posted on 2021-07-21, 11:34authored byIzabela Jatczak-Pawlik, Michał Gorzkiewicz, Maciej Studzian, Robin Zinke, Dietmar Appelhans, Barbara Klajnert-Maculewicz, Łukasz Pułaski
New therapeutic strategies
for personalized medicine need to involve
innovative pharmaceutical tools, for example, modular nanoparticles
designed for direct immunomodulatory properties. We synthesized mannose-functionalized
poly(propyleneimine) glycodendrimers with a novel architecture, where
freely accessible mannose moieties are presented on poly(ethylene
glycol)-based linkers embedded within an open-shell maltose coating.
This design enhanced glycodendrimer bioactivity and led to complex
functional effects in myeloid cells, with specific induction of interleukin-8
expression by mannose glycodendrimers detected in HL-60 and THP-1
cells. We concentrated on explaining the molecular mechanism of this
phenomenon, which turned out to be different in both investigated
cell lines: in HL-60 cells, transcriptional activation via AP-1 binding
to the promoter predominated, while in THP-1 cells (which initially
expressed less IL-8), induction was mediated mainly by mRNA stabilization.
The success of directed immunomodulation, with synthetic design guided
by assumptions about mannose-modified dendrimers as exogenous regulators
of pro-inflammatory chemokine levels, opens new possibilities for
designing bioactive nanoparticles.