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<font face="Futura,Arial,Frutiger" font size="24px">PROJECT</font>
<font face="Futura,Arial,Frutiger" font size="24px">PROJECT</font>
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<br>
<br>
Artificial immune system for cancer cells
<br>
<br>
<h1 class="title"><a name="background">&nbsp;Background</a></h1>
<h1 class="title"><a name="background">&nbsp;Background</a></h1>
<p class="paragraph">Cancer is a group of diseases which are characterized by the uncontrolled growth of cells that invades tissues and organs in our body; leading to death in some cases. It is one of the most dangerous diseases, causing about 13 percent of human’s death in the world. In our country, Japan, one out of three people get cancer and half of them die.</p>
<p class="paragraph">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. </p>
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<br>
<font style="font-size:30px;">How can we fight against cancer?</font>
<font style="font-size:32px;">&nbsp;&nbsp;<i>Modern Cancer Treatments</i></font>
<br>
<br>
<p class="paragraph">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.</p>
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<p class="paragraph">There are multiple treatments for cancer disease; surgery, radiotherapy and chemotherapy are major remedies.
<font style="font-size:32px;">&nbsp;&nbsp;<i>Drug Delivery Systems</i></font>
Above all, the most popular one is chemotherapy. It uses chemical substances, anti-cancer drug, to kill cancer cells and it is the single systemic therapy in the three major cancer remedies. Chemotherapy, however, can cause serious side effects because anti-cancer drug attacks to normal cells as well as cancer cells. In order to solve this problem, drug delivery system (DDS) has been studied enthusiastically.</p>
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<font style="font-size:30px;">What is "DDS"?</font>
<br>
<br>
<p class="paragraph">DDS is a general term for the various ways to deliver drugs selectively to tumors, not to normal cells. Though DDS is an amazing invention of treatments for cancer, it still has some demerits; one of them is that it cannot always deliver drugs to the place where we expected, because movements of drug carriers mainly depend on the diffusion in blood vessels.</p>
<a name="1"></a>
<br>
<br>
<p class="paragraph">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.<a name="2">&nbsp;</a></p>
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<br>
<br>
<br>
<h1 class="title"><a name="background">&nbsp;Motivation</a></h1>
<h1 class="title"><a name="background">&nbsp;Motivation</a></h1>
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<br>
<font style="font-size:30px;">"Let’s design a self moving carrier!"</font>
<font style="font-size:32px;">&nbsp;&nbsp;<i>Creating a New Way of Delivery</font> <font style="font-size:20px;"> - self-mobile, effective DDS</i></font>
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<br>
<div class="imagebox">
<p class="image"><img src="http://openwetware.org/images/f/f6/Police_vs_DDS.png" width="300px" height="175px"></p>
<p class="caption">Fig.1. Difference between ordinary DDS and PoLICe.</p>
</div>
<p class="paragraph">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.</p>
<br clear="right">
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<p class="paragraph">In order to overcome the pre-stated demerit, we decided to build a vessel which moves by not only diffusion but also its internal force; like a ship swims around in the sea by its motor.</p>
<font style="font-size:32px;">&nbsp;&nbsp;<i>Strategy of the Self-Moving Robot</i></font>
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<br>
<font style="font-size:30px;">"But how can we move a carrier?"</font>
<p class="paragraph">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.</p>
<br>
<p class="paragraph">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.</p>
<br>
<p class="paragraph">As we modeled this polymerizing-in-a-liposome system based on a dendritic immune cell, we named it "<b>Polymeric and Liposomal Immune Cell (PoLICe)</b>."<a name="3">&nbsp;</a></p>
<p class="paragraph">Facing this difficult problem, we believed we can get an idea from an actual cell in a human body. A dendritic cell, an antigen-presenting cell of the mammalian immune system, moves in a body by migration. The cell has spines which are small actin-rich protrusions; by remodeling (polymerizing and depolymerizing) actin filaments inside, it can change shape and migrate.</p>
 
<p class="paragraph">So that is it! We planned to develop an actin-like monomer (named “Motor-Monomer”) that polymerizes on one end and depolymerizes on the other end to allow mobilization, just as actin filaments in dendritic cells do. We put the Motor-Monomers into a liposome which the Receptor was connected as a starter switch. This Receptor recognizes the outside signal and emits the Polymerization Initiator so that the Motor-Monomers grow to the Motor-Polymer and a liposome starts patrolling a body to find cancer markers.</p>
<p class="paragraph">As we modeled this polymerizing-in-a-liposome system on a dendritic immune cell, we named it "Polymeric and Liposomal Immune Cell (PoLICe)."</p>
<a name="3"></a>
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<br>
<br>
<br>
<h1 class="title"><a name="background">&nbsp;Project Goals</a></h1>
<p class="paragraph">As a first stage of building PoLICe, we aimed to <b>achieve a simple deformation of a liposome after given stimulus</b>. The components of the simple PoLICe can be separated into three parts.</p>
<center>
<table align="left" style="margin:5px;">
<tr>
<th><img src="http://openwetware.org/images/c/c5/Project1Kashiwa.png" width="175px" height="200px"></th>
<th><img src="http://openwetware.org/images/c/c9/Project2Kashiwa.png" width="175px" height="200px"></th>
<th><img src="http://openwetware.org/images/a/ad/Project3Kashiwa.png" width="175px" height="200px"></th>
<th><img src="http://openwetware.org/images/4/46/Project4Kashiwa.png" width="200px" height="190px"></th>
</tr>
<tr>
<td>
<p class="cap">Fig.2. PoLICe before recognition of outside signal.</p></td> <td> <p class="cap">Fig.3. The Motor gets activated upon recognition of outside signal.</p></td>
<td><p class="cap">Fig.4. Polymerization of the Motor-Monomers.</p></td><td><p class="cap">Fig.5. Deformation of liposome.</p></td>
</div></tr>
</table></center>
<p class="paragraph">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.</p>
<br clear="right">
<p class="paragraph">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.</p>
<p class="paragraph">Finally, we need to connect two systems with each other and experimentally verify the deformation of the liposome.</p>
<br clear="right">
<br>
<br>
<h1 class="title"><a name="Goals">&nbsp;Project Goals</a></h1>
<p class="paragraph">The goal we set to achieve during the summer is to build a self moving cell made of a liposome. To win this goal, we planned two main steps.</p>
<p class="paragraph">
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<br>
<br>
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<h2 class="reference">Reference</h2>
<p class="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</p>
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   <li><a href="http://openwetware.org/wiki/Biomod/2014/Kashiwa"><img src="http://openwetware.org/images/e/ec/LogoKashiwa.png" onmouseover="this.src='http://openwetware.org/images/7/7a/Logo2Kashiwa.png'" onclick="this.src='http://openwetware.org/images/1/1d/Logo2.5.png'" onmouseout="this.src='http://openwetware.org/images/e/ec/LogoKashiwa.png'" height="80px" width="120px" name="def"></a>
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   <li><a href="http://openwetware.org/wiki/Biomod/2014/Kashiwa/Project" onMouseOver="On('img1')" onMouseOut="Off()"><span style="font-size:12pt;">PROJECT</span></a>
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       <li><a href="http://openwetware.org/wiki/Biomod/2014/Kashiwa/Project#1" onMouseOver="On('img1')" onMouseOut="Off()"><span style="font-size:12pt;">Background</span></a></li>
       <li><a href="http://openwetware.org/wiki/Biomod/2014/Kashiwa/Project#2" onMouseOver="On('img1')" onMouseOut="Off()"><span style="font-size:12pt;">Motivation</span></a></li>
       <li><a href="http://openwetware.org/wiki/Biomod/2014/Kashiwa/Project#3" onMouseOver="On('img1')" onMouseOut="Off()"><span style="font-size:12pt;">Project Goals</span></a></li>
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   <li><a href="http://openwetware.org/wiki/Biomod/2014/Kashiwa/Trial" onMouseOver="On('img1')" onMouseOut="Off()"><span style="font-size:12pt;">&nbsp;EARLY TRIAL&nbsp;</span></a>
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       <li><a href="http://openwetware.org/wiki/Biomod/2014/Kashiwa/Trial#1" onMouseOver="On('img1')" onMouseOut="Off()"><span style="font-size:12pt;">Design</span></a></li>
       <li><a href="http://openwetware.org/wiki/Biomod/2014/Kashiwa/Trial#2" onMouseOver="On('img1')" onMouseOut="Off()"><span style="font-size:12pt;">Approaches</span></a></li>
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   <li><a href="http://openwetware.org/wiki/Biomod/2014/Kashiwa/Design" onMouseOver="On('img1')" onMouseOut="Off()"><span style="font-size:12pt;">DESIGN</span></a>
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       <li><a href="http://openwetware.org/wiki/Biomod/2014/Kashiwa/Design#2" onMouseOver="On('img1')" onMouseOut="Off()"><span style="font-size:12pt;">The Receptor</span></a></li>
       <li><a href="http://openwetware.org/wiki/Biomod/2014/Kashiwa/Design#1" onMouseOver="On('img1')" onMouseOut="Off()"><span style="font-size:12pt;">The Motor</span></a></li>
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       <li><a href="http://openwetware.org/wiki/Biomod/2014/Kashiwa/Highlights" onMouseOver="On('img1')" onMouseOut="Off()"><span style="font-size:12pt;">Highlights</span></a></li>
       <li><a href="http://openwetware.org/wiki/Biomod/2014/Kashiwa/Receptor" onMouseOver="On('img1')" onMouseOut="Off()"><span style="font-size:12pt;">The Receptor</span></a></li>
       <li><a href="http://openwetware.org/wiki/Biomod/2014/Kashiwa/Motor" onMouseOver="On('img1')" onMouseOut="Off()"><span style="font-size:12pt;">The Motor</span></a></li>
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   <li><a href="http://openwetware.org/wiki/Biomod/2014/Kashiwa/Discussion" onMouseOver="On('img1')" onMouseOut="Off()"><span style="font-size:12pt;">&nbsp;&nbsp;DISCUSSION&nbsp;</span></a>
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       <li><a href="http://openwetware.org/wiki/Biomod/2014/Kashiwa/Discussion#1" onMouseOver="On('img1')" onMouseOut="Off()"><span style="font-size:12pt;">Achievements</span></a></li>
       <li><a href="http://openwetware.org/wiki/Biomod/2014/Kashiwa/Discussion#2" onMouseOver="On('img1')" onMouseOut="Off()"><span style="font-size:12pt;">Future</span></a></li>
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   <li><a href="http://openwetware.org/wiki/Biomod/2014/Kashiwa/Protocols" onMouseOver="On('img1')" onMouseOut="Off()"><span style="font-size:12pt;">PROTOCOL</span></a>
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   <li><a href="http://openwetware.org/wiki/Biomod/2014/Kashiwa/Team" onMouseOver="On('img1')" onMouseOut="Off()"><span style="font-size:12pt;">TEAM</span></a>
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       <li><a href="http://openwetware.org/wiki/Biomod/2014/Kashiwa/Team#1" onMouseOver="On('img1')" onMouseOut="Off()"><span style="font-size:12pt;">Members</span></a></li>
       <li><a href="http://openwetware.org/wiki/Biomod/2014/Kashiwa/Team#2" onMouseOver="On('img1')" onMouseOut="Off()"><span style="font-size:12pt;">Sponsors</span></a></li>
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<body> <a name="1"></a> <font face="Futura,Arial,Frutiger" font size="24px">PROJECT</font> <br> <br> <h1 class="title"><a name="background">&nbsp;Background</a></h1> <p class="paragraph">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. </p> <br> <font style="font-size:32px;">&nbsp;&nbsp;<i>Modern Cancer Treatments</i></font> <br> <p class="paragraph">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.</p> <br> <font style="font-size:32px;">&nbsp;&nbsp;<i>Drug Delivery Systems</i></font> <br> <p class="paragraph">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.<a name="2">&nbsp;</a></p>

<br> <br> <h1 class="title"><a name="background">&nbsp;Motivation</a></h1> <br> <font style="font-size:32px;">&nbsp;&nbsp;<i>Creating a New Way of Delivery</font> <font style="font-size:20px;"> - self-mobile, effective DDS</i></font> <br>

<div class="imagebox"> <p class="image"><img src="http://openwetware.org/images/f/f6/Police_vs_DDS.png" width="300px" height="175px"></p> <p class="caption">Fig.1. Difference between ordinary DDS and PoLICe.</p> </div>

<p class="paragraph">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.</p> <br clear="right">

<br> <font style="font-size:32px;">&nbsp;&nbsp;<i>Strategy of the Self-Moving Robot</i></font> <br> <p class="paragraph">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.</p> <p class="paragraph">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.</p> <p class="paragraph">As we modeled this polymerizing-in-a-liposome system based on a dendritic immune cell, we named it "<b>Polymeric and Liposomal Immune Cell (PoLICe)</b>."<a name="3">&nbsp;</a></p>

<br> <br> <h1 class="title"><a name="background">&nbsp;Project Goals</a></h1> <p class="paragraph">As a first stage of building PoLICe, we aimed to <b>achieve a simple deformation of a liposome after given stimulus</b>. The components of the simple PoLICe can be separated into three parts.</p>

<center> <table align="left" style="margin:5px;"> <tr> <th><img src="http://openwetware.org/images/c/c5/Project1Kashiwa.png" width="175px" height="200px"></th> <th><img src="http://openwetware.org/images/c/c9/Project2Kashiwa.png" width="175px" height="200px"></th> <th><img src="http://openwetware.org/images/a/ad/Project3Kashiwa.png" width="175px" height="200px"></th> <th><img src="http://openwetware.org/images/4/46/Project4Kashiwa.png" width="200px" height="190px"></th> </tr> <tr> <td> <p class="cap">Fig.2. PoLICe before recognition of outside signal.</p></td> <td> <p class="cap">Fig.3. The Motor gets activated upon recognition of outside signal.</p></td> <td><p class="cap">Fig.4. Polymerization of the Motor-Monomers.</p></td><td><p class="cap">Fig.5. Deformation of liposome.</p></td> </div></tr> </table></center>

<p class="paragraph">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.</p> <br clear="right">

<p class="paragraph">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.</p> <p class="paragraph">Finally, we need to connect two systems with each other and experimentally verify the deformation of the liposome.</p> <br clear="right"> <br> <br> <br> <h2 class="reference">Reference</h2> <p class="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</p> </body>

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