Journal
JOURNAL OF CONTROLLED RELEASE
Volume 326, Issue -, Pages 172-180Publisher
ELSEVIER
DOI: 10.1016/j.jconrel.2020.07.005
Keywords
PEGylation; Strain promoted azide alkyne cycloaddition (SPAAC); Genetic code expansion; Macrophage polarization; Folate; Antigen induced-arthritis
Funding
- BMBF (German Federal Ministry of Education and Research) [13N13454]
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Anti-inflammatory cytokines are a promising class of therapeutics for treatment of rheumatoid arthritis (RA), but their use is currently limited by a rapid clearance and systemic toxicity. Interleukin-4 is a small cytokine with potential for RA therapy. To increase its pharmacokinetic features, we engineered a murine IL4 conjugate by incorporating an unnatural amino acid through genetic code expansion to which PEG-folate, as a targeting moiety and PEG alone as control, were site-specifically bound. Both IL4 conjugates retained bioactivity and induced primary murine macrophage polarization into an alternatively activated (M2) related phenotype. The PEGylated conjugates had a terminal half-life of about four hours in healthy mice compared to unPEGylated IL4 (0.76 h). We showed that both conjugates successfully accumulated into arthritic joints in an antigen-induced arthritis (AIA) mouse model, as assessed by non-invasive fluorescence imaging. The modular nature of the IL4 conjugate chemistry presented herein facilitates easy adaption of PEG chain length and targeting moieties for further improvement of half-life and targeting function for future efficacy studies.
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