Stimuli-responsive release of doxorubicin from layer-by-layer films of Poly(2-isopropyl-2-oxazoline) and tannic acid

Haktanıyan, Meltem
Stimuli responsive polymers are promising materials for biomedical applications due to change in their properties in response to changes in environmental conditions. Among all the stimuli, pH and temperature are the most extensively studied ones in biomedical applications. pH is an internal trigger. pH changes at different regions of the body. Besides, pH is more acidic than the pH at tumor tissues or at an infected site in the body. Temperature can behave as both an internal and an external trigger. Increase in temperature during a disease state is an example of an internal trigger. Applying heat externally to increase the temperature of a specific part in the body during hyperthermia treatment is an example of an external trigger. Temperature responsive polymers change their solubility with changing temperature. Thermoresponsive polymers are classified into two: i) polymers exhibiting lower critical solution temperature (LCST) in aqueous solution and ii) polymers exhibiting upper critical solution temperature (UCST) in aqueous solution. If the polymer solution shows phase separation with increasing temperature, this polymer solution has lower critical solution temperature (LCST). If the polymer solution shows phase separation upon cooling, the polymer solution has an upper critical solution temperature (UCST). Recently, poly(2-alkly-2-oxazoline)s which show LCST-type vi behavior in aqueous solution have been of interest as an alternative to poly(N-isopropylacrylamide) (PNIPAM), a commonly used polymer exhibiting LCST-type behavior in aqueous solution in biomedical applications. Layer-by-layer (LbL) self-assembly technique is an efficient and a practical method for preparation of ultra-thin multilayer films. By using stimuli responsive polymers as building blocks during multilayer assembly, the resulting LbL films can be made responsive to changes in environmental conditions. This feature specifically makes LbL films promising polymer platforms for controlled release applications from surfaces. The study presented in this thesis reports on the fabrication of anti-cancer drug, Doxorubicin (DOX) containing multilayers of poly(2-isopropyl-2-oxazoline) (PIPOX) and Tannic acid (TA) and release of DOX from the multilayers at moderately acidic conditions. Moreover, the effect of temperature on the pH-induced release of DOX from the surface and correlated the results with the LCST behavior of PIPOX were investigated. First, PIPOX was synthesized via cationic ring opening polymerization. Prior to film construction, water soluble complexes of TA and DOX (TA-DOX) were prepared. PIPOX and TA-DOX were deposited on the surface using LbL technique through hydrogen bonding interactions at pH 6.5. Minimal amount of DOX was released at physiological pH. In contrast, pH-induced release of DOX was observed at moderately acidic conditions due to protonation of TA as the acidity increased and loss of electrostatic interactions among TA and DOX. Moreover, it is observed that raising the temperature from 25 °C to 37.5 °C increased the amount of DOX released from the surface due to conformational changes within the multilayers correlated with the lower critical solution temperature (LCST) behavior of PIPOX. This study is the first one reporting the pH- and/or temperature-induced release of DOX from poly(2-alkyl-2-oxazoline) based hydrogen-bonded multilayers. Considering the temperature-responsive behavior of PIPOX and important biological properties of PIPOX and TA, combined with the acidic nature of tumor tissues, these multilayers which release DOX at moderately acidic conditions, can be promising drug carriers for controlled release of DOX from surfaces.