ABSTRACT
Figure 7.1 Schema for the multiple functionality of the dendrimer, including multimodal imaging, drug delivery and molecular targeting.Dendrimers represent a subset of nanoparticles with considerable potential in nanomedicine. The precise nanoscale scaffolding, nanocontainer properties, and tunable variation in size, surface chemistry, and interior void space make dendrimers unique nanoparticles with considerable potential as nanoimaging contrast agents as well as targetable nanocontainers for site-specific drug delivery [52]. The word “dendrimer” originates from the Greek word dendron, meaning “tree,” and refers Nanoimaging Edited by Beth Goins and William Phillips Copyright © 2011 by Pan Stanford Publishing Pte. Ltd. www.panstanford.com
to the basic structure of the particle: a central core that gives rise to numerous branches. The basic dendrimer structure consists of a central core surrounded concentrically by annular interior shells (or branches), which terminate peripherally to provide numerous functional groups on the surface of the dendrimer [52]. These surface groups create an abundance of potential binding sites for targeting ligands, such as monoclonal antibodies or peptides, for site-specific delivery of imaging payloads or therapeutic agents [49]. The branching creates a flexible interior space within the dendrimer that can carry therapeutic payloads (Fig. 7.1). The space within the molecule is an isolated microenvironment, which effectively shields the payload from enzymatic destruction while decreasing its toxicity [49] as well as enabling the controlled release of the payload after target binding. The many highly tunable properties of dendrimers make them attractive nanoparticles for multimodal imaging. Although the complexities of dendrimer chemistry are beyond the scope of this review, basic aspects of surface and interior chemistry are important. The surface residues vary extensively; however, amine, carboxyl, or alcohol groups, are often utilized due to the ease of conjugation that can be achieved with imaging agents or targeting molecules. The ability to modify and expand dendrimer surface groups permits the rational manipulation of agent biodistribution via changes in agent diameter (through the addition of annular shells or generations) and payload deposition through controlled release by receptor-mediated targeting. Dendrimers are composed of various core types, including ethylene diamine (EDA) and diaminobutyl (DAB), as well as several interior types, such as polyamidoamine (PAMAM) and polypropylimine (PPI). The interiors typically used in imaging agents, such as PAMAM or PPI dendrimers, are highly soluble in aqueous solution and possess a primary amine-rich surface that is totally uncharged at pH greater than 9 or a carboxyl-rich surface that is totally uncharged at pH less than 4.The abundance of primary amine functional groups on the exterior shell serve as optimal attachment sites for chelating agents in the development of macromolecular contrast agents, or for antibody molecules for site-specific targeting.The ability to attach both targeting and chelating moieties to PPI and PAMAM dendrimers has propelled their use as contrast agents for molecular imaging. In comparison to EDA and DAB dendrimer cores, which have diamine core components, newer families of dendrimers possess a cystamine core, which, when subjected to traditional redox reactions, dissociates to produce free sulfhydryl groups and permits the use of maleimide and sulfohydryl coupling reactions, for the conjugation of peptides, monoclonal antibodies, biotin, or other targeting moieties.The ability to optimize dendrimer biodistribution and pharmacokinetics through modification of particle size offers optimization of biocompatibility and control of agent biodistribution in vivo. In general, greater biocompatibility is associated with lower generation numbers and anionic or neutral surface groups compared to similar particles of higher generation or those with cationic surface groups. Increased biocompatibility is also achieved through the attachment of small molecules or
PEGylating the surface, which increases the hydrophilicity and decreases agent immunogenicity. Among the tunable properties, size has been shown to have a tremendous effect on in vivo behavior, even when comparing molecules with similar chemical properties [10-12]. Surprisingly small changes (of only several nanometers) in diameter can greatly impact the pharmacokinetics, permeability across the vascular wall, excretion route, and recognition by the reticuloendothelial system [19]. In vivo studies have demonstrated that particles with smaller generation numbers (<4 nm diameter; which are found in dendrimers smaller than the generation 3 EDA/PAMAM dendrimer) demonstrate leakage of the agent from the vascular space and rapid renal excretion. Therefore, smaller generation dendrimers that are excreted rapidly through the kidney may be useful in assessing renal function or in rapidly clearing unbound but targeted payload-carrying dendrimers [8, 9, 20, 21, 24]. Intermediate dendrimer generations between 5 and 8 nm (G4 or G7) in diameter leak through hyperpermeable tumor vasculature but are retained within normal vessels [2]. Larger generation dendrimers, greater than 13 nm in diameter (G9 and G10), provide excellent enhancement of the reticuloendothelial system of the liver and spleen. The intermediate generation dendrimers (G6 to G8) demonstrate blood-pool retention of both normal and tumor vessels and are therefore excellent candidates for vascular imaging agents [27, 30, 31]. In addition to size, the chemical characteristics of dendrimers impact in vivo behavior. Among the characteristics, particle hydrophilicity greatly impacts agent pharmacokinetics. Increasing the hydrophilicity of G4-PAMAM dendrimers by PEGylation decreases both the renal excretion and the liver accumulation of these particles, increasing particle half-life and improving vascular retention [26]. Conversely, hydrophobic dendrimers, such as those with DAB cores even of small diameter, preferentially accumulate in the liver in contrast to similar-sized PAMAM agents, making them promising hepatic imaging agents [25]. Medical imaging represents a promising application of dendrimers within the broader field of medical nanotechnology. Developments in medical imaging include applications in magnetic resonance (MR) imaging, computer tomography (CT), and radionuclide and optical imaging. Dendrimer-based contrast agents offer considerable advantages compared with conventional agents. Most conventional imaging agents are low in molecular weight and therefore demonstrate rapid clearance from vascular circulation and excretion from the body through renal filtration. The rapid clearance properties of low-molecular-weight (LMW) agents limit their utility in time-dependent imaging studies in which longer particle circulation and retention times are needed. Unlike LMW agents, macromolecular agents, such as dendrimers, display desirable blood-pool properties with longer circulation and retention times. In addition, dendrimer-based agents are able to depict the lymphatic system after interstitial injection due to the preferential retention of such agents within the lymphatic channels [28]. Among the macromolecular agents, dendrimers offer a unique platform for the attachment of imaging and targeting moieties, and as discussed herein, dendrimers represent an optimal particle for multimodal imaging.
