New Linear and Star-Shaped Thermogelling Poly([R]-3-hydroxybutyrate) Copolymers

• Published in: Chemistry : a European journal Vol. 22; no. 30; pp. 10501 - 10512
• Main Authors: Barouti, Ghislaine, Liow, Sing Shy, Dou, Qingqing, Ye, Hongye, Orione, Clément, Guillaume, Sophie M., Loh, Xian Jun
• Format: Journal Article
• Language: English
• Published: Germany Blackwell Publishing Ltd 18.07.2016; Wiley Subscription Services, Inc; Wiley-VCH Verlag
• Subjects: Acrylic Resins - chemistry; Assembly; Biocompatibility; Biomaterials; Biomedical materials; Block copolymers; Body temperature; Calorimetry; Cell Line; Cell Survival; Chemical Sciences; Chemical synthesis; Chemistry; Chromatography; Copolymers; Correlation; Differential scanning calorimetry; Doxorubicin - chemistry; Drug Carriers - chemistry; drug delivery; Drug delivery systems; Drug Liberation; Ethers; Fibroblasts - cytology; Fibroblasts - drug effects; Gelation; Gels; Glycols; Heat measurement; Humans; Hydrogels; Hydrogels - chemical synthesis; Hydrogels - chemistry; Hydrogels - toxicity; Hydrophobic and Hydrophilic Interactions; Hydrophobicity; Hydroxybutyrates - chemical synthesis; Hydroxybutyrates - chemistry; Hydroxybutyrates - toxicity; Isopropylacrylamide; Magnetic resonance spectroscopy; Mechanical properties; Methacrylates - chemistry; Micelles; Molecular Structure; multi-arm polymers; NMR; Nuclear magnetic resonance; Poly(N-isopropylacrylamide); polyesters; Polyesters - chemical synthesis; Polyesters - chemistry; Polyesters - toxicity; Polyethylene glycol; Polyethylene Glycols - chemistry; Polyisopropyl acrylamide; Polymerization; Polymers; Polymers - chemistry; Polymethacrylic Acids - chemistry; Propylene glycol; Propylene Glycols - chemistry; Self assembly; Size exclusion chromatography; Spectroscopic analysis; Spectroscopy; Surgical implants; Temperature; Temperature effects; Thermal analysis; thermo-responsive polymers; Thermogravimetric analysis; water-soluble polymers; hydrogels; water-soluble polymers; multi-arm polymers; drug delivery; polyesters; thermo-responsive polymers; Poly([R]-3-hydroxybutyrate) (PHB); polyester; hydrogel; water-soluble polymer; multi-arm polymer; thermo-responsive polymer
• ISSN: 0947-6539; 1521-3765; 1521-3765
• DOI: 10.1002/chem.201601404

The synthesis of multi‐arm poly([R]‐3‐hydroxybutyrate) (PHB)‐based triblock copolymers (poly([R]‐3‐hydroxybutyrate)‐b‐poly(N‐isopropylacrylamide)‐b‐[[poly(methyl ether methacrylate)‐g‐poly(ethylene glycol)]‐co‐[poly(methacrylate)‐g‐poly(propylene glycol)]], PHB‐b‐PNIPAAM‐b‐(PPEGMEMA‐co‐PPPGMA), and their subsequent self‐assembly into thermo‐responsive hydrogels is described. Atom transfer radical polymerization (ATRP) of N‐isopropylacrylamide (NIPAAM) followed by poly(ethylene glycol) methyl ether methacrylate (PEGMEMA) and poly(propylene glycol) methacrylate (PPGMA) was achieved from bromoesterified multi‐arm PHB macroinitiators. The composition of the resulting copolymers was investigated by 1H and 13C J‐MOD NMR spectroscopy as well as size‐exclusion chromatography (SEC), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). The copolymers featuring different architectures and distinct hydrophilic/hydrophobic contents were found to self‐assemble into thermo‐responsive gels in aqueous solution. Rheological studies indicated that the linear one‐arm PHB‐based copolymer tend to form a micellar solution, whereas the two‐ and four‐arm PHB‐based copolymers afforded gels with enhanced mechanical properties and solid‐like behavior. These investigations are the first to correlate the gelation properties to the arm number of a PHB‐based copolymer. All copolymers revealed a double thermo‐responsive behavior due to the NIPAAM and PPGMA blocks, thus allowing first the copolymer self‐assembly at room temperature, and then the delivery of a drug at body temperature (37 °C). The non‐significant toxic response of the gels, as assessed by the cell viability of the CCD‐112CoN human fibroblast cell line with different concentrations of the triblock copolymers ranging from 0.03 to 1 mg mL−1, suggest that these PHB‐based thermo‐responsive gels are promising candidate biomaterials for drug‐delivery applications. How many arms? Multi‐arm poly([R]‐3‐hydroxybutyrate) (PHB)‐based triblock copolymers have been synthesized and their ability to form hydrogels has been investigated. The two‐ and four‐arm PHB‐based copolymers were found to form thermo‐responsive hydrogels (see figure), which might be candidates for drug‐delivery systems.