Abstract
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.
Highlights
All clinical treatments affect the immunological system in ways that can strongly vary from patient to patient, driving the development of directed immunomodulators for a personalized medicine setting
Our research focused on interleukin-8 (IL-8), the mRNA expression of which has been shown to increase significantly in cells stimulated with glycodendrimers.[6]
IL-8 protein levels in the medium are calculated from the reference enzyme-linked immunosorbent assay (ELISA) curve and presented as the absolute concentration in the conditioned medium. # Statistically significant difference compared to control at p < 0.05. † Statistically significant difference compared to OS-PEG at p < 0.05
Summary
All clinical treatments affect the immunological system in ways that can strongly vary from patient to patient, driving the development of directed immunomodulators for a personalized medicine setting. Novel biofunctional nanoparticles are a promising tool for directed immunomodulation, where specific intracellular mechanisms in immune cells are activated or repressed to obtain potentially clinically significant outcomes (immunostimulation or immunosuppression). The great variety of both dendritic scaffolds and carbohydrates gives the opportunity to develop different branched glycopolymers with unique properties. This creates several possibilities for specific immunomodulation in pharmacology, enabling controlled inhibition or activation of immune cell proliferation, cytokine release, or antibody secretion without detrimental side effects associated with the currently available chemical immunomodulators.[4]
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