posted on 2021-04-19, 17:03authored byCarlisle
R. DeJulius, Bryan R. Dollinger, Taylor E. Kavanaugh, Eric Dailing, Fang Yu, Shubham Gulati, Angelo Miskalis, Caiyun Zhang, Jashim Uddin, Sergey Dikalov, Craig L. Duvall
Oxidative
stress is broadly implicated in chronic, inflammatory
diseases because it causes protein and lipid damage, cell death, and
stimulation of inflammatory signaling. Supplementation of innate antioxidant
mechanisms with drugs such as the superoxide dismutase (SOD) mimetic
compound 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) is a promising
strategy for reducing oxidative stress-driven pathologies. TEMPO is
inexpensive to produce and has strong antioxidant activity, but it
is limited as a drug due to rapid clearance from the body. It is also
challenging to encapsulate into micellar nanoparticles or polymer
microparticles, because it is a small, water soluble molecule that
does not efficiently load into hydrophobic carrier systems. In this
work, we pursued a polymeric form of TEMPO [poly(TEMPO)] to increase
its molecular weight with the goal of improving in vivo bioavailability. High density of TEMPO on the poly(TEMPO) backbone
limited water solubility and bioactivity of the product, a challenge
that was overcome by tuning the density of TEMPO in the polymer by
copolymerization with the hydrophilic monomer dimethylacrylamide (DMA).
Using this strategy, we formed a series of poly(DMA-co-TEMPO) random copolymers. An optimal composition of 40 mol % TEMPO/60
mol % DMA was identified for water solubility and O2•– scavenging in vitro. In an
air pouch model of acute local inflammation, the optimized copolymer
outperformed both the free drug and a 100% poly(TEMPO) formulation
in O2•– scavenging, retention,
and reduction of TNFα levels. Additionally, the optimized copolymer
reduced ROS levels after systemic injection in a footpad model of
inflammation. These results demonstrate the benefit of polymerizing
TEMPO for in vivo efficacy and could lead to a useful
antioxidant polymer formulation for next-generation anti-inflammatory
treatments.