(119f) Protein Nanocluster Dispersions With Tunable Size and Low Viscosities for Drug Delivery
AIChE Annual Meeting
Monday, November 4, 2013 - 2:00pm to 2:18pm
Protein solutions and dispersions at high concentrations (e.g., greater than 250 mg/ml) are of broad interest in subcutaneous drug delivery for treatment of cancer and many other diseases. At these concentrations, proteins have a tendency to undergo irreversible aggregation or gelation as a consequence of specific short ranged forces. Herein, we create highly concentrated dispersions (~ 250 mg/ml) comprising dense protein nanoclusters that have very low viscosities in the sub-100 cp range and which yield, upon dilution, monomeric protein molecules in their native state. The low viscosities result from weak interactions between the nanoclusters as characterized by reduced intrinsic viscosities as compared to monomer solutions. We observe lack of shear thinning at low Peclet number for nanoclusters of several different proteins including BSA and monoclonal antibodies in contrast with the behavior for protein solutions. These results are consistent with the nanoclusters being farther apart (on average) and more weakly interacting than the monomers, such that they do not form networks that would otherwise be deformed by equivalent amounts of shear. The nanoclusters were formed by addition of a variety of excipients with different polarities, charges and sizes to produce a short-ranged effective attraction between protein molecules. This attraction is balanced by electrostatic repulsion to yield a tunable cluster size suggesting equilibrium aspects. The protein nanocluster diameter can be reversibly tuned from 1 to 10 times the monomer diameter as shown by dynamic light scattering (DLS) and electron microscopy at a pH near their isoelectric point (pI). Upon dilution of the dispersion, the clusters rapidly dissociate into protein monomers as shown by size exclusion chromatography (SEC) and dynamic light scattering (DLS). Stable protein dispersions with low viscosities may potentially enable patient self-administration by subcutaneous injection of antibody therapeutics currently being discovered and developed.