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<ul> 

  	    <li class='active '><a href="http://openwetware.org/wiki/Biomod/2014/Tianjin"><span>Home</span></a></li>
  	    <li class='has-sub'><a href="http://openwetware.org/wiki/Biomod/2014/wiki-2%27.html"><span>Project</span></a>
  	        <ul>
  	            <li><a href='http://openwetware.org/wiki/Biomod/2014/wiki-2%27.html#motivation'><span>Motivation</span></a></li>
                   <li><a href='http://openwetware.org/wiki/Biomod/2014/wiki-2%27.html#design'><span>Design</span></a></li>
                   <li><a href='http://openwetware.org/wiki/Biomod/2014/wiki-2%27.html#process'><span>Process</span></a></li>
                   <li><a href="http://openwetware.org/wiki/Biomod/2012/Tianjin/Project/Origami"><span>The Origami Amplifier</span></a></li>
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           <li class='has-sub'><a href="http://openwetware.org/wiki/Biomod/2014/experiment.html"><span>Experiment</span></a>
  	        <ul>
  	            <li><a href='http://openwetware.org/wiki/Biomod/2012/Tianjin/Result/LogicGate'><span>The Logic Gate</span></a></li>
                   <li><a href='http://openwetware.org/wiki/Biomod/2012/Tianjin/Result/YDNA'><span>Y-DNA</span></a></li>
                   <li><a href='http://openwetware.org/wiki/Biomod/2012/Tianjin/Result/Origami'><span>The Origami Amplifier</span></a></li>
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           <li class='active'><a href="http://openwetware.org/wiki/Biomod/2014/acknowledgement.html"><span>Acknowledgement</span></a></li>

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DESIGN

ABSTRACT

GOAL
 

MATERIALS

METHODS

DISCUSSION

 
PROJECT
<a href="#motivation">※MOTIVATION</a>
<a href="#design">※DESIGN</a><a href="#abstract"></a>
<a href="#process">※PROCESS</a>
 
<img src="1.png" alt="" width="219" height="300" />

 

<a name="process" id="process"></a>※PROCESS
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<img src="Tianjin_index15.png" width="45" height="45" align="absmiddle"><a name="motivation" id="motivation"></a>※MOTIVATION
A. Use light instead of strand displacement to open DNA origami.

    Generally strand displacement is used to open DNA origami. If we use DNA origami to transport drugs in human body, it’s difficult and unsafe to add single-stranded DNA to human body to open DNA origami. So we want to open DNA origami in a physical way.
    We want to use light to open DNA origami because light control has many advantages.

  1. light is cheap and easy to get
  2. it is convenient to control the intensity of light
  3. light won’t damage human body

B. Open different DNA origami selectively

    In severe and advanced tumors, combined drug chemotherapy is gaining importance, which has already been proven to be clinically successful. Cancer stem cells that are diagnosed pose a new challenge to existing chemotherapy and radiation therapies, as they are intrinsically resistant by being inactive or adopting a drug efflux mechanism or enhanced antiapoptotic protein and DNA repairing ability. Hence to cure this, drug combinations are explored. In contrast to single drug chemotherapy, the combined drugs treatment may show additive or synergistic or antagonistic effects. The pharmaco-kinetics show spotentiative or reductive responses with reference to the choice of drugs combination.
    For example, the treatment of advanced breast cancer using paclitaxel and cisplatin drug combinations indicated a high efficacy in overall response rate. In a word, the combined chemotherapy strongly demands an efficient delivery vehicle that can carry multiple cargos to the target site with less accumulation in the nontarget site so that the trade-off on dosage amount can be brought closer. A mixed group of DNA origami has the potential to carry different types of drugs.

C. Transport drugs to tumor site precisely

<img src="Tianjin_index13.png" width="45" height="45" align="absmiddle"><a name="design" id="design"></a>※DESIGN
   The frequence that DNA is used as the engineering material of choice for the construction of nanoscale circuits, structures, and motors is much higher. Many of these enzyme-free constructions function by DNA strand displacement reactions.
 

 DNA strand displacement 

     Strand  displacement means that one strand of DNA displaces another in binding to a  third strand with partial complementarity to both. It is highly desireable.

 Strand displacement  is the process through which two strands with partial or full complementarity  hybridize to each other, displacing one or more pre-hybridized strands in the  process. Strand displacement can be initiated at complementary single-stranded  domains (referred to as toeholds) and progresses through a branch migration  process that resembles a random walk. By varying the strength (length and  sequence composition) of toeholds, the rate of strand-displacement reactions  can be quantitatively controlled over a factor of 10^6. Importantly, this  feature allows engineering control over the kinetics of synthetic DNA devices.

    In  molecular biology, strand displacement frequently denotes a process mediated by  enzymes such as polymerases, but the reaction as defined above is guided by the  biophysics of DNA and occurs independently of enzymes.  Enzyme-free strand displacement and branch  migration have been studied since the 1970s, but have only been applied to DNA  nanotechnology within the past decade.    

 

 <img width="554" height="204" src="wiki-2'_clip_image002_0002.jpg">

Purpose

   We use DNA sequence to connect the DNA origami which is loaded with drugs with the Au nanoparticle. And then, on the one hand, the purpose and the function of this DNA sequence is to release the drugs after under certain temperature and will never be back to the nanoparticle. And on the other hand, we hope that it can release different drugs under different thermal condition.


 Design 

 Inreversible release

 

      To make the  process of releasing drugs inreversible, we need to design a kind of DNA  sequence which will be inactive at the single state, while active when it is  complementary.

     We find out the hairpin structure which  can exactly suit our idea.

 <img width="147" height="270" src="wiki-2'_clip_image005_0001.jpg" align="left" hspace="12">   Because of the toehold’s role in  initiating strand displacement reactions, strands can be rendered effectively  unreactive if the toehold domain is made inaccessible by toehold sequestering. Toehold  sequestering can be achieved in a number of ways, the two most common of which  are hybridization of the toehold to a complementary domain and isolation of the  toehold in a short hairpin structure where helix formation is difficult.  Programmed sequestering and subsequent exposure of toehold domains allows  precise control of order and timing over the reactions and has been used in  conjunction with toehold-mediated strand displacement to construct molecular motors,  polymerization reactions, catalytic reactions, and logic gates.


Multistage release

<img width="217" height="164" src="wiki-2'_clip_image008_0000.jpg" align="left" hspace="12">   To make the multistage release of the design possible without more difficult steps, we decide to change the tm of the complementary domain by change the length of one single strand which will be connected with the DNA origami and drugs.

    Like the figure strand A will be connected with the DNA origami and strand B will combine with the Au nanoparticle.

  Structure

 <img src="wiki-2'_clip_image010_0000.jpg" width="127" height="180" hspace="12" align="top">

    The hairpin motif like figure comprises four concatenated domains, red yellow blue and green. And two basic reactions can be programmed using this motif, as illustrated for the example of catalytic duplex formation in this figure.


Assemble

<img src="untitled11.jpg" alt="" width="289" height="265">
    First, an assembly reaction (1) occurs when a single-stranded initiator I, containing an exposed toehold a*, nucleates at the exposed toehold a of hairpin A, initiating a branch migration that opens the hairpin. Hairpin domains yellow and blue were exposed, and can then serve as assembly initiators for other suitably defined hairpins, permitting cascading (like B’s hairpin).
    Second, the same strand displacement reaction (2) occurs between strand B and A to form the polymer A, B and I.
    Third a disassembly reaction (3) occurs when a single-stranded domain (yellow domain of B) initiates a branch migration that displaces the initiator I from A. In this example, I catalyses the formation of duplex A and B through a prescribed reaction pathway.
    And finally, the green domain of A and the blue domain of B partially assemble and open the green hairpin of A. What’s more with the change of the length of the green domain of A, and let the blue domain of B be always complementary to the loop of the green hairpin, then we can make the purpose of multistage release.  

Process of our drug delivery system

  1. Apply magnetic field to transport drug carriers(DNA origami) to tumor cells directly.
  2. Use light of low intensity to open DNA origami A and release drug A to kill tumor.
  3. Use light of high intensity to open DNA origami B and release drug B to kill tumor.


  1.  Drive our DNA spaceship(DNA origami) to a specific planet(tumor cells)
  2.  Use light of low intensity to open our DNA spaceship, astronaut A(drug A) comes out and lands on the planet.
  3.  Use light of high intensity to open our DNA spaceship, astronaut B(drug B) comes out and lands on the planet.
<img src="wiki-2'_clip_image002_0000.jpg" alt="" width="434" height="239">

    Because our drug delivery system is similar to the real spaceship. Therefore, we termed the project”DNA spaceship”.

© COPYRIGHT TJU BIOMOD TEAM 2014, ALL RIGHTS RESERVED

Release

   With different degrees of heat, the hydrogen bond between these two strands will be broken and the two strands will be set apart and come back to form two hairpins and can never combine any more.


Logic

<img src="wiki-2'_clip_image017_0000.jpg" alt="" width="78" height="85" hspace="12" align="left"><img width="190" height="198" src="wiki-2'_clip_image019_0000.jpg" align="left" hspace="12">   To assist in programming more complex reaction pathways, we abstract the motif as a node with four ports like figure. The state of each port is either accessible (open triangle/circle) or inaccessible (solid triangle/circle), depending on whether the toehold of the corresponding motif domain is exposed or sequestered.
    And the secondary reaction mechanism can use this kind of way to express.

 

 

 

 How to open DNA  origami using light signal?

     This kind of  light control to open DNA origami is achieved by gold nanoparticles(AuNPs). AuNPs can turn light power into heat  power. AuNPs are attached to DNA origami  using DNA linkers. After optical stimulation, the AuNPs will locally generate  heat which breaks the DNA double strands that allow DNA origami to close. Thus  our DNA origami is opened and drug loaded inside is released. AuNPs are like  the keys to open the DNA door of origami.

 

 <img width="273" height="226" src="wiki-2'_clip_image002.jpg"><img width="286" height="167" src="wiki-2'_clip_image004.jpg">

 

  1. Details about properties of AuNPs

    Currently a popular area in nanomedicine is the implementation of plasmonic nano-particles for cancer diagnosis and photothermal therapy, attributed to the intriguing optical properties of the nanoparticles. The surface plasmon resonance, a unique phenomenon to plasmonic nanoparticles leads to strong electromagnetic fields on the particle surface and consequently enhances all the radiative properties such as absorption and scattering.
    Plasmon-resonant nanoparticles (NPs) are generating much enthusiasm due to their extraordinary optical properties, particularly in the fields of life sciences and medicine. A special property of these plasmon-resonant NPs is their heat generation upon excitation of the collective electron resonance by a certain laser frequency. The determination of the temperature of plasmon-resonant NPs appears essential for a number of different applications.
    Noble metal nanoparticles, especially gold nanoparticles (AuNPs), have immense potential for the selective laser photothermal therapy of cancer due to their ability to efficiently convert surface plasmon resonance-enhanced absorbed light into localized heat. Gold nanoparticles exhibit NIR activated photothermal activity due to their geometry dependent plasmon resonance, resulting from collective oscillation of surface electrons upon excitation with light at the resonance frequency. Gold is also attractive because due to its inertness , biocompatibility , low cytotoxicity and long history of medical use.


  2. We choose NIR laser as our light signal

    In recent years, the near infrared (NIR) laser (in the region of 650 to 1100 nm) mediated photothermal ablation (PTA) therapy has attracted increased attentions for effective cancer therapy. NIR laser irradiation can induce hyperthermia damage of cancer cells and tumor organ with deep tissue penetration. Additionally, PTA also possesses minimal invasiveness and precise spatial-temporal selectivity in comparison with conventional therapeutic modalities (i.e. surgical resection, radiotherapy and chemotherapy), since its therapeutic effect happens only at the tumor site where both light-absorbent and localized photo-irradiation coexist. Among various NIR absorbents reported so far, gold nanocrystals (i.e. gold nanorods , gold nanoshells , and gold nanocages et al.) were most extensively investigated due to their excellent biocompatibility and tunable surface plasmon resonance (SPR) property to convert NIR light into local heat.

How to open different DNA origami selectively using light?
    Temperature increase of Au particle can be calculated. And the temperature increase of Au particles is related to the intensity and wavelength of light as well as the diameter of Au particles. Generally, if the other factors remain unchanged, the more intense light we use, the hotter Au particles could be. We designed two kinds of DNA origami. These two kinds of DNA origami have different DNA double lock strands. And melting temperature of this two types of DNA lock strands is different.
Initially we use light of low intensity to irradiate Au nanoparticles. Correspondingly Au particles create a low temperature increase. DNA lock strands of low melting temperature will break. And DNA origami with lock strands of low melting temperature on it would open and release drugs inside.
    Next we use light of high intensity instead. In the same way DNA origami with lock strands of high melting temperature on it would open and release a different kind of drugs inside.
    Thus with the help of Au nanoparticles we can open different DNA origamis and release different drugs step by step.

<img width="554" height="293" src="wiki-2'_clip_image005.jpg">

 How to transport  drugs to tumor site precisely？

 
 
     Usually anticancer drugs aren’t targeted, which means  they will attack tumor as well as normal cells. To solve this problem, magnetic  nanoparticles(Fe3O4) are attached on our DNA origami to  control the transportation of the DNA origami more precisely. Thus with the  help of magnetic field, drugs can be transported to tumor site directly without  attacking normal cells.

 <img width="303" height="289" src="wiki-2'_clip_image006.jpg">

<img src="untitled.jpg" alt="" width="363" height="278">

 

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