Functionalized poly(lactide)s: Synthesis, characterization and biological applications

Synthetic polymers have become an integral portion of modern biomedicine, for example as drug carriers or tissue engineering scaffolds. Polymer chemistry allows for precision-made polymers with defined molecular weights and narrow dispersities and can incorporate bioactive signaling molecules or solubilizing groups. Nevertheless, many reported polymers have non-degradable backbones and their long-term fate in vivo is often unknown. Biodegradable poly(ester)s can address this shortcoming; however, they are hydrophobic and lack functional groups for covalent functionalization.;The research presented in this thesis targets a universal biodegradable and biocompatible polymer scaffold with increased hydrophilicity and functional handles for postpolymerization functionalization. Biodegradability and biocompatibility are imparted via utilizing poly(lactide) as the scaffold polymer. Bottom-up monomer syntheses can equip lactide analogues with solubilizing oligo(ethylene glycol)-chains that suppress non-specific protein adhesion, as well as azide functional moieties. A polymer that is studded with azide moieties enables a plethora of high-yielding postpolymerization reactions with bioactive signaling peptides or drug molecules. This proof-of-concept is demonstrated via successful Staudinger ligation and strain-promoted azide-alkyne cycloaddition, leading to covalent attachment of pharmaceutically-relevant molecules to the biodegradable polymer scaffold.;The modular synthesis allows for tailoring the scaffold to the biomedical application of interest: examples relevant for both tissue engineering and drug delivery application are presented. The fibronectin-derived pentapeptide GRGDS is attached to the poly(lactide)-graft-poly(ethylene glycol) copolymer via Staudinger ligation and represents one of the few biodegradable peptide-polymer conjugates reported to date. Detailed characterization is possible through the judicious choice of the Staudinger reagent for peptide attachment. To install two orthogonal functional groups on poly(lactide), a functional initiator is applied in the ring-opening polymerization. Both drug-mimicking dyes and a cell internalization peptide are installed successfully and the conjugate is evaluated in cell uptake studies, resulting in one of the few biodegradable drug delivery vehicles to date.;Overall, the results described herein pave the way for more ample applications of biodegradable poly(lactide) in biomedicine. Two major shortcomings of poly(ester)s, namely hydrophobicity and functional group paucity, are addressed and two scaffolds for specific applications introduced. represents one of the few biodegradable peptide-polymer conjugates reported to date. Detailed characterization is possible through the judicious choice of the Staudinger reagent for peptide attachment. To install two orthogonal functional groups on poly(lactide), a functional initiator is applied in the ring-opening polymerization. Both drug-mimicking dyes and a cell internalization peptide are installed successfully and the conjugate is evaluated in cell uptake studies, resulting in one of the few biodegradable drug delivery vehicles to date.;Overall, the results described herein pave the way for more ample applications of biodegradable poly(lactide) in biomedicine. Two major shortcomings of poly(ester)s, namely hydrophobicity and functional group paucity, are addressed and two scaffolds for specific applications introduced.