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Taxi.Coli: smart drug delivery

Taxi.Coli: smart drug delivery EPF_Lausanne’s team is proud to participate to iGEM 2013 and excited to present their project: Taxi.Coli: smart drug delivery. The team’s vision is to build a biosynthetic drug delivery concept. The key word of this project is “adaptability”. Our goal is to explore a way of using E.Coli as a highly modular carrier, opening the gate to several applications and alternatives in disease treatments. Using the principles of synthetic biology, we engineered a gelatinase secreting E. Coli able to bind gelatin nanoparticles using a biotin-streptavidin interaction and release them in a corresponding location. The drug delivery system is built in three parts: 1) the nanoparticle binding and 2) the environment sensing that 3) triggers the gelatinase release of the engineered E. Coli, liberating the content of the nanoparticle. The nanoparticles made of gelatin are able to carry any type of organic compound leading to a wide range of applications.

Safety

In order to enable safe application of engineered cells in the microencapsulation based therapy we designed three safety mechanisms to degrade the alginate capsules at the end of the therapy, terminate the therapeutic cells by induction of apoptosis and to tag any escaped cells for elimination by the host's natural killer cells. <a href="https://2012.igem.org/Team:Slovenia/SafetyMechanisms">Read more...</a>

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Implementation

In consultations with medical experts we tailored our therapeutic devices based on implanted microencapsulated engineered cells to the treatments of hepatitis C and ischaemic heart disease by in situ production of therapeutic protein effectors whose efficiency has already been demonstrated. In agreement with our pharmacokinetic models, this strategy could reduce side effects and improve efficiency of these therapies. Switching between production of effectors with antiviral or anti-inflammatory and tissue regenerative effect could be regulated by administrating a small molecule inducer. <a href="https://2012.igem.org/Team:Slovenia/Implementation">Read more...</a>

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Modeling

Modeling was used to simulate and improve the properties of the switch and the pharmacokinetic distribution of drugs in the tissue, which is required for an effective therapy and decreased side effects. We introduced improved methods of switch simulations such as a quantitative parameter derivation and algorithmic/mixed simulation that can capture mixed regulator binding to operators. We also included into the wiki a server for online switch simulation. A pharmacokinetic model of the local delivery of therapeutics by microencapsulated cells predicted that this type of drug delivery should have reduced systemic side effects.

Exhaustive modeling of the switch demonstrated that the classic genetic toggle switch arrangement is not stable without cooperativity, but it confirmed functionality and improved robustness of the our switch design with two positive feedback loops. This topology does not require cooperativity since nonlinearity is introduced by the positive feedback loop. <a href="https://2012.igem.org/Team:Slovenia/Modeling">Read more...</a>

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Society

Different aspects of general medical applications of synthetic biology and our project specifically were discussed with a wide range of stakeholders, including medical professionals, patients, experts on the law and ethics of GMO use and release, scientists, the media and the general public that will all have to participate in a successful introduction of synthetic biology applications to clinical use. We attempted to organize a network of Slovenian high schools to share the excitement of synthetic biology with younger generations and to demonstrate its application in medicine and other fields. <a href="https://2012.igem.org/Team:Slovenia/Society">Read more...</a>

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Perspectives

We anticipate that designed DNA-binding element-based transcriptional factor logic will play a very important role in the development of synthetic biology,
TAL-based switches allow simultaneous introduction of multiple switches to adopt multiple cellular states with numerous medical and other applications ,
The safety mechanisms, including the inducible leak-free termination (prodrug), escape detection and capsule degradation components will allow implementation for different therapeutic purposes,
for an effective application stable cell lines containing integrated switches with selected therapeutic effectors and safety mechanisms will have to be established, most likely by the use of human artificial chromosomes,
we plan to initiate in vivo experiments first on ischaemia and wound healing.

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Team:EPF Lausanne

From 2013.igem.org

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