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Dendritic Building Blocks

By: 1Dr. Michael Malkoch and 2Dr. Andreas M. Nyström, Material Matters, 2012 v7, n3
1Associate Professor, Division of Coating Technology, Fibre and Polymer Technology, KTH Royal Institute of Technology, and Chief Technology Officer, Polymer Factory Sweden AB
2Associate Professor of Nanomedicine, Swedish Medical Nanoscience Center, Karolinska Institutet, Chief Executive Officer, Polymer Factory Sweden AB

Dr. Michael Malkoch and Dr. Andreas M. Nyström

Introduction: Click-ready Dendritic Building Blocks

Dendrimers and dendrons are symmetrically branched polymer structures that possess a well-defined spatial distribution of functional groups. These dendritic materials have attracted considerable interest due to their monodisperse nature and other unique properties such as enhanced solubility and reduced viscosity, relative to their linear analogues. A range of advanced applications have been proposed for dendrimers and dendrons in diverse areas such as drug delivery, diagnostic imaging, hydrogels, catalysis, and as optical materials.1

Despite the breadth of applications available, most of the current research activities of dendrimers and dendrons has, up to recent years, been 1) restricted to exclusive academic research groups with in-depth knowledge in dendrimer chemistry and 2) limited to a small number of commercially accessible dendritic building blocks, mainly PAMAM dendrimers. Recently, a range of polyester dendrons and poly(ethylene glycol) (PEG) dendrimers based on the bis-MPA (2,2-bis(methylol) propionic acid) building block were made available to researchers globally by Aldrich® Materials Science. Polymer Factory, offering hyperbranched polymers, dendrimers, and dendrons to the market since 2006, is known for high quality dendritic structures and materials. This article will showcase some recent advances and applications of these materials, utilizing different types of click chemistries including thiol-ene and azide-acetylene conjugations.2

Click chemistry was introduced in 2001 by Prof. K. B. Sharpless3 and today covers a set of highly reliable and synthetically simple chemical reactions known to proceed in a wide range of solvents, including organic and aqueous conditions, with high conversions in short reaction times. The introduction of popular "clickable groups" such as primary acetylenes (-C=CH), organic azides (-N3), thiols (-SH), or unsaturated vinylic (-CH-CH2) groups to dendritic structures enables their exploration by non-chemists as well. Using these functional groups, dendrimers and dendrons based on bis-MPA have been successfully conjugated to bioactive moieties, such as carbohydrate, disaccharides, fluorescent dyes, etc. and then evaluated in solution as well as on surfaces.

Scheme 1. Click-ready dendritic building blocks.

Biological Applications

Polyester dendrimers and dendrons based on the bis-MPA building block have been extensively explored for biological applications involving in vitro4 toxicological studies and in vivo5-10 via radionuclide labeling and optical imaging. As recently shown in a study utilizing human primary macrophages as a model for immunoactivation and toxicity,4 bis-MPA based dendritic materials and building blocks have low or no toxicity, are degradable under physiological conditions, and do not show immunogenic properties, which is of utmost importance in biomedical applications. In the in vivo setting, biodistribution (BioD) studies of high generation dendrons (up to 7th generation) show these materials do not demonstrate any specific organ accumulation in healthy rats via radiolabeling of the focal point and imaging via singlephoton emission computed tomography (SPECT).9 Fréchet and his research team11 spent considerable efforts to modulate blood circulation time of chemotherapeutic conjugated bis-MPA dendrimers by coupling PEG chains to the surface of the dendrimer.7 The dendrimers were tuned with respect to circulation time allowing for substantial increases in tumor specific uptake and low bystander tissue uptake (Scheme 2). A dendrimer based drug delivery system with one of the best efficacy and survivability rates reported in the literature was developed by combining dendrimers with a potent and often clinically employed chemotherapeutic, such as doxorubicin.7

The monodisperse nature of dendrons allows researchers to create their own dendritic-drug conjugate with considerably lower variation in molecular weight compared to linear polymers, while allowing the drug candidate to be modified in a modular fashion using various forms of chemistry tailored to the diverse set of functionalities offered on the dendrons, -SH/-allyl, -N3/-acetylene, -COOH/-NH2.

Scheme 2. Drug delivery applications of bis-MPA dendrimers, (left) dendritic bow-tie structure with poly(ethylene glycol) chains on one side for tailored pharma-co-kinetics and chemotherapeutics (Doxorubicin) on the other side. (Right, top) structure of Doxorubicin, (right, bottom) typical release behavior of a hydrozone linked pH triggered pharmaceutical.7

Engineering Applications and the Construction of Multivalent Surfaces and Gels

Dendron building blocks are highly interesting as scaffolds for the creation of multivalent binding systems in biosensor applications, as well as the construction of surfaces where the high density of functional groups can be advantageous. A recent paper by Malkoch et al. attached acetylene functional bis-MPA dendrons to filter paper via copper catalyzed click chemistry.2 The surface groups of the dendrons were post-functionalized with mannose, creating a lectin binding sensor with increased sensitivity compared to mono-mannosylated surfaces (Scheme 3).12 Similarly, asymmetric dendrimers can be coupled to a Janus-type structure using complementary azide/acetylene dendrons bridging different functionalities.13 Thiol-containing dendrons can be utilized in copper-free thiol-ene click chemistry for the construction of advanced functional nanomaterials, including complementary dendrons bearing thiol and ene focal points. Thiols also allow for functionalization of gold surfaces in a robust manner, where high functional group density allows for post-functionalization of gold surfaces.14

Other advanced applications include dip-pen nanolithography based click chemistry with bis-MPA dendrons bearing focal point azides and acetylene functional silicon wafers as substrates.15 This general strategy can be further developed from its initial laboratory proof of principle to dip-pen lithography of surface functional dendrons that offer both precise tailoring of the spatial resolution and high density functionality. These functional dendrons can also be used for the creation of tailored linear-dendritic polymers with tunable hydrophilicity to create novel block copolymers that form ordered isoporous membranes.16 Gilles et al. have recently shown several beautiful examples of effective postfunctionalization of nanoscale vesicles, polymer micelles,17 and iron oxide nanoparticles18 bearing click-ready groups on the surface. They tuned the nanostructures using functional bis-MPA dendrons bearing fluorescent moieties. Such applications open a new area for nanoparticle functionalization, utilizing the dendrons to provide multivalent interactions for tissue specific targeting in nanomedicine applications.

In addition to functional dendrons, dendritic PEGs are another type of click ready material now commercially available. Materials comprised of a PEG core flanked by functional dendrons have been used to construct advanced hydrogels with superior mechanical properties such as high elongation at break and flexibility in terms of additives that can be incorporated into the gels prior to crosslinking.19,20 Aida et al. have explored such structures for the construction of aerogels in which guanidinium groups on PEG bis-MPA dendrimers exfoliate nanoclay and form free-standing moldable and self-healing gels with only 2-3 weight % of solid content.21

Scheme 3. Click chemistry applications of bis-MPA dendrons of surface functionalization.12

Outlook

A complete set of dendrons and linear-dendritic PEG hybrids made commercially available with varying size and functionalities opens a horizon of new possibilities for researchers to explore and develop novel dendritic materials. Dendritic polymers, due to their unique properties, have been successfully utilized in a range of advanced applications from hydrogels for engineering and biomedical applications, to nanoscale surface modification, and the development of novel biosensors and molecular imaging agents. Furthermore, bis-MPA based materials have shown superior properties in terms of their lack of in vitro toxicity, in vivo compatibility, and high efficacy towards cancer in drug delivery systems.

Materials

     

 References

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