Small molecule drugs typically suffer from poor in vivo properties, imparting a significant limitation on the dose that can be administered and in turn, reaches disease sites to exert a therapeutic effect. Polymer nanomedicines can address these shortcomings by increasing specificity of delivery and enhancing uptake in disease sites, thereby improving the clinical outcomes for disease targets such as cancer. It is known that the size, shape, and underlying chemistries of drug delivery particles are key parameters which govern their ultimate performance in vivo. Responsive particles are desirable for triggered drug delivery, achievable through architecture change and biodegradation to control in vivo fate. To this end, we synthesized polymeric materials with linear, hyperbranched, star, and micellar-like architectures based on 2-hydroxypropyl methacrylamide (HPMA), and the effects of 3D architecture and redox-responsive biodegradation on biological transport were investigated. Variations in “stealth” behavior between the materials were quantified in vitro and in vivo, whereby reduction-responsive hyperbranched polymers most successfully avoided accumulation within the liver, and none of the materials targeted the spleen or lungs. Functionalization of selected architectures with doxorubicin (DOX) demonstrated enhanced efficacy over the free drug in 2D and 3D in vitro models, and enhanced efficacy in vivo in a highly aggressive orthotopic breast cancer model when dosed over schedules accounting for the biodistribution of the carriers. These data show it is possible to direct materials of the same chemistries into different cellular and physiological regions via modulation of their 3D architectures, and thus the work overall provides valuable new insight into how nanoparticle architecture and programmed degradation can be tailored to elicit specific biological responses for drug delivery.

Understanding structure-activity relationships of polymeric nanoparticles in biological applications

ACS Spring 2022

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