Design, Synthesis And Characterization Of Novel Stimuli-responsive Poly(Ether Urethane)s

Stimuli-responsive polymers are able to undergo relatively large and abrupt, physical or chemical changes in response to small external changes in the environmental conditions. They are of fundamental importance in biomedical areas and have been extensively developed for drug delivery systems considering the special microenvironment in many pathological sites. During the past two decades, there have been numerous reports on stimuli-sensitive polymeric systems. But a majority of them deal with response to single stimulus. In nature, however, the change in behavior of a macromolecule (proteins and nucleic acids) is often a result of its response to a combination of environmental changes other than a single factor. To mimic this feature, formulation of materials which can sense specific changes and respond to multiple stimuli in a predictable manner would be of great interest. Polyurethanes are one of the most widely used biomaterials in medical applications due to their excellent biocompatibility, biodegradation, mechanical and processing properties. In the recent years, some kinds of biodegradable polyurethanes have been developed for drug delivery systems. Nevertheless, very little attention has been paid to the stimuli-responsive polyurethane especially multi-responsive polyurethane nanoparticles as drug delivery systems. In this thesis, we summarize the recent advances in design and development of stimuli-responsive polymers and polyurethanes as drug delivery systems. Based on previous studies, several kinds of single stimuli or multi-stimuli responsive polyurethanes were designed and synthesized using a facile one-pot method. The whole process for the responsive behaviours of the poly(ether urethane) nanoparticles is confirmed by light transmission, dynamic light scattering, nuclear magnetic resonance and transmission electron microscopy. The potential use of these polymers for flexible control of drug release in vivo and vitro is also explored, using doxorubicin (DOX) as the model drug. (1) A series of temperature-responsive poly(ether urethane)s with alternative hydrophilic/hydrophobic segments was synthesized using a facile one-pot approach, from PEG-diisocyanates and aliphatic diols. Nanoparticles prepared by self-assembly of the resulting copolymers showed sharp temperature-responsive phase transition. The phase transition temperature could be easily modulated by the length of hydrophilic or hydrophobic segments of the polymer. In the presence of these obtained poly(ether-urethane)s, doxorubicin (DOX) could be dispersed into aqueous solution. The ratio of DOX release from the polymeric particles increased sharply above the phase transition temperature, while the release was suppressed below the phase transition temperature. A controlled drug release can be achieved by changing the environmental temperature. The easy-prepared polymeric nanoparticles, with features of biocompatibility, biodegradability, and tail-made temperature responsiveness, are a kind of promising carriers for temperature-controllable drug release.(2) A series of linear temperature-and pH-responsive poly(ether urethane)s was synthesized using a facile one-pot method from PEG-diisocyanates of different molecular weight and N-methyldiethanolamine containing ternary amino moieties. In aqueous solution, the amphiphilic copolymers could be self-assembled into nanoparticles, which showed temperature and pH dually responsive characters. The phase transition temperature (Tp) of the nanoparticles could be modulated by changing the molecular weight of PEG segments. The encapsulation and release of doxorubicine (DOX) were investigated using the obtained polymeric nanoparticles as carriers. The system showed a temperature-triggered pH-dependent drug release. The viability of liver hepatocellular cells (HepG2cells) treated with the DOX-loaded polymeric nanoparticles was observed using microscopy. The results demonstrated that the therapeutic activity and the DOX distribution could be precisely controlled by the novel dually responsive system.(3) A series of temperature-and redox-responsive poly(ether urethane)s have been achieved using a facile one-pot approach. The amphiphilic poly(ether urethane)s were comprised of2,2’-dithiodiethanol, hydrophobic hexamethylene diisocyanate and hydrophilic Poly(ethylene glycol)(PEG) segments. In aqueous solution, the amphiphilic copolymers could be self-assembled into their nanoparticles, which showed temperature and redox dually responsive characters. The phase transition temperature (Tp) of the prepared poly(ether urethane)s in aqueous solution could be easily controlled by changing the length of PEG segment or the ratio of PEG to2,2’-dithiodiethanol and Tp could be used to trigger the redox-degradable behavior. The Doxorubicin (DOX)-loaded poly(ether urethane) nanoparticles were prepared in order to investigate their stimuli-responsive release. Drug release profiles showed that a transient or slow release was obtained when a temperature or redox stimulus was applied by itself. A long-term accelerated drug release could be obtained through the redox-responsive degradation at a higher temperature above Tp. This polymeric carrier system provides an opportunity to fine-tune release kinetics resulting in a desired release profile through the synergistic effect of these two stimuli.(4) A series of multi-responsive degradable poly(ether urethane)s have been achieved using a facile one-pot method. The multi-segmented poly(ether urethane)s were synthesized through a simple one-pot condensation polymerization of poly (ethylene glycol),2,2’-dithiodiethanol, N-methyldiethanolamine and hexamethylene diisocyanate. The obtained amphiphilic copolymers could be self-assembled into their nanoparticles in aqueous solution, which were responsive respectively to temperature, pH and redox potential with tailored phase transition temperature. The nanoparticles possessed the encapsulation of hydrophobic drugs and showed a temperature-triggered accelerated and complete drug release profile. These results presented the polymeric nanoparticles as effective multi-responsive degradable nanocarriers to achieve on-off drug release.