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Special Issue "Dendrimers: A Themed Issue in Honor of Professor Donald A. Tomalia on the Occasion of His 80th Birthday"

A special issue of Molecules (ISSN 1420-3049).

Deadline for manuscript submissions: closed (5 March 2018)

Special Issue Editor

Guest Editor
Prof. Dr. Ashok Kakkar

Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, Quebec, H3A 0B8, Canada
Website | E-Mail
Interests: nanostructures; soft nanoparticles; macromolecules; dendrimers; miktoarm polymers; telodendrimers, naked nanocarriers; metal nanoparticles; gold nanoshells; iron oxide nanoparticles; nanomedicine; drug delivery; diagnostics

Special Issue Information

Dear Colleagues,

Dr. Donald A. Tomalia, one of the pioneers in the development of monodisperse and highly branched macromolecules, who coined the term “Dendrimers” in 1985 in reference to their tree like structure, has played a key role in establishing their place in polymer chemistry, and provided continued inspiration to many in expanding the scope and potential of these well-defined architectures. The divergent synthetic methodology to dendrimers, coupled with the convergent approach developed by Dr. Jean Fréchet, provided access to and an insight into the unique properties offered by these spherical macromolecules, which sparked an explosive growth of the dendrimer field. With excellent contributions of several leaders that followed, dendrimers have demonstrated potential and find applications in numerous areas including medicine, catalysis, sensors, etc.

“Molecules” is highly pleased to host a Themed Issue honoring Dr. Donald A. Tomalia for his outstanding achievements in advancing the field of dendrimers on the occasion of his 80th birthday.

Dr. Donald Tomalia obtained his B.A. in Chemistry from University of Michigan, subsequently joined Dow Chemical, and while there, completed his PhD in physical-organic chemistry from Michigan State University under the direction of Professor Harold Hart. His initial studies on cationic polymerization were recognized by international industrial awards for creative research in 1978 and 1986, and followed by another similar award in 1991 for the discovery of dendrimers. He has received several other accolades including Leonardo da Vinci award (1996) and Society of Polymer Science Japan award (2003) for discovering dendritic polymers. He worked at Michigan Molecular Institute from 1990-1999 in the capacity as Professor and Director. He currently serves as Adjunct Professor in the Department of Chemistry at the University of Pennsylvania. He co-founded Dendritech in 1992, the first supplier of commercially available dendrimers, founded Dendritech Nanotechnologies in 2002 in collaboration with Starpharma, and is currently the founder and CEO of Nanosynthons. Dr. Tomalia has authored/co-authored more than 200 peer-reviewed publications including books on dendrimers, and holds more than 100 dendrimer-based patents in the USA. He is an Associate Editor of Journal of Nanoparticle Research (Springer), and on the Honorary Editorial Board of Nanomedicine: Nanotechnology, Biology and Medicine (Elsevier). He is a Faculty Member in Faculty 1000 Prime.

Molecules invites scientists to submit original contributions to “Dendrimers: A Themed Issue in Honor of Professor Donald A. Tomalia on the Occasion of his 80th Birthday”, and join us in collectively congratulating him for his outstanding accomplishments.

Prof. Dr. Ashok Kakkar
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Dendrimers
  • Dendrons
  • Hyperbranched macromolecules
  • Divergent and convergent methodologies
  • Dendrimer conjugates
  • Metallodendrimers
  • Dendrimers in biomedicine
  • Light harvesting dendrimers
  • Dendrimers-based catalysis
  • Supramolecular dendrimers
  • Dendrimers for drug and gene delivery
  • Dendrimer-based sensors
  • Dendrimers as blood substitutes

Published Papers (12 papers)

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Editorial

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Open AccessFeature PaperEditorial A Serendipitous Journey Leading to My Love of Dendritic Patterns and Chemistry
Molecules 2018, 23(4), 824; https://doi.org/10.3390/molecules23040824
Received: 30 March 2018 / Revised: 1 April 2018 / Accepted: 2 April 2018 / Published: 4 April 2018
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Abstract
As the oldest of four Midwestern boys who were offsprings of an accountant and a housewife, each with less than a formal high school degree, we were blessed to have such parents.[...] Full article

Research

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Open AccessFeature PaperArticle Preferential and Increased Uptake of Hydroxyl-Terminated PAMAM Dendrimers by Activated Microglia in Rabbit Brain Mixed Glial Culture
Molecules 2018, 23(5), 1025; https://doi.org/10.3390/molecules23051025
Received: 20 March 2018 / Revised: 18 April 2018 / Accepted: 20 April 2018 / Published: 27 April 2018
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Abstract
Polyamidoamine (PAMAM) dendrimers are multifunctional nanoparticles with tunable physicochemical features, making them promising candidates for targeted drug delivery in the central nervous system (CNS). Systemically administered dendrimers have been shown to localize in activated glial cells, which mediate neuroinflammation in the CNS. These
[...] Read more.
Polyamidoamine (PAMAM) dendrimers are multifunctional nanoparticles with tunable physicochemical features, making them promising candidates for targeted drug delivery in the central nervous system (CNS). Systemically administered dendrimers have been shown to localize in activated glial cells, which mediate neuroinflammation in the CNS. These dendrimers delivered drugs specifically to activated microglia, producing significant neurological improvements in multiple brain injury models, including in a neonatal rabbit model of cerebral palsy. To gain further insight into the mechanism of dendrimer cell uptake, we utilized an in vitro model of primary glial cells isolated from newborn rabbits to assess the differences in hydroxyl-terminated generation 4 PAMAM dendrimer (D4-OH) uptake by activated and non-activated glial cells. We used fluorescently-labelled D4-OH (D-Cy5) as a tool for investigating the mechanism of dendrimer uptake. D4-OH PAMAM dendrimer uptake was determined by fluorescence quantification using confocal microscopy and flow cytometry. Our results indicate that although microglial cells in the mixed cell population demonstrate early uptake of dendrimers in this in vitro system, activated microglia take up more dendrimer compared to resting microglia. Astrocytes showed delayed and limited uptake. We also illustrated the differences in mechanism of uptake between resting and activated microglia using different pathway inhibitors. Both resting and activated microglia primarily employed endocytotic pathways, which are enhanced in activated microglial cells. Additionally, we demonstrated that hydroxyl terminated dendrimers are taken up by primary microglia using other mechanisms including pinocytosis, caveolae, and aquaporin channels for dendrimer uptake. Full article
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Open AccessArticle Dendrimeric Antigens for Drug Allergy Diagnosis: A New Approach for Basophil Activation Tests
Molecules 2018, 23(5), 997; https://doi.org/10.3390/molecules23050997
Received: 5 March 2018 / Revised: 6 April 2018 / Accepted: 20 April 2018 / Published: 24 April 2018
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Abstract
Dendrimeric Antigens (DeAns) consist of dendrimers decorated with multiple units of drug antigenic determinants. These conjugates have been shown to be a powerful tool for diagnosing penicillin allergy using in vitro immunoassays, in which they are recognized by specific IgE from allergic patients.
[...] Read more.
Dendrimeric Antigens (DeAns) consist of dendrimers decorated with multiple units of drug antigenic determinants. These conjugates have been shown to be a powerful tool for diagnosing penicillin allergy using in vitro immunoassays, in which they are recognized by specific IgE from allergic patients. Here we propose a new diagnostic approach using DeAns in cellular tests, in which recognition occurs through IgE bound to the basophil surface. Both IgE molecular recognition and subsequent cell activation may be influenced by the tridimensional architecture and size of the immunogens. Structural features of benzylpenicilloyl-DeAn and amoxicilloyl-DeAn (G2 and G4 PAMAM) were studied by diffusion Nuclear Magnetic Resonance (NMR) experiments and are discussed in relation to molecular dynamics simulation (MDS) observations. IgE recognition was clinically evaluated using the basophil activation test (BAT) for allergic patients and tolerant subjects. Diffusion NMR experiments, MDS and cellular studies provide evidence that the size of the DeAn, its antigen composition and tridimensional distribution play key roles in IgE-antigen recognition at the effector cell surface. These results indicate that the fourth generation DeAns induce a higher level of basophil activation in allergic patients. This approach can be considered as a potential complementary diagnostic method for evaluating penicillin allergy. Full article
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Open AccessFeature PaperArticle Dendrimers for Drug Delivery
Molecules 2018, 23(4), 938; https://doi.org/10.3390/molecules23040938
Received: 26 March 2018 / Revised: 13 April 2018 / Accepted: 15 April 2018 / Published: 18 April 2018
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Abstract
Dendrimers have come a long way in the last 25 years since their inception. Originally created as a wonder molecule of chemistry, dendrimer is now in the fourth class of polymers. Dr. Donald Tomalia first published his seminal work on Poly(amidoamine) (PAMAM) dendrimers
[...] Read more.
Dendrimers have come a long way in the last 25 years since their inception. Originally created as a wonder molecule of chemistry, dendrimer is now in the fourth class of polymers. Dr. Donald Tomalia first published his seminal work on Poly(amidoamine) (PAMAM) dendrimers in 1985. Application of dendrimers as a drug delivery system started in late 1990s. Dendrimers for drug delivery are employed using two approaches: (i) formulation and (ii) nanoconstruct. In the formulation approach, drugs are physically entrapped in a dendrimer using non-covalent interactions, whereas drugs are covalently coupled on dendrimers in the nanoconstruct approach. We have demonstrated the utility of PAMAM dendrimers for enhancing solubility, stability and oral bioavailability of various drugs. Drug entrapment and drug release from dendrimers can be controlled by modifying dendrimer surfaces and generations. PAMAM dendrimers are also shown to increase transdermal permeation and specific drug targeting. Dendrimer platforms can be engineered to attach targeting ligands and imaging molecules to create a nanodevice. Dendrimer nanotechnology, due to its multifunctional ability, has the potential to create next generation nanodevices. Full article
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Open AccessFeature PaperArticle Fluorescent Dendritic Micro-Hydrogels: Synthesis, Analysis and Use in Single-Cell Detection
Molecules 2018, 23(4), 936; https://doi.org/10.3390/molecules23040936
Received: 21 March 2018 / Revised: 10 April 2018 / Accepted: 11 April 2018 / Published: 18 April 2018
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Abstract
Hydrogels are of keen interest for a wide range of medical and biotechnological applications including as 3D substrate structures for the detection of proteins, nucleic acids, and cells. Hydrogel parameters such as polymer wt % and crosslink density are typically altered for a
[...] Read more.
Hydrogels are of keen interest for a wide range of medical and biotechnological applications including as 3D substrate structures for the detection of proteins, nucleic acids, and cells. Hydrogel parameters such as polymer wt % and crosslink density are typically altered for a specific application; now, fluorescence can be incorporated into such criteria by specific macromonomer selection. Intrinsic fluorescence was observed at λmax 445 nm from hydrogels polymerized from lysine and aldehyde- terminated poly(ethylene glycol) macromonomers upon excitation with visible light. The hydrogel’s photochemical properties are consistent with formation of a nitrone functionality. Printed hydrogels of 150 μm were used to detect individual cell adherence via a decreased in fluorescence. The use of such intrinsically fluorescent hydrogels as a platform for cell sorting and detection expands the current repertoire of tools available. Full article
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Open AccessArticle On-Demand Bioadhesive Dendrimers with Reduced Cytotoxicity
Molecules 2018, 23(4), 796; https://doi.org/10.3390/molecules23040796
Received: 22 March 2018 / Revised: 22 March 2018 / Accepted: 27 March 2018 / Published: 30 March 2018
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Abstract
Tissue adhesives based on polyamidoamine (PAMAM) dendrimer, grafted with UV-sensitive aryldiazirine (PAMAM-g-diazirine) are promising new candidates for light active adhesion on soft tissues. Diazirine carbene precursors form interfacial and intermolecular covalent crosslinks with tissues after UV light activation that requires no premixing or
[...] Read more.
Tissue adhesives based on polyamidoamine (PAMAM) dendrimer, grafted with UV-sensitive aryldiazirine (PAMAM-g-diazirine) are promising new candidates for light active adhesion on soft tissues. Diazirine carbene precursors form interfacial and intermolecular covalent crosslinks with tissues after UV light activation that requires no premixing or inclusion of free radical initiators. However, primary amines on the PAMAM dendrimer surface present a potential risk due to their cytotoxic and immunological effects. PAMAM-g-diazirine formulations with cationic pendant amines converted into neutral amide groups were evaluated. In vitro toxicity is reduced by an order of magnitude upon amine capping while retaining bioadhesive properties. The in vivo immunological response to PAMAM-g-diazirine formulations was found to be optimal in comparison to standard poly(lactic-co-glycolic acid) (PLGA) thin films. Full article
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Open AccessFeature PaperArticle Epitaxially Grown Ultra-Flat Self-Assembling Monolayers with Dendrimers
Molecules 2018, 23(2), 485; https://doi.org/10.3390/molecules23020485
Received: 17 January 2018 / Revised: 13 February 2018 / Accepted: 14 February 2018 / Published: 23 February 2018
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Abstract
Mono-molecular films formed by physical adsorption and dendrimer self-assembly were prepared on various substrate surfaces. It was demonstrated that a uniform dendrimer-based monolayer on the subnanometer scale can be easily constructed via simple dip coating. Furthermore, it was shown that an epitaxially grown
[...] Read more.
Mono-molecular films formed by physical adsorption and dendrimer self-assembly were prepared on various substrate surfaces. It was demonstrated that a uniform dendrimer-based monolayer on the subnanometer scale can be easily constructed via simple dip coating. Furthermore, it was shown that an epitaxially grown monolayer film reflecting the crystal structure of the substrate (highly ordered pyrolytic graphite (HOPG)) can also be formed by aligning specific conditions. Full article
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Open AccessArticle Design and Synthesis of Dendrimers with Facile Surface Group Functionalization, and an Evaluation of Their Bactericidal Efficacy
Molecules 2017, 22(6), 868; https://doi.org/10.3390/molecules22060868
Received: 5 May 2017 / Revised: 18 May 2017 / Accepted: 18 May 2017 / Published: 24 May 2017
Cited by 4 | PDF Full-text (1697 KB) | HTML Full-text | XML Full-text
Abstract
We report a versatile divergent methodology to construct dendrimers from a tetrafunctional core, utilizing the robust copper(I) catalyzed alkyne-azide cycloaddition (CuAAC, “click”) reaction for both dendrimer synthesis and post-synthesis functionalization. Dendrimers of generations 1–3 with 8–32 protected or free OH and acetylene surface
[...] Read more.
We report a versatile divergent methodology to construct dendrimers from a tetrafunctional core, utilizing the robust copper(I) catalyzed alkyne-azide cycloaddition (CuAAC, “click”) reaction for both dendrimer synthesis and post-synthesis functionalization. Dendrimers of generations 1–3 with 8–32 protected or free OH and acetylene surface groups, were synthesized using building blocks that included acetylene- or azide-terminated molecules with carboxylic acid or diol end groups, respectively. The acetylene surface groups were subsequently used to covalently link cationic amino groups. A preliminary evaluation indicated that the generation one dendrimer with terminal NH3+ groups was the most effective bactericide, and it was more potent than several previously studied dendrimers. Our results suggest that size, functional end groups and hydrophilicity are important parameters to consider in designing efficient antimicrobial dendrimers. Full article
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Open AccessArticle Cation, Anion and Ion-Pair Complexes with a G-3 Poly(ethylene imine) Dendrimer in Aqueous Solution
Molecules 2017, 22(5), 816; https://doi.org/10.3390/molecules22050816
Received: 12 April 2017 / Revised: 12 May 2017 / Accepted: 12 May 2017 / Published: 16 May 2017
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Abstract
The G-3 poly(ethylene imine) ligand L2 shows a multifaceted coordination ability, being able to bind metal cations, anions and ion-pairs. The equilibrium constants for the formation of metal (Cu2+, Zn2+), anion (SO42−) and ion-pair (Cu2+
[...] Read more.
The G-3 poly(ethylene imine) ligand L2 shows a multifaceted coordination ability, being able to bind metal cations, anions and ion-pairs. The equilibrium constants for the formation of metal (Cu2+, Zn2+), anion (SO42−) and ion-pair (Cu2+/SO42−) complexes were determined in 0.1 M Me4NCl aqueous solution at 298.1 ± 0.1 K by means of potentiometric titrations. Thanks to its dendrimeric nature, L2 can form highly nucleated metal complexes, such as Cu5L210+ and Zn4L28+, in successive and well-defined complexation steps. Protonated forms of L2 give rise to relatively weak anion complexes with SO42−, but the addition of Cu2+ significantly enhances the binding ability of the ligand toward this anion below pH 9. In more alkaline solutions, an opposite trend is observed. The coordination properties of L2 are discussed with the support of modelling calculations. According to results, L2 is a promising molecule for the preparation of solid supported materials for the recovery of cations and anions from aqueous media and/or for applications in heterogeneous catalysis. Full article
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Review

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Open AccessFeature PaperReview Dentromers, a Family of Super Dendrimers with Specific Properties and Applications
Molecules 2018, 23(4), 966; https://doi.org/10.3390/molecules23040966
Received: 22 March 2018 / Revised: 16 April 2018 / Accepted: 18 April 2018 / Published: 20 April 2018
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Abstract
Dentromers (from dentro, δεντρο: tree in Greek), and meros (μεροσ, in greek: part) are introduced as a family of dendrimers constructed according to successive divergent 1 → 3 branching. The smaller dentromers have 27 terminal branches. With alcohol termini they were originally
[...] Read more.
Dentromers (from dentro, δεντρο: tree in Greek), and meros (μεροσ, in greek: part) are introduced as a family of dendrimers constructed according to successive divergent 1 → 3 branching. The smaller dentromers have 27 terminal branches. With alcohol termini they were originally named arborols by Newkome, who pioneered 1 → 3 constructions of dendrimers and dendrons. Giant dentromers have been constructed and decorated in particular with ferrocene and other redox active groups. The synthesis, specific properties, and applications are examined in this mini review article dedicated to Don Tomalia, with an emphasis on dense peripheral packing favoring the functions of encapsulation, redox sensing, and micellar template for catalysis in water and aqueous solvents. Full article
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Open AccessReview Hyperbranched Macromolecules: From Synthesis to Applications
Molecules 2018, 23(3), 657; https://doi.org/10.3390/molecules23030657
Received: 11 February 2018 / Revised: 9 March 2018 / Accepted: 10 March 2018 / Published: 14 March 2018
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Abstract
Hyperbranched macromolecules (HMs, also called hyperbranched polymers) are highly branched three-dimensional (3D) structures in which all bonds converge to a focal point or core, and which have a multiplicity of reactive chain-ends. This review summarizes major types of synthetic strategies exploited to produce
[...] Read more.
Hyperbranched macromolecules (HMs, also called hyperbranched polymers) are highly branched three-dimensional (3D) structures in which all bonds converge to a focal point or core, and which have a multiplicity of reactive chain-ends. This review summarizes major types of synthetic strategies exploited to produce HMs, including the step-growth polycondensation, the self-condensing vinyl polymerization and ring opening polymerization. Compared to linear analogues, the globular and dendritic architectures of HMs endow new characteristics, such as abundant functional groups, intramolecular cavities, low viscosity, and high solubility. After discussing the general concepts, synthesis, and properties, various applications of HMs are also covered. HMs continue being materials for topical interest, and thus this review offers both concise summary for those new to the topic and for those with more experience in the field of HMs. Full article
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Open AccessFeature PaperReview Which Dendrimer to Attain the Desired Properties? Focus on Phosphorhydrazone Dendrimers
Molecules 2018, 23(3), 622; https://doi.org/10.3390/molecules23030622
Received: 12 February 2018 / Revised: 6 March 2018 / Accepted: 7 March 2018 / Published: 9 March 2018
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Abstract
Among the six Critical Nanoscale Design Parameters (CNDPs) proposed by Prof. Donald A. Tomalia, this review illustrates the influence of the sixth one, which concerns the elemental composition, on the properties of dendrimers. After a large introduction that summarizes different types of dendrimers
[...] Read more.
Among the six Critical Nanoscale Design Parameters (CNDPs) proposed by Prof. Donald A. Tomalia, this review illustrates the influence of the sixth one, which concerns the elemental composition, on the properties of dendrimers. After a large introduction that summarizes different types of dendrimers that have been compared with PolyAMidoAMine (PAMAM) dendrimers, this review will focus on the properties of positively and negatively charged phosphorhydrazone (PPH) dendrimers, especially in the field of biology, compared with other types of dendrimers, in particular PAMAM dendrimers, as well as polypropyleneimine (PPI), carbosilane, and p-Lysine dendrimers. Full article
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