1063 Review ISSN 1743-5889 Nanomedicine (2011) 6(6), 1063–1084 10.2217/NNM.11.67 © CJH Porter Dendrimer pharmacokinetics: the effect of size, structure and surface characteristics on ADME properties Dendrimers are branched synthetic polymers that can be synthesized to provide macromo- lecular constructs with hydrodynamic radii in the low nanometer size range and with excel- lent control over size and surface functional- ity. Dendrimer-based systems therefore show promise as nanomedicines [1–4] , gene-delivery vectors [5] , biological adhesives [6] and imaging agents [7] . There is considerable variation in potential dendrimer structure since modifica- tions can be made to the nature of the core and the scaffold, and the polyfunctional dendrimer surface allows the attachment of almost any functional group or bioactive agent. A general schematic representation of dendrimer struc- ture is given in FIGURE 1 and a number of exam- ples of dendrimer classes are shown in FIGURE 2. Dendrimers can be constructed via divergent (involving sequential addition of layers or ‘gen- erations’ of monomers to a central core) or con- vergent routes (involving prior construction of dendrimer segments followed by convergence into a single structure). These synthetic strat- egies provide good control over structural identity for the small- to intermediate-sized dendrimers (typically smaller than sixth gen- eration) that are typically employed for in vivo biomedical applications. For a more complete review of dendrimer synthesis see [8–11] . The macromolecular nature of dendrimers limits epithelial permeability, and as such, dendrimer-based delivery systems, in common with most nanoparticulate delivery systems, are usually administered parenterally (e.g., via intravenous, subcutaneous or intraperitoneal administration). After intravenous administra- tion, in vivo disposition is defined by the man- ner in which the delivery system interacts with potential routes of elimination and also by the patterns of extravasation and uptake into target and nontarget organs. In particular, for delivery systems to persist in the systemic circulation, dendrimers must avoid renal excretion and cir- cumvent clearance by the cells and organs of the reticuloendothelial system (RES; primarily the liver and spleen). Patterns of biodistribution are also critical to the ability to provide for site- specific delivery and are largely dictated by size and the potential for specific interaction of the surface (including surface-presented targeting groups, such as antibodies) with a target. Where parenteral routes of administration other than the intravenous route are utilized, transport from the injection site to the systemic circula- tion becomes an additional consideration and one which is complicated by the potential role of both vascular and lymphatic capillaries in the drainage of macromolecules from interstitial injection sites. Whilst parenteral administration has been utilized in the majority of studies, increasing evidence also suggests the potential for den- drimer absorption across various epithelial bar- riers, including the intestine and the skin. In this case, an understanding of the ultimate patterns of in vivo disposition requires evaluation of the impact of dendrimer structure on absorption and subsequently on systemic disposition. Dendrimers show increasing promise as drug-delivery vectors and can be generated with a wide range of scaffold structures, sizes and surface functionalities. To this point, the majority of studies of dendrimer- based drug-delivery systems have detailed pharmacodynamic outcomes, or have followed the pharmacokinetics of a solubilized or conjugated drug. By contrast, detailed commentary on the in vivo fate of the dendrimer carrier is less evident, even though the pharmacokinetics of the carrier will likely dictate both pharmacodynamic and toxicokinetic outcomes. In the current article, the influence of size, structure and surface functionality on the absorption, distribution, metabolism and elimination (ADME) properties of dendrimers have been examined and the implications of these findings for delivery system design are discussed. KEYWORDS: absorption n biodistribution n dendrimer n elimination n metabolism n pharmacokinetics Lisa M Kaminskas 1 , Ben J Boyd 1 & Christopher JH Porter †1 1 Drug Delivery Disposiion & Dynamics, Monash Insitute of Pharmaceuical Sciences, Monash University. 381 Royal Parade, Parkville, VIC, 3052, Australia † Author for correspondence: Tel.: +61 399 039 649 Fax: +61 399 039 583 chris.porter@monash.edu For reprint orders, please contact: reprints@futuremedicine.com