Molecular Engineering in Nanotechnology. I: Multifunctional Device for Biomedical Application
Istvan Majoros*, Thommey Thomas, Andrzej Myc, Inhan Lee, Balazs Keszler, and James R. Baker Jr.
University of Michigan, Center for Biologic Nanotechnology,
Ann Arbor, MI 48109-0533 USA
This is an abstract
for a presentation given at the
Foresight Conference on Molecular Nanotechnology.
There will be a link from here to the full article when it is
available on the web.
There is tremendous need for new forms of cancer therapeutics. By using molecular engineering principle we have designed and developed new therapeutics for cancer treatment based on dendritic macromolecules. Covalent assembly of reactive monomers (methyl acrylate and ethylenediamine) around a molecular core (ethylene- diamine) were shyntesized in two iterative reactions steps to form the dendritic structure. Poly(amidoamine), PAMAM dendrimer, generation 5 (G-5) has been synthesized in large scale. This macromolecule represents close to theoretical structure with uniform spherical shape, size (5.3 nm in radius), 120 primary amino groups on the surface (theoretical functionality is 128). Number average number of primary amino groups was determined by potentiometric titration based on electrochemical properties of this dendrimer. Number-, weight-average molecular weight and molecular weight distribution was measured by Waters Wyatt hybrid GPC system (Alliance 2690 unit equipped with UV, MALLS and RI detectors).
The characterized dendrimer (Part II: Molecular engineering in nanotechnology. II. Structure and composition of multifunctional devices for medical application.) vehicle was partially acylated (80%) and by using step by step consecutive reaction sequence and characterization a well-characterized multi-functional device was synthesized. Acylation assures complete solubility and improved specific targeting efficiency for the device in aqueous and physiological solutions. It was fuctionalized with fluorescein for imaging, with folic acid for specific targeting. Taxol and/or Methotrexate were conjugated as drug to the dendrimer. Finally, a short peptide chain with two dyes on it was covalently attached to the multifunctional device to signal the event of apoptosis.
These devices have been used to target folate receptor positive cells (KB cells) and found to be specifically uptaken by cells in vitro. In next set of experiment we examined two of additional functions of the device - cytotoxicity against KB cells and response to apoptosis. Data obtained from these experiments proved that multifunctional device targets specifically to KB cells destroys them reports apoptosis in killed KB cells.
University of Michigan, Center for Biologic Nanotechnology
200 Zina Pitcher, 4026 Kresge II, Ann Arbor, MI 48109-0533 USA