Gabriela Mixová, Eva Tihlaříková, Yaling Zhu, Lucie Schindler, Ladislav Androvič, Lucie Kracíková, Eliška Hrdá, Bedřich Porsch, Michal Pechar, Christopher M Garliss, David Wilson, Hugh C Welles, Jake Holechek, Qiuyin Ren, Geoffrey M Lynn, Vilém Neděla, Richard Laga
{"title":"Synthesis and Structure Optimization of Star Copolymers as Tunable Macromolecular Carriers for Minimal Immunogen Vaccine Delivery.","authors":"Gabriela Mixová, Eva Tihlaříková, Yaling Zhu, Lucie Schindler, Ladislav Androvič, Lucie Kracíková, Eliška Hrdá, Bedřich Porsch, Michal Pechar, Christopher M Garliss, David Wilson, Hugh C Welles, Jake Holechek, Qiuyin Ren, Geoffrey M Lynn, Vilém Neděla, Richard Laga","doi":"10.1021/acs.bioconjchem.4c00273","DOIUrl":null,"url":null,"abstract":"<p><p>Minimal immunogen vaccines are being developed to focus antibody responses against otherwise challenging targets, including human immunodeficiency virus (HIV), but multimerization of the minimal peptide immunogen on a carrier platform is required for activity. Star copolymers comprising multiple hydrophilic polymer chains (\"arms\") radiating from a central dendrimer unit (\"core\") were recently reported to be an effective platform for arraying minimal immunogens for inducing antibody responses in mice and primates. However, the impact of different parameters of the star copolymer (e.g., minimal immunogen density and hydrodynamic size) on antibody responses and the optimal synthetic route for controlling those parameters remains to be fully explored. We synthesized a library of star copolymers composed of poly[<i>N</i>-(2-hydroxypropyl)methacrylamide] hydrophilic arms extending from poly(amidoamine) dendrimer cores with the aim of identifying the optimal composition for use as minimal immunogen vaccines. Our results show that the length of the polymer arms has a crucial impact on the star copolymer hydrodynamic size and is precisely tunable over a range of 20-50 nm diameter, while the dendrimer generation affects the maximum number of arms (and therefore minimal immunogens) that can be attached to the surface of the dendrimer. In addition, high-resolution images of selected star copolymer taken by a custom-modified environmental scanning electron microscope enabled the acquisition of high-resolution images, providing new insights into the star copolymer structure. Finally, <i>in vivo</i> studies assessing a star copolymer vaccine comprising an HIV minimal immunogen showed the criticality of polymer arm length in promoting antibody responses and highlighting the importance of composition tunability to yield the desired biological effect.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":null,"pages":null},"PeriodicalIF":4.0000,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11342300/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioconjugate Chemistry Bioconjugate","FirstCategoryId":"1","ListUrlMain":"https://doi.org/10.1021/acs.bioconjchem.4c00273","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/31 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"BIOCHEMICAL RESEARCH METHODS","Score":null,"Total":0}
引用次数: 0
Abstract
Minimal immunogen vaccines are being developed to focus antibody responses against otherwise challenging targets, including human immunodeficiency virus (HIV), but multimerization of the minimal peptide immunogen on a carrier platform is required for activity. Star copolymers comprising multiple hydrophilic polymer chains ("arms") radiating from a central dendrimer unit ("core") were recently reported to be an effective platform for arraying minimal immunogens for inducing antibody responses in mice and primates. However, the impact of different parameters of the star copolymer (e.g., minimal immunogen density and hydrodynamic size) on antibody responses and the optimal synthetic route for controlling those parameters remains to be fully explored. We synthesized a library of star copolymers composed of poly[N-(2-hydroxypropyl)methacrylamide] hydrophilic arms extending from poly(amidoamine) dendrimer cores with the aim of identifying the optimal composition for use as minimal immunogen vaccines. Our results show that the length of the polymer arms has a crucial impact on the star copolymer hydrodynamic size and is precisely tunable over a range of 20-50 nm diameter, while the dendrimer generation affects the maximum number of arms (and therefore minimal immunogens) that can be attached to the surface of the dendrimer. In addition, high-resolution images of selected star copolymer taken by a custom-modified environmental scanning electron microscope enabled the acquisition of high-resolution images, providing new insights into the star copolymer structure. Finally, in vivo studies assessing a star copolymer vaccine comprising an HIV minimal immunogen showed the criticality of polymer arm length in promoting antibody responses and highlighting the importance of composition tunability to yield the desired biological effect.
期刊介绍:
Bioconjugate Chemistry invites original contributions on all research at the interface between man-made and biological materials. The mission of the journal is to communicate to advances in fields including therapeutic delivery, imaging, bionanotechnology, and synthetic biology. Bioconjugate Chemistry is intended to provide a forum for presentation of research relevant to all aspects of bioconjugates, including the preparation, properties and applications of biomolecular conjugates.