Xuechen's Master 2016

Homeostasis processes are vital for the survival of beings since they keep the human body conditions under control and keep the environment appropriate for metabolism. Generally, homeostasis and diseases are inversely related. Therefore, great efforts have been made in the development of pharmaceutical drug delivery systems targeting homeostasis. Among various drug delivery systems, self-regulated drug delivery systems are able to recognize changes in the concentrations of specific analytes from physiological environment and work to counteract these changes. These systems thus are able to provide a negative feedback loop to sustain physiological homeostasis. However, it is still challenging to adjust the on-off transitions under physiological conditions because of the lack of recognition elements with high specificity. The objective of this thesis was to investigate a sequentially triggered mechanism for self-regulated delivery system to solve this issue. A core-shell structured polymeric system was developed to demonstrate this idea. This system could go through sequential reactions in response to a specific metabolite. In the presence of this metabolite, the core of this system would undergo a localized molecular conformational change and would release a second trigger molecule. This second trigger molecule could then trigger the release of the designated drug stored in the shell of this system. In this study, adenosine and human platelet derived growth factor BB (PDGF-BB) were used as a model for the development of a self-regulated polymeric system. First, three DNA oligonucleotides were designed for adenosine recognition, second trigger molecule interaction, and PDGF-BB loading. Then, adenosine-triggered release behaviors of the second trigger molecule from the core were investigated. Finally, adenosine-triggered PDGF-BB release was characterized in the core-shell structured system. Based on the results, the sequentially triggered mechanism was investigated and a novel self-regulated drug delivery model system was established.