIF":4.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602995","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":"Evaluation of PSMA-Targeted TREN-CAM Conjugates for Targeted Imaging of Cancer with 68Ga(III) and 45Ti(IV)","authors":"Axia Marlin,&nbsp;Phuong Nguyen Tran,&nbsp;Morgan Dierolf,&nbsp;Molly DeLuca,&nbsp;M. Andrey Joaqui Joaqui,&nbsp;Owen M. Glaser,&nbsp;Angus J. Koller,&nbsp;Eduardo Alucio-Sarduy,&nbsp;Mallory Gork,&nbsp;Dariusz Śmiłowicz,&nbsp;Valérie Pierre,&nbsp;Jonathan W. Engle* and Eszter Boros*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c0009910.1021/acs.bioconjchem.5c00099","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00099https://doi.org/10.1021/acs.bioconjchem.5c00099","url":null,"abstract":"<p >Chelation approaches that are compatible with a multitude of isotopes are an important area of development. Here, we introduce the design, synthesis, and evaluation of 2,3-dihydroxyterephthalate/catechol chelator conjugates compatible with the positron emission tomography (PET) isotopes ⁶⁸Ga³⁺ and ⁴⁵Ti⁴⁺, targeting the prostate-specific membrane antigen (PSMA). The conjugates are made in a multistep organic synthesis incorporating 2,3-dihydroxyterephthalate, linked to the amino hexanoic acid-extended, urea-dipeptides EuE or KuE (substrates of the PSMA active site). The radiochemical complexes, [⁴⁵Ti][Ti(TREN-CAM-hex-EuE)]^2–, [⁴⁵Ti][Ti(TREN-CAM-hex-KuE)]^2–, and [⁶⁸Ga][Ga(TREN-CAM-hex-KuE)]^3– form readily at room temperature within 15 min with a molar activity of 24–29 mCi/μmol. The corresponding chelates are stable in phosphate-buffered saline (PBS) solution prior to injection. Subsequent in vivo studies in a bilateral tumor xenograft mouse model were conducted, including 90- and 270-min PET, followed by biodistribution and metabolite analysis at 2 or 5 h postinjection. These studies demonstrated selective uptake of the radiochemical complexes in the PSMA-expressing tumor (17.25 ± 4.15, 13.84 ± 3.85, 15.64 ± 6.37% ID/g for [⁴⁵Ti][Ti(TREN-CAM-hex-EuE)]^2–, [⁴⁵Ti][Ti(TREN-CAM-hex-KuE)]^2– and [⁶⁸Ga][Ga(TREN-CAM-hex-KuE)]^3– respectively), with pharmacokinetics dominated by renal clearance. Delayed clearance of the [⁴⁵Ti][Ti(TREN-CAM-hex-KuE)]^2– complex is observed when compared with that of [⁶⁸Ga][Ga(TREN-CAM-hex-KuE)]^3– as indicated by elevated activity retention in the blood, which we attribute to the charge difference and partial complex dissociation. Urine metabolite analysis shows that [⁶⁸Ga][Ga(TREN-CAM-hex-KuE)]^3– is excreted &gt;98% intact, while [⁴⁵Ti][Ti(TREN-CAM-hex-KuE)]^2– exhibited signs of dechelation. Conclusively, our data support further investigation of bifunctional TREN-CAM derivatives as a synthetically accessible bifunctional chelator class for ⁶⁸Ga³⁺ and ⁴⁵Ti⁴⁺ isotopes.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 4","pages":"859–866 859–866"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832632","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":"Receptor-Mediated Transmembrane Activation of Protein Folding in Synthetic Cells","authors":"Andreas Bo̷tker Pedersen,&nbsp;Dante Guldbrandsen Andersen,&nbsp;Josefine Hammer Jakobsen,&nbsp;Mireia Casanovas Montasell and Alexander N. Zelikin*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c0004310.1021/acs.bioconjchem.5c00043","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00043https://doi.org/10.1021/acs.bioconjchem.5c00043","url":null,"abstract":"<p >Synthetic cells are a rapidly maturing platform with emerging applications in biomedicine and biotechnology. The specific novelty of this work is that we develop synthetic cells that respond to an extracellular stimulus by performing the folding of an encapsulated polypeptide into a functional enzyme. To this end, we developed artificial transmembrane signaling receptors. These contain an extracellular enzyme-responsive group, a self-immolative linker as the mechanism of signal transduction, and a secondary messenger molecule with intracellular activity. The secondary messenger is chosen such that it initiates protein refolding from the denatured polypeptide. Results of this study expand the molecular toolbox for the design of synthetic cells with life-like, responsive behavior.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 4","pages":"782–791 782–791"},"PeriodicalIF":4.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143833098","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":"Bivalent Hapten Display Strategies for Conjugate Vaccines Targeting Opioid Mixtures Containing Fentanyl","authors":"Carly Baehr*,&nbsp;Rajwana Jahan,&nbsp;Ann Gebo,&nbsp;Jennifer Vigliaturo,&nbsp;Daihyun Song,&nbsp;Md Toufiqur Rahman,&nbsp;Davide Tronconi,&nbsp;Aaron Khaimraj,&nbsp;Robert Seaman,&nbsp;Courtney Marecki,&nbsp;Caroline M. Kim,&nbsp;Stefano Persano,&nbsp;Scott P. Runyon and Marco Pravetoni,&nbsp;","doi":"10.1021/acs.bioconjchem.4c0054810.1021/acs.bioconjchem.4c00548","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00548https://doi.org/10.1021/acs.bioconjchem.4c00548","url":null,"abstract":"<p >Increasingly, street mixtures of opioids are reported to contain combinations of synthetic opioids, such as fentanyl with fentanyl analogues or counterfeit oxycodone pills containing fentanyl. While antiopioid immunotherapeutics have been investigated as a possible approach to address the opioid epidemic, the efficacy of vaccines and antibodies is limited to specific target opioids, based on the chemical structure of the haptens used in vaccines. Hence, there is a need for rational design of antiopioid conjugate vaccines that simultaneously target multiple opioids. Here, four novel haptens were synthesized, which were designed to elicit antibodies capable of binding to fentanyl other target opioids, including carfentanil, alfentanil, or oxycodone. Haptens were conjugated to CRM carrier protein and formulated with an aluminum salt adjuvant, and vaccines containing bivalent haptens were compared to admixtures of individual conjugate vaccines targeting the two opioids separately. Rats were immunized with monovalent, admixed, or novel bivalent vaccines, and the blockade of opioid effects was assessed against the individual drugs and their mixtures. Opioid-specific antibody titer was measured, and in vivo effects of vaccines were assessed in terms of preventing opioid-induced antinociception and respiratory depression and opioid distribution to the brain. While the bivalent vaccines reduced the effects of some target opioids, the admixed vaccine formulations were more effective against fentanyl/carfentanil and fentanyl/alfentanil mixtures. The bivalent fentanyl/oxycodone vaccine was as effective as the monovalent vaccines against a single drug challenge. These results inform the design of future vaccines against opioids and other drugs, particularly in the context of vaccines against polysubstance use that require optimization of response against multiple drugs of interest.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 4","pages":"676–687 676–687"},"PeriodicalIF":4.0,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143833094","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":"Rational Design of Site-Specific Fatty Acid Derivatives to Extend the Half-Life of Fibroblast Growth Factor 21","authors":"Chengcheng Wang,&nbsp;Yapeng Wang,&nbsp;Yuanzhen Dong,&nbsp;Yu Duan,&nbsp;Ying Zhang,&nbsp;Hao Huang,&nbsp;Zhiru Xu,&nbsp;Jianguang Lu,&nbsp;Chunyong Ding*,&nbsp;Zhengyan Cai*,&nbsp;Dianwen Ju* and Jun Feng*,&nbsp;","doi":"10.1021/acs.bioconjchem.4c0054910.1021/acs.bioconjchem.4c00549","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00549https://doi.org/10.1021/acs.bioconjchem.4c00549","url":null,"abstract":"<p >Fibroblast growth factor 21 (FGF21) is a crucial regulator of glucose and lipid metabolism, showing significant therapeutic promise for metabolic disorders. However, its clinical application is limited by poor pharmacokinetics. One potential strategy to improve its half-life is to facilitate albumin binding through fatty acid derivation. Despite this promise, achieving site-specific modifications of FGF21 while preserving its biological activity has been challenging. In this study, we applied a rational design approach to create site-specific fatty acid derivatives of FGF21, guided by the structure of the FGF21-receptor complex. This strategy successfully enhances albumin binding without interfering with receptor interactions. The modified FGF21 derivatives exhibited dramatically extended half-lives in mice, increasing from 0.73 h to 11.36 and 13.36 h, respectively. Furthermore, these analogues showed superior biological activity in the presence of albumin, outperforming the C-terminal-derived variant zalfermin. This rational design approach not only improves the pharmacokinetic profile of FGF21 but also provides a framework for enhancing the therapeutic potential of other small proteins.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 4","pages":"688–696 688–696"},"PeriodicalIF":4.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143833091","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":"Exceptional Near-Infrared II Organic Small Molecule Nanoagent for Photoacoustic/Photothermal Imaging-Guided Highly Efficient Therapy in Cancer","authors":"Yidong Bin,&nbsp;Lixian Huang,&nbsp;Jiangke Qin,&nbsp;Shulin Zhao*,&nbsp;Jianniao Tian and Liangliang Zhang*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c0005810.1021/acs.bioconjchem.5c00058","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00058https://doi.org/10.1021/acs.bioconjchem.5c00058","url":null,"abstract":"<p >Near-infrared II (NIR-II) photoacoustic (PA)/photothermal imaging-guided tumor therapy holds great promise in precision medicine for cancer treatment. This work reports on the synthesis and application of an organic small molecule nanoagent that has exceptional PA and photothermal properties in the near-infrared region. BCy-TPE was constructed by linking an NIR-II absorbing cyanine dye BCy-Cl with a twisted tetraphenylethene unit. The synthesized BCy-TPE exhibited an intense absorption peak at 1032 nm. After encapsulation into water-dispersible nanoparticles (NPs), BCy-TPE NPs exhibited two absorption peaks at 880 and 1046 nm. Notably, under 1064 nm laser excitation, BCy-TPE NPs deliver a remarkable photothermal conversion efficiency of 92%, together with superior biocompatibility, photostability, and PA/photothermal imaging capability. Moreover, after intravenous administration of BCy-TPE NPs into 4T1 tumor-bearing mice and treatment with safe-intensity (1.0 W cm^–2 and 1064 nm) laser irradiation, tumor temperature increased rapidly to 52 °C within 1 min and tumors are completely ablated after a single photothermal therapy treatment. Overall, this work offers a novel strategy to develop superb NIR-II photothermal agents for PA/photothermal imaging-guided highly efficient therapy in cancer.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 4","pages":"803–814 803–814"},"PeriodicalIF":4.0,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832987","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":"Indium-111-Labeled Single-Domain Antibody for In Vivo CXCR4 Imaging Using Single-Photon Emission Computed Tomography","authors":"Muriel Aline Spahn,&nbsp;Stephanie Mareike Anbuhl,&nbsp;Kaat Luyten,&nbsp;Tom Van Loy,&nbsp;Matti F. Pronker,&nbsp;Christopher Cawthorne,&nbsp;Christophe M. Deroose,&nbsp;Dominique Schols,&nbsp;Raimond Heukers,&nbsp;Guy Bormans and Frederik Cleeren*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c0002410.1021/acs.bioconjchem.5c00024","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00024https://doi.org/10.1021/acs.bioconjchem.5c00024","url":null,"abstract":"&lt;p &gt;C-X-C chemokine receptor type 4 (CXCR4) is highly expressed in a range of pathologies, including cancers like multiple myeloma and non-Hodgkin lymphoma, inflammatory diseases such as rheumatoid arthritis, and viral infections like HIV. Currently, the most advanced radiotracer for CXCR4 imaging in clinics is [&lt;sup&gt;68&lt;/sup&gt;Ga]PentixaFor. However, its structure is prone to modifications, complicating the development of a specific CXCR4 fluorine-18-labeled tracer with good pharmacokinetic properties. This study aimed to screen multiple CXCR4-targeting variable domains of heavy-chain-only antibody (VHH or single-domain antibody (sdAb)) constructs to identify the most promising sdAb as a vector molecule for the future development of a CXCR4 fluorine-18 tracer. We have generated five CXCR4-specific sdAb constructs with a cysteine-containing C-terminal tag (C-Direct tag) (VUN400-C-Direct, VUN401-C-Direct, VUN410-C-Direct, VUN411-C-Direct, and VUN415-C-Direct) and one probe (VUN400-C) without. The reduced sdAbs were coupled to maleimide-DOTAGA for &lt;sup&gt;111&lt;/sup&gt;In-labeling. Their binding affinity against human CXCR4 (hCXCR4) was assessed by using a previously described BRET-based displacement assay. The &lt;i&gt;in vivo&lt;/i&gt; profile was assessed using naive mice. Based on the plasma stability (60 min post injection (p.i.)), we selected VUN400-C-Direct and its derivative VUN400-C for further evaluation. These compounds ([&lt;sup&gt;111&lt;/sup&gt;In]In-DOTAGA-VUN400-C-Direct and [&lt;sup&gt;111&lt;/sup&gt;In]In-DOTAGA-VUN400-C) were tested in mice bearing xenografts derived from U87.CD4, U87.CXCR4, and U87.CD4.CXCR4 cells through &lt;i&gt;ex vivo&lt;/i&gt; biodistribution studies and SPECT/CT imaging. The six sdAb constructs were labeled with a high radiochemical conversion (75–97%) and purity (&gt;95%). In radioactive binding assays using U87.CD4.CXCR4 cells, [&lt;sup&gt;111&lt;/sup&gt;In]In-DOTAGA-VUN400-C-Direct and [&lt;sup&gt;111&lt;/sup&gt;In]In-DOTAGA-VUN401-C-Direct displayed the highest cellular uptake, achieving 10.4 ± 1.6% and 11.5 ± 1.1%, respectively. In naive mice, [&lt;sup&gt;111&lt;/sup&gt;In]In-DOTAGA-VUN400-C-Direct showed the most favorable biodistribution profile, with low uptake across all organs except the kidneys (Standardized Uptake Value (SUV) &gt; 50, &lt;i&gt;n&lt;/i&gt; = 3, 60 min p.i.), but average plasma stability (40.6 ± 9.4%, &lt;i&gt;n&lt;/i&gt; = 3, 60 min p.i.). In a xenografted tumor model, [&lt;sup&gt;111&lt;/sup&gt;In]In-DOTAGA-VUN400-C-Direct showed only minor uptake (SUV&lt;sub&gt;U87.CXCR4&lt;/sub&gt; 0.71 ± 0.002, &lt;i&gt;n&lt;/i&gt; = 3, 60 min p.i.). [&lt;sup&gt;111&lt;/sup&gt;In]In-DOTAGA-VUN400-C demonstrated nearly identical plasma stability (41.08 ± 5.45%, &lt;i&gt;n&lt;/i&gt; = 4) but showed high and specific uptake in the CXCR4-expressing xenografted tumor (SUV&lt;sub&gt;U87.CD4.CXCR4&lt;/sub&gt; 3.75 ± 1.08 vs SUV&lt;sub&gt;U87.CD4&lt;/sub&gt; = 0.64 ± 0.19, &lt;i&gt;n&lt;/i&gt; = 5, 60 min p.i.), which could be blocked by coinjection of AMD3100 (5 mg/kg) (SUV&lt;sub&gt;U87.CD4.CXCR4&lt;/sub&gt; 0.55 ± 0.32 vs SUV&lt;sub&gt;U87.CD4&lt;/sub&gt; = 0.39 ± 0.07, &lt;i&gt;n&lt;/i&gt; = 2, 60 min p.i.). In conclusion, all six sdAbs exhi","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 4","pages":"737–747 737–747"},"PeriodicalIF":4.0,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832911","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":"Targeted Polymersomes Enable Enhanced Delivery to Peripheral Nerves Post-Injury","authors":"Kayleigh Trumbull,&nbsp;Sophia Fetten,&nbsp;Noah Arnold,&nbsp;Vanessa Marahrens,&nbsp;Dru Montgomery,&nbsp;Olivia Myers,&nbsp;Jeffery L. Twiss and Jessica Larsen*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c0007210.1021/acs.bioconjchem.5c00072","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00072https://doi.org/10.1021/acs.bioconjchem.5c00072","url":null,"abstract":"<p >The gold standard therapy for peripheral nerve injuries involves surgical repair, which is invasive and leads to major variations in therapeutic outcomes. Because of this, smaller injuries often go untreated. However, alternative, noninvasive routes of administration are currently unviable due to the presence of the blood–nerve barrier (BNB), which prevents passage of small molecules from the blood into the endoneurium and the nerve. This paper demonstrates that ligands on the surface of nanoparticles, called polymersomes, can enable delivery to the nerve through noninvasive intramuscular injections. Polymersomes made from polyethylene glycol (PEG)-<i>b</i>-polylactic acid (PLA) were conjugated with either apolipoprotein E (ApoE) or rabies virus glycoprotein-based peptide RVG29 (RVG) and loaded with near-infrared dye, AlexaFluor647. ApoE was used to target receptors upregulated in post-injury inflammation, while RVG targets neural-specific receptors. Untagged, ApoE-tagged, and RVG-tagged polymersomes were injected at 100 mM either intranerve (IN) or intramuscular (IM) into Sprague–Dawley rats post sciatic nerve injury. The addition of the ApoE and RVG tags enabled increased AlexaFluor647 fluorescence in the injury site at 1 h post IN injection compared to the untagged polymersome control. However, only the RVG-tagged polymersomes increased the AlexaFluor647 fluorescence after IM injection. Ex vivo analysis of sciatic nerves demonstrated that ApoE-tagged polymersomes enabled the greatest retention of AlexaFluor647 regardless of the injection route. This led us to conclude that using ApoE to target inflammation enabled the greatest retention of polymersome-delivered payloads while using RVG to target neural cells more specifically enabled the penetration of polymersome-delivered payloads. Observations were confirmed by calculating the area under the curve pharmacokinetic parameters and the use of a two-compartment pharmacokinetic model.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 4","pages":"823–837 823–837"},"PeriodicalIF":4.0,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832983","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}