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Transiently thermoresponsive acetal polymers for safe and effective administration of Amphotericin B as a vaccine adjuvant

Simon Van Herck (UGent) , Lien Van Hoecke (UGent) , Benoit Louage (UGent) , Lien Lybaert (UGent) , Ruben De Coen (UGent) , Sabah Kasmi (UGent) , Aaron P Esser-Kahn, Sunil A David, Lutz Nuhn, Bert Schepens (UGent) , et al.
(2018) BIOCONJUGATE CHEMISTRY. 29(3). p.748-760
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Abstract
The quest for new potent and safe adjuvants with which to skew and boost the immune response of vaccines against intracellular pathogens and cancer has led to the discovery of a series of small molecules that can activate Toll-like receptors (TLRs). Whereas many small molecule TLR agonists cope with a problematic safety profile, amphotericin B (AmpB), a Food and Drug Administration approved antifungal drug, has recently been discovered to possess TLR-triggering activity. However, its poor aqueous solubility and cytotoxicity at elevated concentrations currently hampers its development as a vaccine adjuvant. We present a new class of transiently thermoresponsive polymers that, in their native state, have a phase-transition temperature below room temperature but gradually transform into fully soluble polymers through acetal hydrolysis at endosomal pH values. RAFT polymerization afforded well-defined block copolymers that self-assemble into micellar nanoparticles and efficiently encapsulate AmpB. Importantly, nanoencapsulation strongly reduced the cytotoxic effect of AmpB but maintained its TLR-triggering capacity. Studies in mice showed that AmpB-loaded nanoparticles can adjuvant an RSV vaccine candidate with almost equal potency as a highly immunogenic oil-in-water benchmark adjuvant.
Keywords
RESPIRATORY SYNCYTIAL VIRUS, LINKED TLR AGONISTS, IMMUNE-RESPONSES, DRUG-DELIVERY, CANCER-IMMUNOTHERAPY, CYTOKINE RELEASE, NANOPARTICLES, TOXICITY, NANOGELS, PROTEIN

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Chicago
Van Herck, Simon, Lien Van Hoecke, Benoit Louage, Lien Lybaert, Ruben De Coen, Sabah Kasmi, Aaron P Esser-Kahn, et al. 2018. “Transiently Thermoresponsive Acetal Polymers for Safe and Effective Administration of Amphotericin B as a Vaccine Adjuvant.” Bioconjugate Chemistry 29 (3): 748–760.
APA
Van Herck, S., Van Hoecke, L., Louage, B., Lybaert, L., De Coen, R., Kasmi, S., Esser-Kahn, A. P., et al. (2018). Transiently thermoresponsive acetal polymers for safe and effective administration of Amphotericin B as a vaccine adjuvant. BIOCONJUGATE CHEMISTRY, 29(3), 748–760.
Vancouver
1.
Van Herck S, Van Hoecke L, Louage B, Lybaert L, De Coen R, Kasmi S, et al. Transiently thermoresponsive acetal polymers for safe and effective administration of Amphotericin B as a vaccine adjuvant. BIOCONJUGATE CHEMISTRY. 2018;29(3):748–60.
MLA
Van Herck, Simon, Lien Van Hoecke, Benoit Louage, et al. “Transiently Thermoresponsive Acetal Polymers for Safe and Effective Administration of Amphotericin B as a Vaccine Adjuvant.” BIOCONJUGATE CHEMISTRY 29.3 (2018): 748–760. Print.
@article{8583911,
  abstract     = {The quest for new potent and safe adjuvants with which to skew and boost the immune response of vaccines against intracellular pathogens and cancer has led to the discovery of a series of small molecules that can activate Toll-like receptors (TLRs). Whereas many small molecule TLR agonists cope with a problematic safety profile, amphotericin B (AmpB), a Food and Drug Administration approved antifungal drug, has recently been discovered to possess TLR-triggering activity. However, its poor aqueous solubility and cytotoxicity at elevated concentrations currently hampers its development as a vaccine adjuvant. We present a new class of transiently thermoresponsive polymers that, in their native state, have a phase-transition temperature below room temperature but gradually transform into fully soluble polymers through acetal hydrolysis at endosomal pH values. RAFT polymerization afforded well-defined block copolymers that self-assemble into micellar nanoparticles and efficiently encapsulate AmpB. Importantly, nanoencapsulation strongly reduced the cytotoxic effect of AmpB but maintained its TLR-triggering capacity. Studies in mice showed that AmpB-loaded nanoparticles can adjuvant an RSV vaccine candidate with almost equal potency as a highly immunogenic oil-in-water benchmark adjuvant.},
  author       = {Van Herck, Simon and Van Hoecke, Lien and Louage, Benoit and Lybaert, Lien and De Coen, Ruben and Kasmi, Sabah and Esser-Kahn, Aaron P and David, Sunil A and Nuhn, Lutz and Schepens, Bert and Saelens, Xavier and De Geest, Bruno},
  issn         = {1043-1802},
  journal      = {BIOCONJUGATE CHEMISTRY},
  keyword      = {RESPIRATORY SYNCYTIAL VIRUS,LINKED TLR AGONISTS,IMMUNE-RESPONSES,DRUG-DELIVERY,CANCER-IMMUNOTHERAPY,CYTOKINE RELEASE,NANOPARTICLES,TOXICITY,NANOGELS,PROTEIN},
  language     = {eng},
  number       = {3},
  pages        = {748--760},
  title        = {Transiently thermoresponsive acetal polymers for safe and effective administration of Amphotericin B as a vaccine adjuvant},
  url          = {http://dx.doi.org/10.1021/acs.bioconjchem.7b00641},
  volume       = {29},
  year         = {2018},
}

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