Dendrimers and hyperbranched polymers

Anne-Marie Caminade

Anne-Marie Caminade is Director of Research Exceptional Class (CNRS) and head of the “Dendrimers and Heterochemistry” group (LCC-Toulouse). After two PhDs and two Post-docs (IFP-Paris, Alexandre-von-Humboldt fellow (Saarbrücken)), she joined the CNRS (1985). She received the Organic Chemistry Prize of the French Chemical Society (2006). She is an Advisory Board Member for Chemical Society Reviews. She developed several aspects of phosphorus chemistry, including low coordinated compounds, transition metal coordination, and macrocycles. Her current research interest is on dendrimers, in particular for catalysis, nanomaterials and biology/nanomedicine. She is the author/co-author of over 400 publications, 40 book chapters and 30 patents (h index 56).

Deyue Yan

Deyue Yan completed his undergraduate studies at Nankai University in 1961 and graduated from Jilin University in 1965. He started to do research work at East China Institute of Chemical Technology in 1979. He moved to Shanghai Jiao Tong University as a professor in 1984. In the last century he mainly studied nonsteady state theory of polymerization kinetics and conformational statistics of polymers. His research interests then turned to the synthesis and applications of hyperbranched polymers, supramolecular self-assembly, surface modification of carbon nanotubes, drug delivery, etc. To date he has published more than 500 papers (h index 53), and was selected as an Academician of Chinese Academy of Sciences in 2005.

David K. Smith

Professor David K. Smith carried out his DPhil at University of Oxford with Prof. Paul Beer and was then Royal Society European Research Fellow with Prof. Francois Diederich at ETH Zurich. In 1999, he was appointed Lecturer in York, and in 2006 promoted to a Professorship. His research focuses on applying fundamental understanding of supramolecular science, particularly using dendritic molecular-scale architectures, to the self-assembly of nanomaterials and nanomedicines. He has received the RSC Corday Morgan Award for research excellence (2012), a Higher Education Academy National Teaching Fellowship (2013) and was recognised as one of the RSC's Diverse 175 Faces of Chemistry (2014).

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Dendrimers and hyperbranched polymers are hot topics which have attracted broad and persistent interest from both academic and industrial researchers due to their unique three-dimensional highly-branched topologies, multi-functionalities, special chemical and physical properties, and potential applications as catalysts, as materials, and for biology. This themed issue of Chemical Society Reviews on dendrimers and hyperbranched polymers displays selected and up-to-date reviews on hot topics. By no means is this themed issue a comprehensive account of all research carried out on dendrimers and hyperbranched polymers, but the reviews it contains are written by many of the most prominent authors in the field. We believe that researchers new to the area, as well as others actively engaged in this field, will find broad interest in this issue.

Despite their architectural resemblance at first glance, dendrimers and hyperbranched polymers are inherently different from each other in their topological structures. A dendrimer consists of two types of structural units: terminal units on the globular surface and dendritic units inside. As such, dendrimers are well defined in structure. On the other hand, a hyperbranched polymer has three types of structural units: dendritic units, linear units and terminal units. The terminal units are always located at the terminals, however, the dendritic units and linear units are randomly distributed within the macromolecular framework, resulting in irregular structures. The structural differences between dendrimers and hyperbranched polymers are ascribed to their different formation mechanisms, and can be further related to their different synthetic approaches. Dendrimers are synthesized step-by-step in an iterative fashion, most generally by a divergent process starting from a multifunctional core, as illustrated by the pioneers in the field Fritz Vögtle (poly(propyleneimine) PPI cascade synthesis in 1978),¹ Robert G. Denkewalter (poly(L-lysine) in 1981),² Donald A. Tomalia (poly(amidoamine) PAMAM in 1983/1985)³ who created the term “dendrimers”, and George R. Newkome (arborols in 1985).⁴ On the contrary, hyperbranched polymers are generally synthesized in one step, by a polymerization reaction. The concept of hyperbranched polymerisation was disclosed very early on by Paul J. Flory, in 1941.⁵ The consequence of their very different methods of synthesis is a much better structural definition for dendrimers, with low polydispersity and high reproducibility as compared to hyperbranched polymers, although the latter benefit from simple expedient synthesis and low cost. Seven reviews about dendrimers and six reviews about hyperbranched polymers (HBPs) can be found in this issue.

One of the most intriguing aspect of dendrimers is the so-called “dendrimer or dendritic effect”, somehow related to the multivalency effect, well known for biological interactions. Such an effect is observed when a functional group behaves differently when it is alone or linked to a dendrimer; its properties can even vary depending on the size (generation) of the dendrimer, and thus the number or density of terminal groups. The dendritic effect can be observed with any type of dendrimer, and for any type of property, even if it has been most generally investigated in catalysis and biology, and to a lesser extent in the field of materials. In a tutorial review, Anne-Marie Caminade et al. (DOI: 10.1039/c4cs00261j) show that the dendritic effect may enhance catalytic efficiency and enantioselectivity, and facilitate the recovery and reuse of catalytic entities linked to dendrimers. Furthermore, the properties of materials can be deeply modified when they are covered by dendrimers, or when they include dendrimers in their structure, and the efficiency of dendrimers for drug delivery or as drugs themselves may also strongly depend on the size/generation of the dendrimers.

Among all of the types of dendrimers, polyphenylene dendrimers (PPDs), consisting of substituted benzene rings, represent a unique class of compounds based on their rigid and shape persistent chemical structures. Klaus Müllen et al. (DOI: 10.1039/c4cs00245h) give an overview of the versatility of the synthesis of polyphenylene dendrimers through their site-specific chemical functionalization, to produce PPDs with a range of polarities. This is based on strategies that allow for the modification of PPDs at the core, scaffold, and surface to introduce numerous different groups, such as electrolytes, ions, or other polar species. The polyphenylene dendrimers have been synthetically tuned to be used in applications such as stable transition metal catalysts with controlled access to the catalytically active sites, sensors for volatile organic compounds, and nanocarriers to promote the uptake or encapsulation of guest molecules, in particular for biological drug delivery, able to cross the blood–brain barrier, among many others properties and applications.

Self-association of small branched compounds (also called dendrons), may afford original supramolecular architectures, as demonstrated in two papers. After an original introduction about how new chemical innovations occur, in particular in the pre-computer chemical age, and inspired by the architectural patterns of trees, George R. Newkome and Charles N. Moorefield (DOI: 10.1039/c4cs00234b) pre-designed 1 → 3 or 1 → (1 + 2) C-branched building blocks having inherent supramolecular potential and fractal qualities. Both the fractal design and supramolecular aspects can afford a large field of fractal materials that incorporate repeating geometries and which are derived by complementary building block recognition and assembly, in particular based on terpyridine complexes (terpyridine–M²⁺–terpyridine connectivities). Taking advantage of such materials, dendrimers and also a range of fractal objects featuring triangular macrocycles, square-shaped macrocycles, bow-tie or butterfly bicyclic macrocycles, various other rings differing in size and shape, bridged rhomboids, spoked wheels, Sierpinski triangles, and fibers have been synthesized.

In a tutorial review, Virgil Percec et al. (DOI: 10.1039/c4cs00249k) present giant supramolecular assemblies elaborated from self-assembling mini-dendrons, mini-dendrimers (first generation) and dendronized polymers (polymers bearing mini-dendrons as pendant groups). A combination of structural and retro-structural analysis could be used to demonstrate an 82% predictability of primary structures involved in giant supramolecular assemblies. Although, by definition, complex functional systems cannot be designed, this tutorial hints at a methodology based on database analysis principles to facilitate design principles that may help to mediate an accelerated emergence of chemical and physical complex systems. In many cases, the principles involved in the discovery and prediction of the primary structures of self-assembling mini-dendrons, mini-dendrimers, and polymers dendronized with mini-dendrons can be transposed without efforts of special additional structural analysis to their higher generations.

Carbohydrate-containing dendrimers have important biological properties, but carbohydrates are also very useful for the construction of dendrimers; both properties are demonstrated within two reviews. In a tutorial review, René Roy et al. (DOI: 10.1039/c4cs00359d) present a wide range of novel, dense, and chiral dendrimers based on carbohydrate building blocks present in the core (including oligomeric sugar scaffolds) or indeed anywhere in their structure, not only on the surface. When combined with the introduction of an “onion peel” synthetic strategy for layer-by-layer changes in repeat units, carbohydrates constitute powerful and versatile molecular structural components. Carbohydrates exist in enantiomeric states, several conformations, anomeric configurations, possess ranges of functional groups, and can have three to seven carbon units. Furthermore, since a few specific hydroxyl groups can be left intact during the construction process, and only be deprotected at the final stage, such structures offer clear advantages for biological applications or the directed introduction of functional probes. Hence, “glyconanosynthons” offer several advantages not yet accessible from other, more conventional building blocks and scaffolds.

Most carbohydrate-containing dendrimers are built with the sugar residues exposed at the surface for biological interaction with their cognate protein receptors. The review by Dietmar Appelhans, Barbara Klajnert-Maculewicz and Brigitte Voit et al. (DOI: 10.1039/c4cs00339j) presents the synthetic aspects of dendritic glycodendrimers based on polyamine scaffolds, and highlights their potential for biomedical applications. The review outlines the beneficial aspects of glycodendrimers for crossing the blood–brain barrier, for detection and treatment of neurodegenerative diseases, and for drug delivery. Targeting sugar-modified dendritic polyamine scaffolds partially facilitates the cellular uptake of drugs in specific cell lines (e.g. cancer or dendritic cells) and tissues (e.g. lung or liver). All of these oligosaccharide-decorated dendritic polyamine scaffolds have high in vitro and in vivo biocompatibilities compared to the parent dendritic polyamine macromolecules.

In a review article, Sonke Swenson (DOI: 10.1039/c5cs00288e) underlines the dendrimer paradox in relation to nanomedicine: high medical expectations but poor clinical translation. Indeed, this class of compound has not translated into the clinic at an appreciable level despite more than 30 years of research. This review focuses in particular on drug delivery with dendrimers, displaying the problems associated with the physical entrapment of drugs within dendrimers (when compared with competitive nanocarriers such as liposomes and polymersomes), with the chemical conjugation of drugs to dendrimers (which can alter physical behavior such as solubility), and with stochastic multifunctionalization, which results in poorly-defined compound mixtures (unlikely to pass regulatory revision and hence translate into the clinic). In the last part of the review, recent synthetic improvements that could overcome these problems are shown, with an opening towards dendronized polymers and hyperbranched polymers.

In contrast to dendrimers, hyperbranched polymers (HBPs) are easily synthesized in a one-step polymerization process. In a review article, Chao Gao et al. (DOI: 10.1039/c4cs00528g) display great developments in synthetic strategies, from click polymerization to recently reported multicomponent reactions. The degree of branching, molecular weight, and topology are also discussed, in connection with different types of synthetic methodologies. Post functionalization of HBPs, which can modify the periphery, as well as the backbone or the core, is often done in view of applications. Many examples of uses in fields ranging from photoelectric materials (light emitting materials, non-linear optical materials), nanotechnology (HBP-stabilized nanocrystals, in particular nanodots), biomedicine (supramolecular self-assemblies and encapsulation), surface coatings, nanocomposites, modifiers (toughening or reinforcing), sensors, adhesives, catalysts, and so forth are indicated. Most of these applications are detailed further within several reviews in this special issue.

Advanced optical, electrical and magnetic properties of functional hyperbranched polymers are presented in the review by Zhen Li et al. (DOI: 10.1039/c4cs00224e). Hyperbranched polymers with advanced optical properties (such as light-emitting materials, fluorescent hyperbranched chemosensors, fluorescent HBPs for bioimaging, and nonlinear optical materials), HBPs with advanced electrical properties, in particular as components of solar cells, such as as polymeric donors (although they were unable to form good heterojunctions when mixed with the acceptors), or as dye-sensitizers, and HBPs with magnetic properties, are presented. The conclusion of this review reflects on the future of HBPs and their comparison with dendrimers, hoping in particular to find a way to combine the easy one-step synthesis of hyperbranched polymers with the defect-free structure of dendrimers.

The characterization, formation mechanisms, properties and applications of vesicles obtained by the supramolecular self-assembly of hyperbranched polymers, also defined as branched-polymersomes (BPs), are described in the tutorial review presented by Yongfeng Zhou et al. (DOI: 10.1039/c4cs00274a). The most important outcomes of this relatively new field (first discovered in 2004) are summarized, displaying the syntheses of vesicle-forming hyperbranched polymers and the stability, permeability, functionalization, self-assembly methods and self-assembly mechanisms of BPs. Despite this extensive work connected to the synthesis, characterization and properties of BPs, studies on their applications are still at an early stage. A few examples concern cytomimetic applications (membrane fusion and fission, vesicle aggregation), fabrication of monodisperse nanoparticles, and imaging of both cellular and endosomal membranes with fluorescently labelled vesicles.

Three reviews present more specifically the biological applications of hyperbranched polymers. In a review article, Xinyuan Zhu, Wenxin Wang et al. (DOI: 10.1039/c4cs00229f) give a general overview of this topic. HBPs display attractive features like highly branched topological structures, spatial cavities, numerous terminal functional groups, convenient synthetic procedures, and unique physical/chemical properties. HBPs therefore afford unique advantages in biological and biomedical systems and devices, in particular for therapeutic applications. They have been used for drug delivery and release, for targeting, for gene transfection, and for protein delivery. They have also been used for bioimaging and diagnosis, as fluorescent probes, as MRI contrast agents, for nuclear tomographic imaging, and for multimodal imaging. HBPs have also been used for the biomineralization of calcium carbonate or silica, for tissue engineering, and for antimicrobial applications, to name a few.

The tutorial review presented by Wei Huang, Deyue Yan, et al. (DOI: 10.1039/c5cs00318k) focuses on a new type of HBPs, hyperbranched polyphosphates, comprised of repeating phosphate groups, which possess interesting biomedical applications. Owing to their excellent water solubility, biocompatibility (very low toxicity against different cell lines), enhanced cellular uptake efficiency, biodegradability, simple one-pot preparation and functionalization, HB polyphosphates have promising biomedical applications, such as potent anti-cancer agents (HB poly(diselenide-phosphate)), or as advanced drug delivery systems (self-delivery, stimuli-responsive delivery or smart delivery). Promising results have been obtained in vitro, but the behavior of such systems in vivo has not been presented to date.

The review by Rainer Haag et al. (DOI: 10.1039/c4cs00333k) explores the use of hyperbranched polymers as water-soluble nanocarriers for drugs, as well as for dyes and other guest molecules. Different types of HBPs are presented, together with their uses as nanocarriers – in particular HB polyethers, polyesters, polyethylenes, polystyrenes, poly(urea-urethanes), polyethylenimines, poly(amido amine)s, polyphosphates, polypeptides, polyacrylates, and β-cyclodextrins. On encapsulation of the guest, the properties of the host modify the fate of the guest, in particular its solubility, and the hyperbranched host can also shield the guest from the environment and protect it from degradation and deactivation. Nanocarriers based on dendritic polymers often exhibit excellent in vivo stability, but additional properties such as the degradability and/or elimination of the nanocarrier after the delivery, high stability on the shelf as well as under physiological conditions, and targeting of the diseased tissue are also desirable.

This themed issue on dendrimers and hyperbranched polymers displays the large diversity of structures and properties already known, in addition to many promising properties, in particular in the field of nanomedicine. Despite or because of the differences and similarities between dendrimers and hyperbranched polymers, both have found their own fields of use. For the future both areas need new design ideas and new synthetic strategies, to afford specifically engineered structures, depending on the desired targeted properties. In particular, methods such as orthogonal functionalisation and the controlled growth of non-symmetric structures, which allow precise and site-specific modification of these complex nanostructures, will become increasingly desirable. We would like to take this opportunity to thank all of the authors and co-authors who contributed to this exciting themed issue.

References

1. E. Buhleier, W. Wehner and F. Vögtle, Synthesis, 1978, 155–158.
2. R. G. Denkewalter, J. Kolc and W. J. Lukasavage, US Pat., US 4289872 A 19810915, 1981.
3. (a) D. A. Tomalia and J. R. Dewald, US Pat., 0456226 19830107, 1983; (b) D. A. Tomalia, H. Baker, J. Dewald, M. Hall, G. Kallos, S. Martin, J. Roeck, J. Ryder and P. Smith, Polym. J., 1985, 17, 117–132.
4. G. R. Newkome, Z. Yao, G. R. Baker and V. K. Gupta, J. Org. Chem., 1985, 50, 2003–2004.
5. P. J. Flory, J. Am. Chem. Soc., 1941, 63, 3083–3090.

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