Photopolymerizable Hydrogels Made from Polymer‐Conjugated Albumin for Affinity‐Based Drug Delivery

Abstract

As a drug delivery vehicle, biodegradable albumin hydrogels can combine the high binding capacity of albumin with the structural stability of a polymeric hydrogel network to enable controlled release of small molecules based on both binding affinity and physical interactions. In the present study, we report on the development of a hybrid hydrogel composed of albumin conjugated to poly(ethylene glycol) (PEG) for drug delivery applications where controlled release is accomplished using the natural affinity of the drugs to the serum albumin. Bovine serum albumin was conjugated to PEG‐diacrylate having a molecular weight of 1.5, 4, or 10 kDa to form a PEGylated albumin macromolecule (mono‐PEGylated or multi‐PEGylated). Biodegradable hydrogels were formed from the PEGylated albumin using photopolymerization. Two model drugs, Warfarin and Naproxen, were used for equilibrium dialysis and release experiments from the hydrogels, both having relatively low molecular weights and a known high affinity for albumin. Equilibrium dialysis experiments showed that multi‐PEGylation of albumin significantly decreased the drug affinity to the protein compared to non‐PEGylated controls, irrespective of the PEG molecular weight. However, the results from drug release experiments showed that mono‐PEGylation of albumin did not change its natural affinity to the drug. Comparing the release profiles with a Fickian diffusion model provided strong evidence that hydrogels containing mono‐PEGylated albumin exhibited sub‐diffusive drug release properties based on the affinity of the drug to the tethered protein.

Polymer-conjugated albumin and fibrinogen composite hydrogels as cell scaffolds designed for affinity-based drug delivery

“…Mono-PEGylation of albumin was conducted in a similar fashion with minor modifications, according to the PEGylation protocol described by Oss-Ronen and Seliktar [7]. In brief, a solution of linear PEG DA (MW 10 or 4 kDa, 1:1 molar ratio of PEG to albumin cysteines) was added to a 7 mg ml À1 solution of bovine serum albumin (MP Biomedicals, Solon, OH) in 150 mM PBS with 8 M urea and allowed to react at room temperature for up to 30 min or overnight, for 10 and 4 kDa PEGylation, respectively.…”

“…Gel filtration (or size exclusion chromatography) was used to purify the 10 kDa mono-PEGylated albumin species from the mixture of wild-type, mono-PEGylated and multi-PEGylated species produced during the reaction of albumin with PEG DA, as described earlier [7]. In brief, Sephacryl™ S-300 high resolution prepacked gel filtration columns (Amersham Biosiences, Uppsala, Sweden) were used in a BioLogic DuoFlow™ Chromatography system (BioRad Laboratories, Hercules, CA).…”

“…Both the affinity of the drug molecule and the release kinetics from the albumin hydrogel are dictated by the immobilization methodology. In our earlier work we used a synthetic polymeric linker molecule, poly(ethylene glycol) (PEG), to immobilize albumin by covalent attachment [6,7]. The conjugation of albumin to PEG, termed PEGylation, was first described in 1977 by Abuchowski et al [8] for the purpose of reducing the immunogenicity of the protein.…”

“…In the albumin-based hydrogel design presented in earlier studies; the PEG and albumin were conjugated to achieve affinity-based drug delivery, where controlled drug release was accomplished using the natural affinity of the drug for the PEGylated albumin carrier [7]. The multi-PEGylation reaction used for the albumin hydrogel formation in that study resulted in certain conformational changes to the albumin tertiary structure, thus reducing its binding abilities in this regard.…”

“…The multi-PEGylation reaction used for the albumin hydrogel formation in that study resulted in certain conformational changes to the albumin tertiary structure, thus reducing its binding abilities in this regard. Specifically, an irreversible reduction of the 17 disulfide bridges, which form the unique tertiary structure of the albumin protein, was required for covalent binding of the multiple PEG molecules [2,7]. Subsequent work was done to produce hydrogels containing mono-PEGylated albumin, i.e.…”