Holger Frey

Dendrimers: relationship between structure and biocompatibility in vitro, and preliminary studies on the biodistribution of 125I-labelled polyamidoamine dendrimers in vivo.

Dendrimers are highly branched macromolecules of low polydispersity that provide many exciting opportunities for design of novel drug-carriers, gene delivery systems and imaging agents. They hold promise in tissue targeting applications, controlled drug release and moreover, their interesting nanoscopic architecture might allow easier passage across biological barriers by transcytosis. However, from the vast array of structures currently emerging from synthetic chemistry it is essential to design molecules that have real potential for in vivo biological use. Here, polyamidoamine (PAMAM, Starburst), poly(propyleneimine) with either diaminobutane or diaminoethane as core, and poly(ethylene oxide) (PEO) grafted carbosilane (CSi-PEO) dendrimers were used to study systematically the effect of dendrimer generation and surface functionality on biological properties in vitro. Generally, dendrimers bearing -NH(2) termini displayed concentration- and in the case of PAMAM dendrimers generation-dependent haemolysis, and changes in red cell morphology were observed after 1 h even at low concentrations (10 microg/ml). At concentrations below 1 mg/ml CSi-PEO dendrimers and those dendrimers with carboxylate (COONa) terminal groups were neither haemolytic nor cytotoxic towards a panel of cell lines in vitro. In general, cationic dendrimers were cytotoxic (72 h incubation), displaying IC(50) values=50-300 microg/ml dependent on dendrimer-type, cell-type and generation. Preliminary studies with polyether dendrimers prepared by the convergent route showed that dendrimers with carboxylate and malonate surfaces were not haemolytic at 1 h, but after 24 h, unlike anionic PAMAM dendrimers they were lytic. Cationic 125I-labelled PAMAM dendrimers (gen 3 and 4) administered intravenously (i.v.) to Wistar rats ( approximately 10 microg/ml) were cleared rapidly from the circulation (<2% recovered dose in blood at 1 h). Anionic PAMAM dendrimers (gen 2.5, 3.5 and 5.5) showed longer circulation times ( approximately 20-40% recovered dose in blood at 1 h) with generation-dependent clearance rates; lower generations circulated longer. For both anionic and cationic species blood levels at 1 h correlated with the extent of liver capture observed (30-90% recovered dose at 1 h). 125I-Labelled PAMAM dendrimers injected intraperitoneally were transferred to the bloodstream within an hour and their subsequent biodistribution mirrored that seen following i.v. injection. Inherent toxicity would suggest it unlikely that higher generation cationic dendrimers will be suitable for parenteral administration, especially if they are to be used at a high dose. In addition it is clear that dendrimer structure must also be carefully tailored to avoid rapid hepatic uptake if targeting elsewhere (e.g. tumour targeting) is a primary objective.

Dendritic Polymers in Biomedical Applications: From Potential to Clinical Use in Diagnostics and Therapy

Dendrimers are characterized by a combination of high end-group functionality and a compact, precisely defined molecular structure. These characteristics can be used in biomedical applications, for example, for the amplification or multiplication of effects on a molecular level, or to create extremely high local concentrations of drugs, molecular labels, or probe moieties. A brief summary of the current state of the art in the field is given, and focuses on the application of dendrimers both in diagnostics as well as in therapy. In diagnostics, dendrimers that bear GdIII complexes are used as contrast agents in magnetic resonance imaging. DNA dendrimers have potential for routine use in high-throughput functional genomic analysis, as well as for DNA biosensors. Dendrimers are also being investigated for therapeutics, for example, as carriers for controlled drug delivery, in gene transfection, as well as in boron neutron-capture therapy. Furthermore, the antimicrobial activity of dendrimers has been studied.

Hyperbranched Polyglycerols: From the Controlled Synthesis of Biocompatible Polyether Polyols to Multipurpose Applications

Dendritic macromolecules with random branch-on-branch topology, termed hyperbranched polymers in the late 1980s, have a decided advantage over symmetrical dendrimers by virtue of typically being accessible in a one-step synthesis. Saving this synthetic effort once had an unfortunate consequence, though: hyperbranching polymerization used to result in a broad distribution of molecular weights (that is, very high polydispersities, often M(w)/M(n) > 5). By contrast, a typical dendrimer synthesis yields a single molecule (in other words, M(w)/M(n) = 1.0), albeit by a labor-intensive, multistep process. But 10 years ago, Sunder and colleagues reported the controlled synthesis of well-defined hyperbranched polyglycerol (PG) via ring-opening multibranching polymerization (ROMBP) of glycidol. Since then, hyperbranched and polyfunctional polyethers with controlled molar mass and low polydispersities (M(w)/M(n) = 1.2-1.9) have been prepared, through various monomer addition protocols, by ROMBP. In this Account, we review the progress in the preparation and application of these uniquely versatile polyether polyols over the past decade. Hyperbranched PGs combine several remarkable features, including a highly flexible aliphatic polyether backbone, multiple hydrophilic groups, and excellent biocompatibility. Within the past decade, intense efforts have been directed at the optimization of synthetic procedures affording PG homo- and copolymers with different molecular weight characteristics and topology. Fundamental parameters of hyperbranched polymers include molar mass, polydispersity, degree of branching, and end-group functionality. Selected approaches for optimizing and tailoring these characteristics are presented and classified with respect to their application potential. Specific functionalization in the core and at the periphery of hyperbranched PG has been pursued to meet the growing demand for novel specialty materials in academia and industry. A variety of fascinating synthetic approaches now provide access to well-defined, complex macromolecular architectures based on polyether polyols with low polydispersity. For instance, a variety of linear-hyperbranched block copolymers has been reported. The inherent attributes of PG-based materials are useful for a number of individual implementation concepts, such as drug encapsulation or surface modification. The excellent biocompatibility of PG has also led to rapidly growing significance in biomedical applications, for example, bioconjugation with peptides, as well as surface attachment for the creation of protein-resistant surfaces.

Controlling the Growth of Polymer Trees: Concepts and Perspectives For Hyperbranched Polymers

This article summarizes basic principles and recent progress in the field of cascade-branched polymers. Methods for the preparation of macromolecules with hyperbranched structures are presented and compared concerning the extent of control over molecular weights and polydispersity. Step-growth and recently developed chain-growth strategies as well as enzyme and transition metal catalyzed polymerizations are discussed with respect to mechanism and future potential.

Molecular Nanocapsules Based on Amphiphilic Hyperbranched Polyglycerols.

Polar dyes can be solubilized in apolar media-molecular nanocapsules with hydrophilic interiors have been prepared (see schematic representation) using polyglycerols with narrow polydispersity and simple esterification with fatty acids. These unimolecular micelles offer attractive potential for a variety of applications ranging from controlled drug release to the design of microreactors and catalysts.

Hyperbranched Polyether Polyols: A Modular Approach to Complex Polymer Architectures

In recent years, highly branched polymers have gained widespread attention due to their unique properties, which differ significantly from their linear counterparts. Great emphasis in this area has been placed on polymers with treelike or acascade-typeo branching, with a branch-onbranch topology. These macromolecules typically exhibit compact, globular structures in combination with a high number of functional groups. Since the conformation of such polymers is restricted by their molecular architecture, in contrast to linear polymer chains, entanglements are neglectable. Currently, there is rapidly growing interest in this type of materials for numerous applications. The low viscosity in combination with the high functionality may be useful for a wide variety of possible uses, ranging from functional crosslinkers, additives, and rheology modifiers to components in adhesives, advanced coatings, structured hydrogels, and dental composites. Such polymers might also be of interest in nanotechnology, for example, as building blocks for nanoscale reaction compartments, as a template for nanoporous materials with low dielectric constants, or for the fabrication of defined hybrid particles (e.g., biomineralization techniques). Other fields considered are biochemistry and biomedicine, where such macromolecules could act as carriers, either highly loaded for diagnostic purposes (e.g., for magnetic resonance imaging (MRI) of blood vessels) or as host compartments for controlled drug-release. Finally, their use as homogeneous supports for recyclable catalysts and for supported organic and biochemical syntheses has been suggested. Commonly, the perfectly branched dendrimers have been discussed in this context. However, dendrimers have to be prepared in tedious multistep syntheses, which obviously is a limiting factor for most applications. In contrast to dendrimers, the less structurally perfect (i.e., randomly branched) hyperbranched polymers synthesized via one-step reactions have been considered as possible alternative, since structural perfection may not be a strict prerequisite for many applications. So far, hyperbranched polymers have been regarded as the apoor cousinso of dendrimers because they commonly possess broad polydispersity (often exceeding Mw/Mn = 5!). In addition, their randomly branched architecture (Fig. 1) has been thought to be unsuitable for the construction of complex polymer architectures with, for instance, core±shell topology or defined cavities that would permit the entrapment and release of guests. Furthermore, due to intramolecular cyclization during the synthesis, hyperbranched polymers possess no defined single focal point, such as dendrimer segments (adendronso) that permits further monofunctionalization or attachment to a core as well as polymer chains.

Hyperbranched Polymers: Synthesis, Properties, and Applications

Written by leading scientists in academia and industry, this book provides for the first time a comprehensive overview of the topic, bringing together in one complete volume a wealth of information previously available only in articles scattered across the literature. Drawing on their work at the cutting edge of this dynamic area of research, the authors cover everything readers need to know about hyperbranched polymers when designing highly functional materials. Clear, thorough discussions include:

Multifunctional Poly(ethylene glycol)s

In the rapidly evolving multidisciplinary field of polymer therapeutics, tailored polymer structures represent the key constituent to explore and harvest the potential of bioactive macromolecular hybrid structures. In light of the recent developments for anticancer drug conjugates, multifunctional polymers are becoming ever more relevant as drug carriers. However, the potentially best suited polymer, poly(ethylene glycol) (PEG), is unfavorable owing to its limited functionality. Therefore, multifunctional linear copolymers (mf-PEGs) based on ethylene oxide (EO) and appropriate epoxide comonomers are attracting increased attention. Precisely engineered via living anionic polymerization and defined with state-of-the-art characterization techniques-for example real-time (1)H NMR spectroscopy monitoring of the EO polymerization kinetics-this emerging class of polymers embodies a powerful platform for bio- and drug conjugation.

Towards the Generation of Self-Healing Materials by Means of a Reversible Photo-induced Approach

Photo-induced reversibility as a tool for self-healing: a reversible photo-induced dendritic macromonomer was synthesized and proven to form networks with different features depending on the crosslinking conditions. While networks formed from aqueous systems exhibited a reversible change in their crosslinking degree, networks generated in bulk underwent fully reversibility. The latter was then exploited for generating self-healing materials by means of a photo-induced treatment.

Synthesis and noncovalent protein conjugation of linear-hyperbranched PEG-poly(glycerol) alpha,omega(n)-telechelics.

Linear-hyperbranched, heterobifunctional alpha,omega(n) telechelic block copolymers consisting of a linear poly(ethylene glycol) (PEG) chain and a hyperbranched polyglycerol (PG) block have been prepared in five steps, using a protected amino-functional initiator. The polyfunctionality omega(n) (OH groups) can be adjusted by the degree of polymerization (DP(n)) of the polyglycerol block. Subsequent introduction of a single biotin unit by amidation in alpha-position permitted noncovalent bioconjugation with avidin.