Acid-sensitive particulate carriers of biological macromolecules: Effects of physicochemical characteristics on in vitro and in vivo behavior.

摘要

Polymer-based particulate carriers developed to deliver biological macromolecules have tremendous potential to improve the prevention and treatment of disease. Acid-sensitive systems have particularly desirable characteristics, as payload release can be triggered in response to endosomal acidification upon uptake. However, effects of minor changes to physicochemical properties of the carrier to improve the efficacy of the system may have major consequences on both in vitro an in vivo behavior. This highlights the need for comprehensive characterization of the in vitro and in vivo behavior of acid-sensitive particle delivery systems, motivating the work described herein.;Chapter 1 introduces polymer-based carriers of biological macromolecules. The advantages of systems capable of triggered payload release in response to acidic environments are discussed. Two acid-sensitive delivery systems studied in the remaining chapters are described. Physicochemical properties of particles that can influence their biological behavior are presented. The need for comprehensive in vitro and in vivo testing of particle systems is outlined.;In Chapter 2, the role of particle size on the efficacy of acid-sensitive hydrogel systems for vaccine applications is discussed. Two types of particles with diameters in the nanometer and micron ranges are synthesized and evaluated for their ability to induce cellular immune responses in vivo. Both sizes of particles were similar in their efficacy, despite literature reports suggesting otherwise for carriers prepared from different materials.;In Chapter 3, the role of particle size and functionalization with cationic peptides on pulmonary delivery using hydrogel particles is investigated. Particles are characterized to determine their in vivo behavior in terms of lung retention, localization within specific cell types, and potential for inducing inflammatory responses. We found that altering both size and surface functionalization significantly affected the in vivo behavior of the particle system.;In Chapter 4, the role of particle degradation rate and functionalization with cationic peptides on the efficacy of gene delivery is studied in vitro. Acid-sensitive particles based on acetal-modified dextran are investigated. Altering particle degradation rate had a profound impact on transfection efficiency. In addition, surface functionalization was required for transfection of non-phagocytic cells, but not for phagocytic cells.