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Tecto-Dendrimers

Structure

Synthesis

Function

The Michigan Nanotechnology Institute for Medicine and Biological Sciences (MNIMBS) is successfully achieving two results: the creation of working functional components for nanodevices, and the creation of the first members of a vast array of nanodevices using these components. In the Dendrimer section of this website, there is a description of the components.

A generalized "smart" therapeutic will have components which perform these functions:

  • Diseased cell recognition
  • Diagnosis of disease state
  • Drug delivery
  • Reporting location
  • Reporting outcome of therapy

The tecto-dendrimers under development will have all five of these functions. The Institute has already made and tested functional dendrimers which perform each of these functions.

Once the Institute has a working component which can recognize apoptosis (cell death), that component can be used as part of a larger nanodevice to report successful therapy delivery to any kind of diseased cell, e.g. a cancer cell or a cell infected with a virus.

Dendrimer Cluster Agent

Figure 1: Dendrimer Cluster Agent

 

Structure
Tecto-dendrimers are composed of a core dendrimer, which may or may not contain the therapeutic agent, surrounded by dendrimers. The surrounding dendrimers are of several types, each type designed to perform a function necessary to a smart therapeutic nanodevice.

Agents attached to a dendrimer

Figure 2: Agents attached to a dendrimer

 

By careful construction, the Institute can build a nanodevice with a distinct center and four or five distinct kinds of dendrimers. The Institute has built and tested the individual components, and is now working on the synthesis of the complete tecto-dendrimer. Even as this synthetic work is underway, research continues into the best way to engineer the functions, e.g., should the therapeutic agent be carried in the core dendrimer or in one of the shell dendrimers?

There are several questions about which architecture will make the best tecto-dendrimer. One question concerns the method of connecting the dendrimers to make a tecto-dendrimer-Van Der Waals, ionic, covalent? Or a molecular linker? Another question concerns the best ratio of shell dendrimers to the core. Currently work is underway to decide which architecture is best.

Synthesis
The Institute is currently working out synthetic methods. There have been several successes to date. As these processes are still in the experimental stage, the details are not yet ready for publication.

The synthesis is challenging, requiring a high level of skill to produce a precise product. Each type of dendrimer in the syntheses has a multifunctional surface. In organic synthetic chemistry, "multifunctional" means the ability to react with multiple molecules. Any of the four possible shell dendrimers can react with multiple core dendrimers, creating a multi-branched, large polymer of dendrimers. Suppressing this uncontrolled polymerization is difficult.

The Institute has uniquely qualified chemists who have experience working with dendrimers. They are making steady progress in producing highly pure samples of tecto-dendrimers with precisely defined structures.

Unwanted polymer structure.

Figure 3: Unwanted polymer structure.
To avoid this useless polymer requires careful synthesis.

Function
By building the tecto-dendrimers out of components, the Institute is able to successfully produce an array of smart therapeutic nanodevices with little effort. For instance, once apoptosis reporting, contrast enhancing, and chemotherapeutic releasing dendrimers are made and attached to the core dendrimer, it should be possible to make very large amounts of this tecto-dendrimer as a starting material which will be the framework structure that will be customized to fight a particular cancer, with the addition of any one of many possible distinct cancer recognition dendrimers. This will become a means for destroying a specific cancer type while sparing the healthy, normal cells.

Standard tecto-dendrimer

Figure 4: Standard tecto-dendrimer

 

As the genomic revolution in biomedicine proceeds, proteins unique to each kind of cancer are being identified. Already a half dozen cancer cell types have been studied, and for each it has been possible to find at least one unique protein which dendrimers could use to identify the cell as cancerous. Scientists at the Institute envision the day when there will be a recognition dendrimer for each type of cancer.

The dendrimeric architecture is a generalizable one. It could be used to treat many diseases besides cancer. For instance, to cure viral infections it is necessary for the body to kill cells infected with the virus. Infected cells are easy to recognize, since they have non-human viral proteins on their surfaces.

The Institute expects that a warehouse of viral protein recognition dendrimers will be stocked. Then it will be possible to build any particular anti-viral tecto-dendrimer by coupling the appropriate targeting dendrimer from the warehouse to the standard tecto-dendrimer. This same strategy could apply to parasites, which also have unique, non-human surface proteins. It might even be possible to target parasites which are hiding inside human cells, such as malaria.

 

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