While small molecule drugs realize delivery benefits, protein-based drugs often fare poorly in poly(lactide-co-glycolide) (PLG) microsphere depot systems due to interactions with the oil/water (O/W) and solid/water (S/W) interfaces generated during formulation and release.  Adsorption can be irreversible and can result in protein denaturation, aggregation and, ultimately, bioactivity loss.  Protein PEGylation has been shown to mitigate this effect at the S/W interface in addition to imbuing conjugates with several other useful properties.  We studied ribonuclease A (RNase A, a stable protein) and apo-a-lactalbumin (ALA, a marginally stable protein) grafted with 20kDa PEG chains at the ethyl acetate/water interface to determine if PEGylation affords similar protection at typical O/W interfaces.  We used spectroscopic and optical techniques to assess the adsorbed amount, structural state and aggregation state of both unmodified and PEGylated proteins.   ALA was found to be more denatured than RNaseA, as expected.  Surprisingly, PEGylation actually enhanced ALA denaturation.

Behavior of PEGylated proteins at oil/water interfaces relevant to formulation in and delivery from poly(lactide-co-glycolide) microspheres

243rd National Meeting (2012)

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