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<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 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. The factor makes cancer treatment so difficult is metastatic cancer.</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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<font style="font-size:30px;">&nbsp;&nbsp;Metastatic Cancer</font>
<font style="font-size:32px;">&nbsp;&nbsp;<i>Modern Cancer Treatments</i></font>
<br>
<br>
<p class="paragraph">Metastatic cancer is a cancer that has spread from the primary site to other parts of the body. The cancer cells change their charactor to adapt new location when they arrive at organ, which makes metastatic cancer troublesome. In order to prevent the spread, we have to kill all cancer cells at the primary site.</p>
<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>
<p class="paragraph">Chemotherapy, uses chemical drugs, is the most popular way to kill cancer cells because it is the only systemic therapy among major procedures used by oncologists. However, it is hard to kill cancer cells completely, because anti-cancer drugs can affect normal cells as well and cause serious side effects. In order to target only cancer cells, drug delivery systems (DDS) have been widely researched by scientists.</p>
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<font style="font-size:30px;">&nbsp;&nbsp;Drug Delivery Systems (DDS)</font>
<font style="font-size:32px;">&nbsp;&nbsp;<i>Drug Delivery Systems</i></font>
<br>
<br>
<p class="paragraph">DDS is a general term for the various ways to deliver drugs selectively to tumors while avoiding normal cells. We can reduce the concentration of anti-cancer drugs by using DDS, leading to the suppression of side effects. Though DDS is a promising strategy, one drawback is that it relies on diffusion in blood vessels, means it is ineffective to kill cancer cells completely.<a name="2">&nbsp;</a></p>
<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>
<p class="paragraph">In order to kill all cancer cells in their early stage before spreading, we aimed at creating a single cell resolution system which can judge whether a cell is cancer or not, should be killed or be kept alive.</p>
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<br>
<font style="font-size:30px;">&nbsp;&nbsp;"Let’s design a self moving patroller!" </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>
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<img src="http://openwetware.org/images/7/70/DDShikaku.png" width="400px" height="264px" align="right">
<font style="font-size:32px;">&nbsp;&nbsp;<i>Strategy of the Self-Moving Robot</i></font>
<p class="paragraph">Our goal is to build a patrolling nano-robot which moves not only by diffusion but also by self-propulsion. We draw inspiration from a dendritic cell which is an antigen-presenting cell of the mammalian immune system that moves in a body by migration. The cell has spines that are small actin-rich protrusions; by remodeling (polymerizing and depolymerizing) actin filaments inside, it can change shape and migrate.</p>
<p class="paragraph">Based on this idea, we will develop an actin-like monomer (named “Motor-Monomer”) that polymerizes on one end and depolymerizes on the other end to allow mobilization. We then put the Motor-Monomers into a liposome which the Receptor is inserted 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, allowing the liposome to start patrolling the 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)."<a name="3">&nbsp;</a></p>
<br>
<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="Goals">&nbsp;Project Goals</a></h1>
<br>
<p class="paragraph">The goal we set to achieve during the summer is to build a self patrolling cell, PoLICe. To achieve this goal, we planned three main steps.</p>
<h1 class="title"><a name="background">&nbsp;Project Goals</a></h1>
<p class="paragraph">First, we need to develop a sensing system which works as a start switch of the Motor, so that we can control when PoLICe starts patrolling. In order to achieve the system, we planned to design the following Receptor: It is embedded to a liposome and when recognizing the outside signal it emits a substance which leads the Motor-Monomers to become the Motor-Polymer. (We call the substance “Polymerization Initiator”; actually it is not the polymerization but it is more convenient.) </p>
<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><tr>
<td><img src="http://openwetware.org/images/a/a9/Project1kashiwa.jpg" width="420px" height="300px"></td><td><img src="http://openwetware.org/images/7/73/Project2kashiwa.jpg" width="420px" height="300px"></td>
</tr></table></center>
<p class="paragraph">Second, we need to develop a moving system which works as the Motor of the PoLICe. In order to achieve the system, we planned to design the following Motor-Monomers: They are put into the liposome at the inactivated state and get activated, begin polymerizing, by catching the Polymerization Initiator.</p>
<table><tr>
<td><img src="http://openwetware.org/images/4/45/Project3.jpg" width="420px"></td><td><img src="http://openwetware.org/images/6/63/Project4.jpg" width="420px"></td>
</tr></table>
<p class="paragraph">Finally, we need to connect two systems with each other and assay to verify if it is the complete ‘PoLICe’ system.</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>
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<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>
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<h1 class="title">Reference</h1>
<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#1" onMouseOver="On('img1')" onMouseOut="Off()"><span style="font-size:12pt;">Background</span></a></li>
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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>
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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#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/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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