Effective Drug Therapies from Functional, Macromolecular Building Blocks with a Biomimetic Design Kui Huang, Teresa A. Croce, Sharon K. Hamilton, Chinessa T. Adkins, Billie L. Evans III, Eva Harth * Summary: The development of suitable delivery systems for intracellular delivery of proteins, peptides and other bioactive materials opens the possibility to establish refined strategies for small drug delivery, gene delivery and vaccination. We present the assembly of advanced drug delivery systems from tailored building blocks to scaffolds and bioactive cargos to afford targeting and transport across biological barriers. In particular, the utilization of novel molecular transporter will advance the bioavailability of small and macromolecular drugs that show targeted intracellular delivery. Keywords: bioactivity; biomimetic; carriers; drug delivery Introduction So far, the limited uptake of bioactive cargos has been a challenge of great significance in chemistry, biology and medicine. [1,2] In order to address critical factors such as targeting, molecular trans- port and drug load, the combinations of biocompatible scaffolds, suitable targeting units as well as vectors of cellular uptake are of fundamental importance. The sophis- tication of biological systems gives means to vectors in which each function is segmented and emerges from architectural features such as antennas for recognition and cell penetration. [3] Consequently, drug delivery strategies that accommodate many func- tions are predestinated to emerge from macromolecules comprising partitioned segments, each one achieving a different level of specification. In order to reach this high level of specification we differentiated the macromolecular delivery vector into building blocks such as the carrier molec- ule, targeting unit and an intracellular transporter entity. In particular, more effective intracellular delivery can revital- ize therapeutics with previously unrealized potential due to poor pharmacokinetic profiles. Many different technologies have been developed to deliver drugs intracellu- larly but often evidence of clinical effec- tiveness has been limited. One of the challenges is not only cellular uptake, but also maintaining targeting of intracellular sites such as the nucleus or the cytosol, in order to limit unwanted intracellular probe metabolism and transport. Technologies that enable the delivery to specific sub- cellular locations are in high demand to reduce non-specific effects, toxicity and dosage levels with the goal to overcome current limitations in drug delivery, gene therapy and vaccination. We sought to develop a molecular transporter from bran- ched dendritic architectures that provide means to target and control intracellular delivery and mimic features of branched polyarginines and linear protein transduc- tion domains (PTD), also called cell penetrating peptides (CPP). [5–7] Dendritic organic structures overcome difficulties of PTDs in that they are easily scalable, show no immune response and functionalities Macromol. Symp. 2007, 255, 20–23 DOI: 10.1002/masy.200750903 20 Department of Chemistry, Vanderbilt University, 7619 Stevenson Center, Nashville, Tennessee 37235 E-mail: eva.m.harth@Vanderbilt.Edu Copyright ß 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim