Mucus linings and immune system protein coronas limit entry, targeting, and
bioavailability of therapeutics. A common strategy to circumvent these barriers is to
sterically stabilize therapeutics. This approach is based on fundamental work in colloid
science but is often neglected in terms of mechanisms and interactions with biological
macromolecules such as mucus and immune system proteins. A challenge is to understand
polymer interactions and architectures in face of mucus and blood proteins to assess their
stability to design colloidal therapeutics with enhanced bioavailability, safety, and
targeting. In this dissertation, total internal reflection microscopy is used to directly,
sensitively, and nonintrusively measure adsorbed PEG and zwitterionic (ZI) layer
interactions against specific ions, proteins, and mucus. The use of TIRM offers kT-scale
and nanometer resolution to offer unique insights needed for stabilizing colloidal
therapeutics.
For the first goal, we report direct measurements of solution behaviour of adsorbed
PEG and ZI triblock copolymers as a function of specific ions. Our findings indicate
qualitatively different and unique behavior for each polymer, where: PEO layers are [NaCl]
independent but collapse with increasing [MgSO4]; PMAPS layers extend with increasing
[NaCl] but becomes less repulsive with increasing [MgSO4], and PMPC layers are
completely insensitive to both salts. A competition between solvated molecular
interactions and structures explains the unique response of each polymer to non-specific
and specific ion effects.
For the second goal, we show how serum albumin and immunoglobin G, interact
with PEG and ZI layers. Our results provide unambiguous evidence of exclusion of
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proteins from adsorbed PEG. Low molecular weight zwitterionic coatings were displaced
by both BSA and IgG unlike PEG. Measured interactions and corresponding exclusion
states were fitted theoretically to reflect penetration and exclusion of both proteins.
Finally, we report kT-scale interactions of ZI and PEG coatings with mucin in
various conditions such as low pH, mucolytic agents, and calcium chloride. Our results
demonstrate that PEG and ZI coatings are repulsive towards mucin and provide a template
for tuning polymer coatings to specifically adhere to mucus to achieve a balance of
mucopenetration and mucoadhesion behavior for successful permeability through mucus
