ABSTRACT:This paper describes the first synthesis of a new class of topological macromolecules which we refer to as "starburst polymers." The fundamental building blocks to this new polymer class are referred to as "dendrimers." These dendrimers differ from classical monomers/ oligomers by their extraordinary symmetry, high branching and maximized (telechelic) terminal functionality density. The dendrimers possess "reactive end groups" which allow (a) controlled moelcular weight building (monodispersity), (b) controlled branching (topology), and (c) versatility in design and modification of the terminal end groups. Dendrimer synthesis is accomplished by a variety of strategies involving "time sequenced propagation" techniques. The resulting dendrimers grow in a geometrically progressive fashion as shown: Chemically bridging these dendrimers leads to the new class of macromolecules-"starburst polymers" (e.g.,

In memoriam Piero PinoStarburst dendrimers are three-dimensional, highly ordered oligomeric and polymeric compounds formed by reiterative reaction sequences starting from smaller molecules-"initiator cores" such as ammonia or pentaerythritol. Protecting group strategies are crucial in these syntheses, which proceed via discrete "Aufbau" stages referred to as generations. Critical molecular design parameters (CMDPs) such as size, shape, and surface chemistry may be controlled by the reactions and synthetic building blocks used. Starburst dendrimers can mimic certain properties of micelles and liposomes and even those of biomolecules and the still more complicated, but highly organized, building blocks of biological systems. Numerous applications of these compounds are conceivable, particularly in mimicking the functions of large biomolecules as drug carriers and immunogens. This new branch of "supramolecular chemistry" should spark new developments in both organic and macromolecular chemistry.

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Starburst polyamidoamine dendrimers are a new class of synthetic polymers with unique structural and physical characteristics. These polymers were investigated for the ability to bind DNA and enhance DNA transfer and expression in a variety of mammalian cell lines. Twenty different types of polyamidoamine dendrimers were synthesized, and the polymer structure was confirmed using welldefined analytical techniques. The efficiency of plasmid DNA transfection using dendrimers was examined using two reporter gene systems: firefly luciferase and bacterial 1B-galactosidase. The transfections were performed using various dendrimers, and levels of expression of the reporter protein were determined. Highly efficient transfection of a broad range of eukaryotic cells and cell lines was achieved with minimal cytotoxicity using the DNA/dendrimer complexes.However, the ability to transfect cells was restricted to certain types of dendrimers and in some situations required the presence of, additional compounds, such as DEAE-dextran, that appeared to alter the nature of the complex. A few cell lines demonstrated enhanced transfection with the addition of chloroquine, indicating endosomal localization of the complexes. The capability of a dendrimer to transfect cells appeared to depend on the size, shape, and number of primary amino groups on the surface of the polymer. However, the specific dendrimer most efficient in achieving transfection varied between different types of cells. These studies demonstrate that Starburst dendrimers can transfect a wide variety of cell types in vitro and offer an efficient method for producing permanently transfected cell lines.

A brief historical perspective relating the discovery of dendrimers and other dendritic polymers is presented. Dendritic polymers are recognized as the fourth major class of macromolecular architecture consisting of four subclasses, namely, (1) random hyperbranched, (2) dendrigrafts, (3) dendrons, and (4) dendrimers. The previous literature is reviewed with anecdotal events leading to implications for dendrimers in the emerging science of nanotechnology. Keywords: dendrimers; nanotechnology; telechelics; artificial proteins; dendrigrafts; hyperbranched Donald A. Tomalia completed his undergraduate chemistry degree at the University of Michigan, Flint College and obtained his Ph.D. degree (physical-organic chemistry) from Michigan State University. He joined the Dow Chemical Company as a synthetic polymer chemist with a focus on functional monomers and polymers, where he held various research and management positions . During that time, he discovered the cationic polymerization of 2-oxazolines (1966) (J Polym Sci, A-1, 2253, 1966) and Starburst® dendrimers (1979) (Polym J, Tokyo, 17, 117, 1985). The oxazoline breakthrough was recognized by I.R.-100 Awards (1978, 1986), and the first dendrimer synthesis was noted by an R&D-100 Award (1991) and the Leonardo da Vinci Prize (Paris, 1996). In 1990, he joined the Michigan Molecular Institute (MMI) as Professor and Director of Nanoscale Chemistry & Architecture (1990)(1991)(1992)(1993)(1994)(1995)(1996)(1997)(1998)(1999). In 1992, he co-founded Dendritech, Inc., the first commercial producer of dendrimers, and was named founding President and Chief Scientist (1992-2000). In 1998, he became Vice President of Technology for MMI (1998)(1999)(2000) while simultaneously serving as Scientific Director for the Biologic Nanotechnology Center, University Michigan

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