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Lymph-node-targeted immune activation by engineered block copolymer amphiphiles-TLR7/8 agonist conjugates

Simon Van Herck (UGent) , Kim Deswarte (UGent) , Lutz Nuhn (UGent) , Zifu Zhong (UGent) , João Portela Catani (UGent) , Yupeng Li, Niek Sanders (UGent) , Stefan Lienenklaus, Stefaan De Koker (UGent) , Bart Lambrecht (UGent) , et al.
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Abstract
Small molecule immuno-modulators such as agonists of Toll-like receptors (TLRs) are attractive compounds to stimulate innate immune cells toward potent antiviral and antitumor responses. However, small molecules rapidly enter the systemic circulation and cause "wasted inflammation". Hence, synthetic strategies to confine their radius of action to lymphoid tissue are of great relevance, to both enhance their efficacy and concomitantly limit toxicity. Here, we demonstrate that covalent conjugation of a small molecule TLR7/8 agonist immunomodulatory to a micelle-forming amphiphilic block copolymer greatly alters the pharmacokinetic profile, resulting in highly efficient lymphatic delivery. Moreover, we designed amphiphilic block copolymers in such a way to form thermodynamically stable micelles through pi-pi stacking between aromatic moieties, and we engineered the block copolymers to undergo an irreversible amphiphilic to hydrophilic transition in response to the acidic endosomal pH.
Keywords
POLYMERIC MICELLES, VACCINES, DELIVERY, STABILITY, NANOGELS, SYSTEM

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Please use this url to cite or link to this publication:

Chicago
Van Herck, Simon, Kim Deswarte, Lutz Nuhn, Zifu Zhong, João Portela Catani, Yupeng Li, Niek Sanders, et al. 2018. “Lymph-node-targeted Immune Activation by Engineered Block Copolymer amphiphiles-TLR7/8 Agonist Conjugates.” Journal of the American Chemical Society 140 (43): 14300–14307.
APA
Van Herck, S., Deswarte, K., Nuhn, L., Zhong, Z., Portela Catani, J., Li, Y., Sanders, N., et al. (2018). Lymph-node-targeted immune activation by engineered block copolymer amphiphiles-TLR7/8 agonist conjugates. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 140(43), 14300–14307.
Vancouver
1.
Van Herck S, Deswarte K, Nuhn L, Zhong Z, Portela Catani J, Li Y, et al. Lymph-node-targeted immune activation by engineered block copolymer amphiphiles-TLR7/8 agonist conjugates. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY. 2018;140(43):14300–7.
MLA
Van Herck, Simon, Kim Deswarte, Lutz Nuhn, et al. “Lymph-node-targeted Immune Activation by Engineered Block Copolymer amphiphiles-TLR7/8 Agonist Conjugates.” JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 140.43 (2018): 14300–14307. Print.
@article{8579008,
  abstract     = {Small molecule immuno-modulators such as agonists of Toll-like receptors (TLRs) are attractive compounds to stimulate innate immune cells toward potent antiviral and antitumor responses. However, small molecules rapidly enter the systemic circulation and cause {\textacutedbl}wasted inflammation{\textacutedbl}. Hence, synthetic strategies to confine their radius of action to lymphoid tissue are of great relevance, to both enhance their efficacy and concomitantly limit toxicity. Here, we demonstrate that covalent conjugation of a small molecule TLR7/8 agonist immunomodulatory to a micelle-forming amphiphilic block copolymer greatly alters the pharmacokinetic profile, resulting in highly efficient lymphatic delivery. Moreover, we designed amphiphilic block copolymers in such a way to form thermodynamically stable micelles through pi-pi stacking between aromatic moieties, and we engineered the block copolymers to undergo an irreversible amphiphilic to hydrophilic transition in response to the acidic endosomal pH.},
  author       = {Van Herck, Simon and Deswarte, Kim and Nuhn, Lutz and Zhong, Zifu and Portela Catani, Jo{\~a}o and Li, Yupeng and Sanders, Niek and Lienenklaus, Stefan and De Koker, Stefaan and Lambrecht, Bart and David, Sunil A and De Geest, Bruno},
  issn         = {0002-7863},
  journal      = {JOURNAL OF THE AMERICAN CHEMICAL SOCIETY},
  language     = {eng},
  number       = {43},
  pages        = {14300--14307},
  title        = {Lymph-node-targeted immune activation by engineered block copolymer amphiphiles-TLR7/8 agonist conjugates},
  url          = {http://dx.doi.org/10.1021/jacs.8b08595},
  volume       = {140},
  year         = {2018},
}

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