Gelation Chemistries for the Encapsulation of Nanoparticles
in Composite Gel Microparticles for Lung Imaging and Drug Delivery
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Abstract
The formation of 10–40 μm
composite gel microparticles
(CGMPs) comprised of ∼100 nm drug containing nanoparticles
(NPs) in a poly(ethylene glycol) (PEG) gel matrix is described. The
CGMP particles enable targeting to the lung by filtration from the
venous circulation. UV radical polymerization and Michael addition
polymerization reactions are compared as approaches to form the PEG
matrix. A fluorescent dye in the solid core of the NP was used to
investigate the effect of reaction chemistry on the integrity of encapsulated
species. When formed via UV radical polymerization, the fluorescence
signal from the NPs indicated degradation of the encapsulated species
by radical attack. The degradation decreased fluorescence by 90% over
15 min of UV exposure. When formed via Michael addition polymerization,
the fluorescence was maintained. Emulsion processing using controlled
shear stress enabled control of droplet size with narrow polydispersity.
To allow for emulsion processing, the gelation rate was delayed by
adjusting the solution pH. At a pH = 5.4, the gelation occurred at
3.5 h. The modulus of the gels was tuned over the range of 5 to 50
kPa by changing the polymer concentration between 20 and 70 vol %.
NP aggregation during polymerization, driven by depletion forces,
was controlled by the reaction kinetics. The ester bonds in the gel
network enabled CGMP degradation. The gel modulus decreased by 50%
over 27 days, followed by complete gel degradation after 55 days.
This permits ultimate clearance of the CGMPs from the lungs. The demonstration
of uniform delivery of 15.8 ± 2.6 μm CGMPs to the lungs
of mice, with no deposition in other organs, is shown, and indicates
the ability to concentrate therapeutics in the lung while avoiding
off-target toxic exposure