Stimuli-Responsive Polymer Systems that Respond to Redox Potential and pH for Controlled Drug Release

Nanocarriers are widely investigated drug delivery systems that can overcome physiological barriers by tuning nanocarrier size, shape, surface chemistry, targeting ligand conjugation, and material composition. Furthermore, they have stimuli-responsive moieties that translate physiological signals, such as pH and redox potential, at the tumor microenvironment into nanocarrier behaviors, like swelling, degradation, morphological change, and charge reversal. Stimuli-responsive nanocarriers exhibit better pharmacokinetic profiles with reduced premature cargo leakage during circulation time and improved tumor targeting efficacies. pH is the most commonly explored stimuli for designing nanocarriers, however there has been a recent interest in redox stimuli-responsive nanocarriers. Redox stimuli-responsive nanocarriers are often incorporated with a glutathione (GSH) sensitive bond, typically disulfide bonds, for intracellular activation or degradation. In these documented series of experiments, I first focus on poly(disulfide)s and report on the synthesis of fully degradable poly(disulfide) cross-linked nanogel drug carriers formed by oxidative radical polymerization of 2,2'-(ethylenedioxy)diethanethiol (EDDET) as a monomer with different cross-linkers, including pentaerythritol tetramercaptoacetate (PETMA), via a single- electron transfer mechanism. Because the poly(EDDET) backbone repeat structure and cross- linking junctions are composed entirely of disulfide bonds, these nanogels specifically degrade to small molecule dithiols intracellularly in response to the reducing agent glutathione present inside of cells. Due to the ease of synthesis, rapid gelation times, and tunable functionality, these non-toxic and fully degradable nanogels offer excellent potential for use in a variety of drug delivery applications. In addition to disulfide bonds, esters are another attractive functional group for the synthesis of degradable polymers for drug delivery, therefore I later discuss experiments and research that I worked on with Dr. Jing Hao, a postdoc in the Siegwart lab, that describes how polyesters can be synthesized in a controlled fashion and how they can be used to deliver siRNA molecules in vitro and in vivo. Specifically, the synthesis of a lipocationic polyester library via ring-opening polymerization (ROP) of functional valerlactones for efficacious siRNA delivery is described. The 139 polymers in the lipocationic polyester library were synthesized in high yield, fast time (minutes), and gram scale. Precise monomer incorporation ratios were achieved to enable tunable hydrophobicity and pKa. Nanoparticles formulated with these polymers were able to enable gene silencing in vitro and in vivo at low doses.