Biomod/2014/Kashiwa/Project

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PROJECT

 Background

Cancer is a group of diseases characterized by uncontrolled cellular proliferation and invasion into bodily tissues and organs. One of the most common causes of mortality, it accounts for about 13 percent of human death in the world.


  Modern Cancer Treatments

Surgery, radiotherapy, and chemotherapy are the three major treatments to cure cancers used by oncologists. The most popular one, chemotherapy, uses chemical drugs that kill cancer cells, and it is the only systemic therapy among the three. Chemotherapy, however, can cause serious side effects because anti-cancer drugs can affect normal cells as well. In order to increase the specificity to cancer cells, drug delivery systems (DDS) have been widely studied by scientists.


  Drug Delivery Systems

DDS is a general term for various ways to deliver drugs selectively to pathogens while avoiding normal cells. Although DDS is a promising strategy, one drawback is that most DDS rely on diffusion to deliver drugs, which limits their mobility and delivering effectiveness. With diffusional DDS, for example, we cannot deliver drugs to tumors that are away from their diffusion paths. Defective drug delivery to any single cancer cell is a crucial problem for the cancer treatments because any remaining cancer cells can reproduce or metastasize, and cause recurrence of the disease. 



 Motivation


  Creating a New Way of Delivery - self-mobile, effective DDS

Fig.1. Difference between ordinary DDS and PoLICe.

The problem with the traditional DDS is its lack of active mobility. In order to overcome this, we decided to build a patrolling nano-robot which moves not only by diffusion but also by self-propulsion to transfer drugs away from their diffusion paths. Moreover, nano-scale movements of the robot enable cell-by-cell analysis in DDS with implemented cancer sensors on its surface, enabling the system to inspect cancer cells at single-cell resolution.



  Strategy of the Self-Moving Robot

To make the nano-robot, we drew inspiration from a dendritic immune cell, which moves in a body by migration. Dendritic cells have spines that are small actin-rich protrusions; by remodeling (polymerizing and depolymerizing) actin filaments inside, they can change their shapes and migrate.

Based on this idea, we developed actin-like monomers (named “Motor-Monomers”) and put them into a liposome equipped with a starter switch (named “Receptor”). When the Receptor recognizes an outside signal, such as a cancer marker, the Motor-Monomers start polymerizing to form the Motor-Polymer. The Motor-Polymer should polymerize in one end and de-polymerize in the other end to move toward a specific direction, mimicking the actin filaments.

As we modeled this polymerizing-in-a-liposome system based on a dendritic immune cell, we named it "Polymeric and Liposomal Immune Cell (PoLICe)." 



 Project Goals

As a first stage of building PoLICe, we aimed to achieve a simple deformation of a liposome after given stimulus. The components of the simple PoLICe can be separated into three parts.

Fig.2. PoLICe before recognition of outside signal.

Fig.3. The Motor gets activated upon recognition of outside signal.

Fig.4. Polymerization of the Motor-Monomers.

Fig.5. Deformation of liposome.

First, we need to develop a sensing system, called Receptor, which works as a starter switch of the Motor, so that we can control the onset of PoLICe patrolling. The Receptor is designed to be embedded across a liposomal membrane, where it reacts with the outside signals in the extra-liposomal domain and activates the Motor-Monomers to polymerize within the intra-liposomal domain.


Second, we need to develop a polymer-based moving system which works as the motor of the PoLICe. In order to achieve the system, we planned to put Motor-Monomers into the liposome at the deactivated state and start polymerization when the Receptor switches on.

Finally, we need to connect two systems with each other and experimentally verify the deformation of the liposome.





Reference

1.All Cancer (excluding non-melanoma skin cancer) Estimated Incidence, Mortality and Prevalence Worldwide in 2012 from International Agency for Research on Cancer website; http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx

© 2014 UTokyo Chem & Bio

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