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Molecular Engineering in Nanotechnology III: Computer Simulation and Visualization of A Multifunctional Device

Inhan Lee, Istvan Majoros*, and James R. Baker, Jr.

Center for Biologic Nanotechnology, University of Michigan,
City, State, etc., Postal code

This is an abstract for a presentation given at the
Ninth Foresight Conference on Molecular Nanotechnology.
There will be a link from here to the full article when it is available on the web.

 

Cancer treatment needs to overcome multiple obstacles: 1. side effects during chemotherapy 2. multiple drug resistance 3. difficulty with in vivo diagnosis of tumor cell deaths 4. recurrence after initial cure. Since side effects can be reduced by tumor-cell specific treatment, cancer targeting is crucial. Multi-drug resistance can be reduced by a combination of drugs and/or conjugation to other anchoring molecules. Sensing molecules can help in vivo diagnosis. Our group is engineering a single molecule with these functions.

In this study, we performed computer simulations of multifunctional devices with a base material of a poly(amidoamine) dendrimer. Since a previous study showed that an acetamide-surface derivatized group was optimal for targeting with folic acid (1), 80 % of initial primary amines were derivatized by acetamide groups in the model. Subsequent computer models and simulations to build a multifunctional device exactly reproduced the chemical reaction steps. The fluorescence sensing moiety was fluorescein, the targeting moiety being folic acid, and drugs being methotrexate and taxol. Two kinds of methotrexate attachment were simulated: amide and ester bond.

Computer models and molecular dynamics simulations were performed using InsightII (Accelrys, Inc.) software on an Onyx workstation (Silicon Graphics, Inc.). All computer models were minimized using steepest descent methods and then annealed at 1000 oK for 5 psec. The major simulations were performed using the Discover module of InsightII with cvff forcefield for 200 psec with 1 fsec time intervals at 298 oK. A distance-dependent dielectric constant was used to mimic the charge shielding effect of water.

Molecular dynamics simulations showed the positions of terminal primary amines of each molecule, prior to further attachment of the other functional moiety. Potential reaction sites among them were randomly selected and the next functional element was attached to those sites. Conformational comparisons between each molecule were performed and compared with experiments. The radii of gyration of the devices and the radial distributions of each functional moiety were also investigated.

References

  1. A. Quintana, L. Piehler, E. Raczka, I. Lee, A. Patri, D. Tomalia, D. Swanson, T. Thomas, A. Myc, and J. R. Baker Jr. Design and Function of a Dendrimer-Based Therapeutic Nanodevice Targeted to Tumor Cells through the Folate Receptor. Proc. Nat. Acad. Sci. (submitted).

*Corresponding Address:
Istvan Majoros
Center for Biologic Nanotechnology, University of Michigan
4027 KresgeII, Ann Arbor, MI 48109 USA
Phone: (734) 615-0618
Fax: (734) 615-0621
Email: majoros@umich.edu



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