Mitigating the Effects of Persistent Antipolymer Immune Reactions in Nanomedicine: Evaluating Materials-Based Approaches Using Molecular Imaging

Poly­(ethylene glycol) (PEG) is a hydrophilic polymer ubiquitously used in both medical and nonmedical goods. Recent debate surrounding the observed stimulation of immune responses against PEG has spurred the development of materials that may be suitable replacements for this common polymeric component. The underlying view is that these alternative materials with comparable physicochemical properties can overcome the unfavorable and unpredictable effects of antibody-mediated clearance by being chemically, and therefore antigenically, distinct from PEG. However, this hypothesis has not been thoroughly tested in any defined manner, and the immune response observed against PEG has not been rigorously investigated within the context of these emerging materials. Consequently, it remains unclear whether immunity-mediated discrimination between polymeric entities even occurs in vivo and, if this is the case, how it may be exploited. In this study, we utilize positron emission tomography–computed tomography molecular imaging in mice immunized to develop specific antibody responses to PEG and an alternative polymer in order to visualize and quantify the influence of antipolymer antibodies on the biodistribution of synthetic polymers in vivo as a function of immunization status. Under the conditions of this experiment, mice could be primed to exhibit both innate and adaptive immunity to all of the polymer systems to which they were exposed. We demonstrate that alternating between chemically disparate polymers is a viable approach to extend their efficacy when antipolymer humoral immune responses arise.