co9b00162_si_001.pdf (1.06 MB)
High-Throughput Synthesis and Screening of Rapidly Degrading Polyanhydride Nanoparticles
journal contribution
posted on 2020-03-11, 17:09 authored by Adam S. Mullis, Sarah J. Jacobson, Balaji NarasimhanCombinatorial techniques
can accelerate the discovery and development of polymeric nanodelivery
devices by pairing high-throughput synthesis with rapid materials
characterization. Biodegradable polyanhydrides demonstrate tunable
release, high cellular internalization, and dose sparing properties
when used as nanodelivery devices. This nanoparticle platform shows
promising potential for small molecule drug delivery, but the pace
of understanding and rational design of these nanomedicines is limited
by the low throughput of conventional characterization. This study
reports the use of a high-throughput method to synthesize libraries
of a newly synthesized, rapidly eroding polyanhydride copolymer based
on 1,8-bis(p-carboxyphenoxy)-3,6-dioxaoctane (CPTEG)
and sebacic acid (SA) monomers. The high-throughput method enabled
efficient screening of copolymer microstructure, revealing weak block-type
and alternating architectures. The high-throughput method was adapted
to synthesize nanoparticle libraries encapsulating hydrophobic model
drugs. Drug release from these nanoparticles was rapid, with a majority
of the payload released within 3 days. Drug release was dramatically
slowed at acidic pH, which could be useful for oral drug delivery.
Rhodamine B (RhoB) release kinetics generally followed patterns of
polymer erosion kinetics, while Coomassie brilliant blue (CBB) released
the fastest from the slowest degrading polymer chemistry and vice
versa. These differences in trends between copolymer chemistry and
release kinetics were hypothesized to arise from differences in mixing
thermodynamics. A high-throughput method was developed to synthesize
polymer–drug film libraries and characterize mixing thermodynamics
by melting point depression. Rhodamine B had a negative χ for
all copolymers with <30 mol % CPTEG tested, indicating a tendency
toward miscibility. By contrast, CBB χ increased, eventually
becoming positive near 15:85 CPTEG:SA, with increasing CPTEG content.
This indicates an increasing tendency toward phase separation in CPTEG-rich
copolymers. These in vitro results screening polymer–drug
interactions showed good agreement with in silico predictions from Hansen solubility parameter estimation and were
able to explain the observed differences in model drug release trends.
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drug releasemodel drug release trendspairing high-throughput synthesisnanodelivery devicespolymer erosion kineticsCBBnanoparticle libraries encapsulatingRhodamine BCPTEGrelease kineticsmolecule drug deliverySAcopolymerRapidly Degrading Polyanhydride Nanoparticles Combinatorial techniqueshigh-throughput methodHansen solubility parameter estimation
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