Synthesis and Evaluation of Environmentally Responsive Polymeric Materials.

摘要

Drug delivery is generally concerned with improving the pharmacokinetics of therapeutic molecules. This can be done by improving distribution to target tissues, improving biological retention time, co-delivery of multiple therapeutics, and decrease in the total amount of therapeutic necessary to get the desired effect. Because they are highly tunable and synthetically addressable, polymeric particulate carriers represent a promising approach for improved delivery of therapeutics, and are the subject of this dissertation. In particular, the development is described for degradable materials, which are capable of releasing encapsulated cargo following uptake by cells and subsequent trafficking to endosomal vesicles. Degradation is responsive to acidic or oxidizing environments found in targeted tissues. Materials developed include hydrogels, hydrophobic microparticles, and liquid-filled microcapsules.;Chapter 1 introduces various delivery strategies for polymeric delivery vehicles and some of their main applications. Additionally, the modes of environmentally responsive degradation are reviewed, with a focus on relevant design criteria for materials intended for delivery applications.;In Chapter 2, the synthesis of a multifunctional acid-sensitive hydrogel carrier is described for immunotherapy applications. Antigen and an immunostimulatory adjuvant are encapsulated in particles decorated with targeting antibodies and the effectiveness of stimulation and targeting are assayed.;Chapters 3 and 4 discuss the synthesis and characterization of a hydrophobic acid-sensitive delivery vehicle based on acetal-modified dextran. The preparation of particles from acetal- modified dextran and their pH-dependent degradation behavior is described. Further optimization acetal modification and its effect on degradation rate and uptake pathways are investigated.;Chapter 5 describes the synthesis and characterization of a hydrophobic oxidation-sensitive delivery vehicle based on a modified dextran. The preparation of particles, their degradation profile, and their use in a proof-of-principle immunostimulation experiment is described.;Chapter 6 describes the synthesis and characterization of a acid-sensitive liquid-filled microcapsules with burst release kinetics. The preparation and degradation of these capsules is investigated and their use in a proof-of-principle cytotoxicity experiment is described.;Chapter 7 describes preliminary work toward the development of materials that feature autocatalytic acid-mediated degradation.