title: Diels-Alder hydrogels with enhanced stability: First step toward controlled release of bevacizumab.
abstract: Eight-armed PEG was functionalized with furyl and maleimide groups (8armPEG20k-Fur and 8armPEG20k-Mal); degradable hydrogels were obtained by cross-linking via Diels-Alder chemistry. To increase the stability to degradation, the macromonomers were modified by introducing a hydrophobic 6-aminohexanoic acid spacer between PEG and the reactive end-groups (8armPEG20k-Ahx-Fur and 8armPEG20k-Ahx-Mal). In an alternative approach, the number of reactive groups per macromonomer was increased by branching the terminal ends of eight-armed PEG with lysine (Lys) and Ahx residues (8armPEG20k-Lys-Ahx-Fur2 and 8armPEG20k-Lys-Ahx-Mal2). The hydrolytic resistance of the synthesized macromonomers was determined by UV spectroscopy; the obtained hydrogels were characterized by rheology and degradation studies. The degradation time of 5% (w/v) 8armPEG20k-Ahx hydrogels (28days) was twice as long as the degradation time of 5% (w/v) 8armPEG20k hydrogels (14days); this is explained by increased hydrolytic resistance of the maleimide group. Using dendritic 8armPEG20k-Lys-Ahx macromonomers substantially increased the stability of the resulting hydrogels; degradation of 5% (w/v) 8armPEG20k-Lys-Ahx hydrogels occurred after 34 weeks. 8armPEG20k hydrogels had the largest mesh size of all tested hydrogels, while hydrogels made from dendritic 8armPEG20k-Lys-Ahx macromonomers showed the smallest value. To evaluate their potential for the controlled release of therapeutic antibodies, the hydrogels were loaded with bevacizumab. The incorporated bevacizumab was released over 10 days (8armPEG20k) and 42days (8armPEG20k-Ahx), respectively; release from 8armPEG20k-Lys-Ahx hydrogels was not completed after 105 days. In summary, we believe that 8armPEG20k-Ahx or 8armPEG20k-Lys-Ahx hydrogels could serve as controlled release system for therapeutic antibodies such as bevacizumab.
authors.affiliation: Department of Pharmaceutical Technology, Faculty of Chemistry and Pharmacy, University of Regensburg, 93040 Regensburg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Kirchhof
authors.affiliation: Department of Pharmaceutical Technology, Faculty of Chemistry and Pharmacy, University of Regensburg, 93040 Regensburg, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Gregoritza
authors.affiliation: Department of Pharmaceutical Technology, Faculty of Chemistry and Pharmacy, University of Regensburg, 93040 Regensburg, Germany.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Messmann
authors.affiliation: Department of Pharmaceutical Technology, Faculty of Chemistry and Pharmacy, University of Regensburg, 93040 Regensburg, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Hammer
authors.affiliation: Department of Pharmaceutical Technology, Faculty of Chemistry and Pharmacy, University of Regensburg, 93040 Regensburg, Germany.
authors.forename: Achim M
authors.initials: AM
authors.lastname: Goepferich
authors.affiliation: Department of Pharmaceutical Technology, Faculty of Chemistry and Pharmacy, University of Regensburg, 93040 Regensburg, Germany. Electronic address: ferdinand.brandl@ur.de.
authors.forename: Ferdinand P
authors.initials: FP
authors.lastname: Brandl
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000032:analysis / Q000737:chemistry*; D000068258:Bevacizumab / Q000008:administration & dosage / Q000032:analysis / Q000737:chemistry*; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000032:analysis / Q000737:chemistry; D004339:Drug Compounding; D065546:Drug Liberation; D004355:Drug Stability; D004356:Drug Storage; D005663:Furans / Q000737:chemistry; D020100:Hydrogels / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D008301:Maleimides / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry*; D016062:Porosity; D055550:Protein Stability; D042442:Vascular Endothelial Growth Factors / Q000037:antagonists & inhibitors*; D014783:Viscosity
chemical_list: D020533:Angiogenesis Inhibitors; D003692:Delayed-Action Preparations; D005663:Furans; D020100:Hydrogels; D008301:Maleimides; D042442:Vascular Endothelial Growth Factors; D000068258:Bevacizumab; D011092:Polyethylene Glycols
keywords: Bevacizumab; Controlled release; Degradation; Diels–Alder reaction; Hydrogel; Poly(ethylene glycol)