Multimodal nanoparticle-containing modified suberoylanilide hydroxamic acid polymer conjugates to mitigate immune...

Area of Science:

• Immunology
• Nanotechnology
• Pharmacology

Background:

• Severe inflammation and sepsis involve complex immune dysregulation, with excessive immune activation and suppression.
• Histone deacetylase inhibitors (HDACi) show potential for immunomodulation, but controlled delivery remains a challenge.

Purpose of the Study:

• To develop and evaluate novel immunomodulatory nanoparticles (iNP-SAHA) for controlled delivery of a histone deacetylase inhibitor (SAHA-OH).
• To investigate the therapeutic efficacy of iNP-SAHA in reducing inflammation and improving survival in preclinical models of sepsis.

Main Methods:

• Covalent modification of poly(lactic-co-glycolic acid) (PLGA) with SAHA-OH to create prodrug nanoparticles (iNP-SAHA).
• In vitro assessment of macrophage survival and cytokine/gene expression under lipopolysaccharide (LPS) challenge.
• In vivo evaluation of iNP-SAHA in a lethal LPS-induced endotoxemia mouse model of sepsis, assessing survival rates, plasma cytokine/chemokine levels, and organ toxicity.

Main Results:

• iNP-SAHA demonstrated controlled release of SAHA-OH, enhancing macrophage survival and reducing pro-inflammatory cytokine and gene expression.
• Administration of iNP-SAHA significantly improved survival in a dose-dependent manner in a mouse model of sepsis.
• iNP-SAHA effectively reduced plasma pro-inflammatory cytokines and chemokines and mitigated spleen and liver toxicity associated with sepsis.

Conclusions:

• iNP-SAHA represents a promising drug delivery system for modulating multifaceted inflammatory responses in sepsis.
• The polypharmacological activity of iNP-SAHA offers a potential therapeutic strategy for complex inflammatory diseases.