Synthesis and Characterization of Thermogelling Copolymers for  Drug Delivery Applications
Creators: Ghasemi, Nasim
Publisher: name: University of Alberta Library
Year: 2022

<p>Thermo-reversible hydrogels, or thermogels, are a category of gel-forming materials that are liquid at lower temperatures but turn into gel at higher temperatures. Thermogels are explored for different applications in drug delivery and tissue engineering fields. In this context, the development of biocompatible and biodegradable hydrogels that can safely be used in humans is of great interest. In this thesis, the development of thermo-reversible hydrogels from block copolymers based on a block of poly(ethylene glycol) (PEG) and two blocks of functionalized poly(ε-caprolactone) was explored. In the first chapter, we investigated the effect of the ring-opening polymerization method (bulk versus solution polymerization) on the properties of prepared block copolymers such as molecular weight, molar mass dispersity, as well as thermo-responsive gelation, and viscoelastic properties of block copolymer solutions in water. Our results showed in block copolymers based on poly(ethylene glycol) as hydrophilic middle block and poly(α-benzyl carboxylate-ε-caprolactone) as the hydrophobic lateral blocks (abbreviated as PBCL-PEG-PBCL) the presence of a specific concentration of a high molecular weight subpopulation was crucial for the formation of thermo-reversible and viscoelastic PBCL-PEG-PBCL hydrogels. The appearance of this subpopulation was attributed to the formation of partially cross-linked or branched polymers during ring opening polymerization of α-benzyl carboxylate-ε-caprolactone by PEG. To test this hypothesis, in the next step, we synthesized chemically cross-linked PBCL-PEG-PBCLs by the manual introduction of different nucleophilic cross-linkers to PBCL-PEG-PBCL copolymers. The effect of the type and/or molar ratio of cross-linker to polymer on the formation of viscoelastic thermogels was then investigated. This step sheds light on the required conditions for the synthesis of PBCL-PEG-PBCLs capable of the formation of viscoelastic thermogels around 30° C.  Such viscoelastic thermogels were prepared using chemical cross-linking of PBCL-PEG-PBCL by PEG400 at a PEG400/BCL molar ratio of 4:10.  In the next chapter, we characterized the effect of benzyl carboxylate conversion to carboxyl groups in partially cross-linked PBCL-PEG-PBCL copolymers, on the thermo-gelling behaviour of produced structures (abbreviated as PCBCL-PEG-PCBCL) in water. The results showed the hydrophilic/lipophilic balance in the polymer structure affects the formation of viscoelastic thermo-gels from partially cross-linked PCBCL-PEG-PCBCL copolymers under study, with the thermo-gels to be formed for PCBCL-PEG-PCBCL with around 35-65 percent COOH substitution on the polymeric backbone. Finally, we developed polymeric micelle loaded liposomal formulation (or lipocell) through encapsulation of triblock copolymer of poly(α-carboxyl-co-benzyl carboxylate-ε-caprolactone)-b-poly(ethylene glycol)-b-poly(α-carboxyl-co-benzyl carboxylate-ε- caprolactone) (PCBCL-PEG-PCBCL) conjugated to doxorubicin (abbreviated as PCB(CL-DOX)-PEG-PCB(CL-DOX)) in liposome via the freeze-thaw method. The success in the encapsulation of polymeric micelles inside liposomes was assessed with a transmission electron microscope (TEM) employing either a negative staining or a cryogenic TEM technique (cryo-TEM). The results of this study identified the required synthesis condition leading to the preparation of viscoelastic thermogels based on PBCL-PEG-PBCL and PCBCL-PEG-PCBCL. It also set the foundation for the preparation of polymeric micelles encapsulated liposomes or lipocells, as a new nanocarrier for future applications in drug delivery.</p>