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DEVELOPMENT OF A LIPOPOLYSACCHARIDE ANTAGONIST FOR THE TREATMENT OF SEPSIS
Sepsis and septic shock are life-threating conditions, which
resulted from a continuum of the body’s response to overwhelming infection.
Elimination of bacteria through antibiotics is not sufficient, because the host
is still left with a large amount of lipopolysaccharide (LPS) that prevents the
host immune system from returning to normal homeostasis. Synthetic LPS antagonists that
can bind to LPS via electrostatic and/or hydrophobic interactions cause systemic toxicities. Moreover, LPS elimination alone may not address already
established complications of sepsis. To address these
challenges, we propose to develop nanoparticle formulations of LPS antagonists (D-TZP)
that can be delivered systemically. Specifically, cholecalciferol (vitamin D) was encapsulated in a self-assembly of
tannic acid/Fe3+ coordination complex (pTA) capsule, forming a core
that could be surface-modified with LPS
adsorbents, such as low molecular weight succinylated chitosan (LMZWC) and polymyxin B (PMB). D-TZP suppressed pro-inflammatory effects of LPS on the
engineered human monocytes with significantly less cytotoxicity than free PMB
at the equivalent dose. D-TZP increased the maximum tolerated dose of PMB by
both intraperitoneal and intravenous administration. In the LPS-induced mouse model
of sepsis, systemic administration of D-TZP immediately after LPS challenge
neutralized the lethal effect of LPS. D-TZP also reduced the mortality of mice when given 2 h after the LPS challenge.
D-TZP inhibited the mortality in the cecal
ligation and puncture (CLP)-induced bacteremia mouse model when given IV 2 h after the insult. In
the CLP model, the D-TZP-treated animals also showed lower levels of both TNF-α
and IL-10 cytokines as well as D-dimer levels, reflecting the attenuation of disseminated
intravascular coagulation, compared to the vehicle-treated control group.
Collectively, these results support that the D-TZP is a safe and effective
systemic intervention of sepsis.