Study of stimuli-responsive degradation using a disulfide platform in different polymeric biomaterials

Polymers have great potential as building blocks to construct biomaterials for applications in biomedicine, pharmaceutics and biotechnology. Their chemical flexibility leads to the synthesis of materials with diverse physical and mechanical properties. Specifically, stimuli-responsive polymers are engineered to undergo chemical or physical transitions in response to specific external triggers. One such response involves the cleavage or degradation of a dynamic covalent bond within the polymer structure. Particularly, the reduction of disulfide bonds has gained significant attention in the development of complex delivery systems for therapeutics. This thesis describes the development of two different reduction-responsive biomaterials. Amphiphilic block copolymers (ABPs) self-assemble in aqueous solutions to form core/shell micelles consisting of a hydrophobic core, capable of carrying a variety of hydrophobic therapeutic agents, and a hydrophilic corona, able to improve circulation time and delay immune responses. This unique property, in addition to enhanced colloidal stability and tunable size with narrow size distribution, makes micelles promising candidates for drug delivery systems. Hence, a polyester-based reduction-responsive degradable ABP with disulfide linkages positioned repeatedly on the main chain at regular intervals is synthesized. These well-defined ABPs were synthesized by a combination of polycondensation and atom transfer radical polymerization (ATRP). These ABPs self-assemble in aqueous solution, resulting in spherical micelles with a monomodal distribution. In the presence of a reducing agent, disulfide bonds are cleaved, leading to a destabilization of the micellar core and thus enhanced release of encapsulated model drugs. Demonstrating the potential drug delivery applications of polymeric micellar systems, functionalization with biotin (vitamin H) leads to bioconjugated micelles capable of potential cell-targeting. Hydrogels are three-dimensional networks of hydrophilic polymers that have shown promise as tissue engineering scaffolds. Thermo-responsive hydrogels expel water above their lower critical solution temperature (LCST), becoming more hydrophobic, and hence lose volume. Hydrogels were synthesized by ATRP using biocompatible oligo(ethylene oxide) as a scaffolding material in the presence of a disulfide-labeled dimethacrylate cross-linker. The amount of cross-linker affects thermo-responsive and mechanical properties. Cleavage of disulfide bonds lead to an increased LCST, enhanced deswelling kinetics and a decrease in mechanical properties caused by the generation of hydrophilic dangling chains, increasing the overall hydrophilicity of hydrogels. Combined with these results, as well as enhanced release of encapsulated hydrophilic model drugs and non-toxicity, these hydrogels show promise for biomedical applications

Reductively degradable polyester-based block copolymers prepared by facile polycondensation and ATRP: synthesis, degradation, and aqueous micellization

Well-defined reductively degradable amphiphilic block copolymers having disulfide linkages positioned repeatedly on hydrophobic chains, thus exhibiting fast degradation, were prepared by a combination of polycondensation and ATRP. The new method consists of three synthetic steps including, (1) polycondensation of commercially available diols and diacids through carbodiimide coupling or high temperature processes to synthesize degradable polyesters with disulfides labeled on the main chain at regular intervals (ssPES–OH), (2) bromination of ssPES–OH to ssPES–Br, and (3) ATRP for chain extension of ssPES–Br with water-soluble polymethacrylate, yielding ssPES-b-polymethacrylate block copolymers (ssABPs). The reductive cleavage of disulfide linkages in reducing conditions resulted in the degradation of ssPES homopolymers; their degradation rate was significantly enhanced with the increasing amounts of disulfide linkages in ssPES–OH and reducing agents. For ATRP, gel permeation chromatography and 1H-NMR results confirmed the synthesis of well-defined ssABPs and revealed that polymerizations were well controlled. Because of their amphiphilic nature, ssABPs self-assembled in water toward the formation of core/shell micelles consisting of a hydrophobic ssPES core surrounded with polymethacrylate coronas. The effects of the corona's chain length on thermal properties and micellization in water of well-defined ssABPs were examined. Moreover, reductive (or thiol-responsive) degradation of ssABP-based micelles enabled fast release of encapsulated model drugs. Cell culture experiments confirmed nontoxicity and biocompatibility of well-defined ssABPs as effect candidates for targeted delivery applications

Rapidly thiol-responsive degradable block copolymer nanocarriers with facile bioconjugation

Degradation of amphiphilic block copolymer (ABP) micelles in response to external stimuli (stimuli-responsive degradation) is a desired property in the design of controlled delivery vehicles. Here, a versatile methodology that combines facile carbodiimide coupling polycondensation with controlled radical polymerization to synthesize thiol-responsive degradable ABP micelles is described. These smart micelles consist of a hydrophobic degradable polyester block with disulfide linkages labeled repeatedly along the main chain; more importantly, in response to thiols they exhibit rapid and controlled degradation, thereby leading to enhanced release of encapsulated model drugs. Moreover, the proposed method allows for a facile bioconjugation of hydrophilic coronas using cell-targeting biomolecules during polymerization

Thiol-responsive block copolymer nanocarriers exhibiting tunable release with morphology changes

New thiol-responsive nanocarriers of amphiphilic block copolymers consisting of a pendent disulfide-labeled methacrylate polymer block (PHMssEt) and a hydrophilic poly(ethylene oxide) (PEO) block were reported. These well-controlled block copolymers were synthesized by atom transfer radical polymerization (ATRP) of a new pendent disulfide-functionalized methacrylate (HMssEt) in the presence of PEO-Br macroinitiator. Due to its amphiphilic nature, the PEO-b-PHMssEt with narrow molecular weight distribution self-assembled in aqueous solution to form monomodal micellar aggregates with PHMssEt cores surrounded with hydrophilic PEO coronas. In response to thiols, the disulfide linkages were cleaved, and thus self-assembled micelles were either converted to core-crosslinked micelles or destabilized to further disintegrate, depending on the amount of added thiols. Such change in morphology led to tunable release of encapsulated model drugs in aqueous solutions