Post-PEGylated and crosslinked polymeric ssRNA nanocomplexes as adjuvants targeting lymph nodes with increased cytolytic T cell inducing properties
Potent adjuvants are highly demanded for most protein and peptides based vaccine candidates in clinical development. Recognition of viral single stranded (ss)RNA by innate toll-like receptors 7/8 in dendritic cells results in a cytokine environment supportive to the establishment of long lasting ant...
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ftunivutrecht:oai:dspace.library.uu.nl:1874/376584 2023-11-12T04:15:48+01:00 Post-PEGylated and crosslinked polymeric ssRNA nanocomplexes as adjuvants targeting lymph nodes with increased cytolytic T cell inducing properties Lou, Bo De Beuckelaer, Ans Dakwar, George R. Remaut, Katrien Grooten, Johan Braeckmans, Kevin De Geest, Bruno G. Mastrobattista, Enrico De Koker, Stefaan Hennink, Wim E. Afd Pharmaceutics Pharmaceutics 2018-08-28 application/pdf https://dspace.library.uu.nl/handle/1874/376584 en eng 0168-3659 https://dspace.library.uu.nl/handle/1874/376584 info:eu-repo/semantics/OpenAccess Adjuvant Click chemistry Lymph node Nanocomplexes ssRNA Pharmaceutical Science Article 2018 ftunivutrecht 2023-11-01T23:19:40Z Potent adjuvants are highly demanded for most protein and peptides based vaccine candidates in clinical development. Recognition of viral single stranded (ss)RNA by innate toll-like receptors 7/8 in dendritic cells results in a cytokine environment supportive to the establishment of long lasting antibody responses and Th1 oriented T cell immunity. To fully exploit the immunestimulatory properties of ssRNA, it needs to be adequately formulated to ensure its optimal delivery to dendritic cells in the vaccine draining lymph nodes. In the present paper, we report on the design of ssRNA nanocomplexes formed by complexation of the cationic poly(carbonic acid 2-dimethylamino-ethyl ester 1-methyl-2-(2-methacryloylamino)-ethyl ester) (pHPMA-DMAE) based polymeric carrier and ssRNA. The resulting ssRNA nanocomplexes were subsequently PEGylated through copper-free click chemistry using PEG-bicyclo[6.1.0]nonyne (PEG-BCN) and cross-linked via disulfide bonds to increase their stability. The obtained near-neutral charged PEGylated ssRNA nanocomplexes (~150 nm) combined ssRNA protection with highly efficient delivery of ssRNA to DCs in the vaccine draining lymph nodes after subcutanuously administration. When co-administrated with a model antigen (soluble ovalbumin (OVA)), ssRNA nanocomplexes were far more efficient at inducing CD8 cytolytic T cells when compared to OVA co-adminstarted with naked ssRNA. Furthermore, IgG2c antibody titers, indicative of Th1 skewed T cell responses, were >10 times increased by complexing ssRNA into the PEGylated nanocomplexes. This study highlights the potential of post-functionalizing ssRNA nanocomplexes by copper-free click chemistry and these findings indcate that this potent ssRNA adjuvant may profoundly improve the efficacy of a variety of vaccines requiring Th1-type immunity. Article in Journal/Newspaper Carbonic acid Utrecht University Repository |
institution |
Open Polar |
collection |
Utrecht University Repository |
op_collection_id |
ftunivutrecht |
language |
English |
topic |
Adjuvant Click chemistry Lymph node Nanocomplexes ssRNA Pharmaceutical Science |
spellingShingle |
Adjuvant Click chemistry Lymph node Nanocomplexes ssRNA Pharmaceutical Science Lou, Bo De Beuckelaer, Ans Dakwar, George R. Remaut, Katrien Grooten, Johan Braeckmans, Kevin De Geest, Bruno G. Mastrobattista, Enrico De Koker, Stefaan Hennink, Wim E. Post-PEGylated and crosslinked polymeric ssRNA nanocomplexes as adjuvants targeting lymph nodes with increased cytolytic T cell inducing properties |
topic_facet |
Adjuvant Click chemistry Lymph node Nanocomplexes ssRNA Pharmaceutical Science |
description |
Potent adjuvants are highly demanded for most protein and peptides based vaccine candidates in clinical development. Recognition of viral single stranded (ss)RNA by innate toll-like receptors 7/8 in dendritic cells results in a cytokine environment supportive to the establishment of long lasting antibody responses and Th1 oriented T cell immunity. To fully exploit the immunestimulatory properties of ssRNA, it needs to be adequately formulated to ensure its optimal delivery to dendritic cells in the vaccine draining lymph nodes. In the present paper, we report on the design of ssRNA nanocomplexes formed by complexation of the cationic poly(carbonic acid 2-dimethylamino-ethyl ester 1-methyl-2-(2-methacryloylamino)-ethyl ester) (pHPMA-DMAE) based polymeric carrier and ssRNA. The resulting ssRNA nanocomplexes were subsequently PEGylated through copper-free click chemistry using PEG-bicyclo[6.1.0]nonyne (PEG-BCN) and cross-linked via disulfide bonds to increase their stability. The obtained near-neutral charged PEGylated ssRNA nanocomplexes (~150 nm) combined ssRNA protection with highly efficient delivery of ssRNA to DCs in the vaccine draining lymph nodes after subcutanuously administration. When co-administrated with a model antigen (soluble ovalbumin (OVA)), ssRNA nanocomplexes were far more efficient at inducing CD8 cytolytic T cells when compared to OVA co-adminstarted with naked ssRNA. Furthermore, IgG2c antibody titers, indicative of Th1 skewed T cell responses, were >10 times increased by complexing ssRNA into the PEGylated nanocomplexes. This study highlights the potential of post-functionalizing ssRNA nanocomplexes by copper-free click chemistry and these findings indcate that this potent ssRNA adjuvant may profoundly improve the efficacy of a variety of vaccines requiring Th1-type immunity. |
author2 |
Afd Pharmaceutics Pharmaceutics |
format |
Article in Journal/Newspaper |
author |
Lou, Bo De Beuckelaer, Ans Dakwar, George R. Remaut, Katrien Grooten, Johan Braeckmans, Kevin De Geest, Bruno G. Mastrobattista, Enrico De Koker, Stefaan Hennink, Wim E. |
author_facet |
Lou, Bo De Beuckelaer, Ans Dakwar, George R. Remaut, Katrien Grooten, Johan Braeckmans, Kevin De Geest, Bruno G. Mastrobattista, Enrico De Koker, Stefaan Hennink, Wim E. |
author_sort |
Lou, Bo |
title |
Post-PEGylated and crosslinked polymeric ssRNA nanocomplexes as adjuvants targeting lymph nodes with increased cytolytic T cell inducing properties |
title_short |
Post-PEGylated and crosslinked polymeric ssRNA nanocomplexes as adjuvants targeting lymph nodes with increased cytolytic T cell inducing properties |
title_full |
Post-PEGylated and crosslinked polymeric ssRNA nanocomplexes as adjuvants targeting lymph nodes with increased cytolytic T cell inducing properties |
title_fullStr |
Post-PEGylated and crosslinked polymeric ssRNA nanocomplexes as adjuvants targeting lymph nodes with increased cytolytic T cell inducing properties |
title_full_unstemmed |
Post-PEGylated and crosslinked polymeric ssRNA nanocomplexes as adjuvants targeting lymph nodes with increased cytolytic T cell inducing properties |
title_sort |
post-pegylated and crosslinked polymeric ssrna nanocomplexes as adjuvants targeting lymph nodes with increased cytolytic t cell inducing properties |
publishDate |
2018 |
url |
https://dspace.library.uu.nl/handle/1874/376584 |
genre |
Carbonic acid |
genre_facet |
Carbonic acid |
op_relation |
0168-3659 https://dspace.library.uu.nl/handle/1874/376584 |
op_rights |
info:eu-repo/semantics/OpenAccess |
_version_ |
1782333069080920064 |