Project

Background

Recently genomics and proteomics have well studied, and new drugs such as siRNA have been developed. As a further effective approach to cure diseases, drug delivery systems (DDS) in living bodies have been studied. Liposome and polymers are usually used in DDS as containers.

Motivation

Controlling the quantity of drug release is very important to develop effective DDS.
Delivering drugs at appropriate places which are usually very narrow spaces is another important point to avoid adverse effect.
If initial releasing signals are released at a very limited place, and if the signals continuously transduce the initial signals with releasing drugs, are the two important points fulfilled? This is the motivation of our project.

Project Goal

Our project aims to construct a chain-reactive molecule-releasing system in a spontaneous manner like organisms. The system requires two sub-systems: “egg-type initiator” and “chain-reactive burst”. Sequential working of these sub-systems is the goal of our project.

1. Egg-type initiator

Eggs are the origin of all animals’ life, and egg-type birth makes it possible to release concentrated chemicals at a narrow space. Such a concentrated release has an advantage to initiate subsequent reactions.
Alginate hydrogel is chosen as a shell membrane of the egg-type. The gels encapsulate solution phase like salmon caviar. The solution phase contains temperature-sensitive liposomes that have some trigger DNAs and chelate compounds inside. Increasing temperature causes collapse of liposomes, and EGTA, a chelate to melt alginate gels, in liposomes is released. As a result, many trigger DNAs are released at a limited point.

2. Chain-reactive burst

Chain-reaction is a way to achieve exponential signal amplification. If chain-reactive collapse of liposomes happens in a limited space, release of drugs inside liposomes is expected to be controlled around a limited space. Our chain-reactive burst system is a good one for doing this strategy.
Each liposome encapsulates trigger DNAs and drugs, and has aptamer DNAs in their outer surface. Hybridizations of trigger DNAs and aptamer DNAs deform liposome rapidly, and consequently, the liposomes are destroyed. This destruction continuously occurs by releasing new trigger DNAs inside liposomes to disrupt neighbor liposomes. These processes achieve concentrated drug release. We call these processes as “Chain-reactive burst.”

Methods

To develop the egg-type initiator, following experiments are needed. We plan to create the egg-type initiator by combining these sub-parts.

(1) Collapse of liposomes by temperature shift
(2) Construction of alginate hydrogel membranes that have many liposomes in their solution phase
(3) Melting the alginate hydrogel membranes by EGTA released from temperature-sensitive liposomes

To develop the chain-reactive burst, following experiments are needed.
(1) Design and construction of trigger DNA and aptamer DNA to cause collapse of liposomes.
(2) Confirm chain reaction of liposomal collapse by new triggers inside disrupt neighbor liposomes.