FY2010 - Oak Ridge National Laboratory

Seed Money Fund—
Chemical Sciences Division
we can synthesize and fully characterize a novel PAMAM dendrimer with a topographic architecture
wherein the peripheral branches regularly alternate between two differently functionalized endgroups in a
well-defined manner; (2) from this dendrimer prepare a series of multivalent ligand–dendrimer conjugates
in which two different bioactive molecules have been attached to the alternating endgroups; and (3)
compare the biological activity of these dendrimer conjugates with analogous PAMAM dendrimer
conjugates possessing the same bioactive molecules attached in an uncontrolled, random spatial
arrangement (via suitable bioassays through a no-cost collaboration with colleagues at the National
Institutes of Health).
Mission Relevance
The project aims to increase the understanding of how the ability to tailor the functional display of
chemical motifs at the nanoscale impacts functionality. These materials are primarily of interest as
therapeutic agents, but there is also potential relevance to sensors for chemical and biological compounds,
and to catalysis. It is our intention to further expand into architecturally designed dendrimer nanoparticles
for biomedical applications. Results generated and capabilities enabled through this project will support
proposals to relevant programs within either the National Institutes of Health (NIH) or the National
Cancer Institute (NCI). There could be significant benefits in the areas of drug delivery for (e.g., cancer)
therapy and imaging, which would support NIH goals of conducting and supporting research “in the
causes, diagnosis, prevention, and cure of human diseases,” (from NIH website) and NCI goals “with
respect to the cause, diagnosis, prevention, and treatment of cancer” (from NCI website).
Results and Accomplishments
We have evaluated and refined the underlying chemistry for attaching a precursor arm to a PAMAM
dendrimer surface, from which we can then attach a second branch. Each branch will later be
functionalized with a different bioactive molecule using orthogonal chemistries. We have established a
useful protocol for attaching the precursor branch and have refined the analytical techniques used to
evaluate the structural changes to the dendrimer. In collaboration with our NIH colleagues, we have
revised the target dendrimer core size, selected appropriate modifying groups to impart better
biocompatibility, and selected the candidate bioactive molecules. The revised dendrimer-bioactive
molecule-conjugate targets were designed to enable a clearer assessment of the effect of the alternating
arrangement of the bioactive molecules on the final multivalent ligand–dendrimer conjugates on
biological activity, as compared with, for example, a random arrangement of the bioactive molecules on
the dendrimer surface.
We plan to complete the synthesis and characterization of the target G4 PAMAM dendrimer
functionalized with two different bioactive molecules (available from NIH), in which the bioactive
molecules are connected to the dendrimer surface in a generally alternating arrangement, by way of
alternating branches. These two bioactive molecules will also be attached to the surface of a G4 PAMAM
dendrimer in an uncontrolled, random spatial arrangement. After characterization, the biological activity
of the dendrimer conjugates will be evaluated in suitable bioassays through collaborators at the NIH.
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