We seek to improve the controlled delivery of proteins from biocompatible poly(lactic-co-glycolic) acid (PLGA) microspheres by increasing their stability. This will further the widespread use of protein pharmaceuticals in health applications which is still limited by their inherent structural lability. We intend to carry out studies that will prevent detrimental protein aggregation and inactivation which occur when they are exposed to the severe stress involved during their encapsulation into PLGA microspheres (e.g., exposure to organic solvent-water interfaces). We hypothesize that this can be achieved by covalent modification of proteins with poly(ethylene glycol) (PEG). Main hypotheses are that covalently attaching PEG to the surface of pharmaceutical proteins will reduce their susceptibility towards aggregation and inactivation (a) upon encapsulation in PLGA microspheres, (b) in the solid state during storage, and (c) during in vitro release. Furthermore, PEG-modification will likely also improve the release of proteins from PLGA microspheres prepared by non-aqueous (e.g., solid-in-oil-in-oil) or semi non-aqueous (i.e., solid-in-oil-in-water) methods. The reason is that PEG-proteins are soluble in many suitable organic solvents. This should result in a better distribution of PEG-protein in the polymer matrix and afford a reduced burst release. We will encapsulate PEG-modified proteins in PLGA microspheres using various methodologies (e.g., water-in-oil-in-water, solid-in-oil-in-water, and ink jet assisted encapsulation). Protein structural and stability data will be obtained using a manifold of spectroscopic (e.g., FT-IR, FT-Raman, circular dichroism and fluorescence spectroscopy) and biochemical techniques. The structural data will be correlated with stability parameters, such as cumulative protein release from the devices, specific biological activity, and protein aggregation. Furthermore, stability and structural data will be related to the chemical nature and degree of surface modification. These data will be used to develop stress-specific strategies to systematically eradicate protein inactivation and aggregation during encapsulation and release.
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