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Anthelmintic activity of chicory (Cichorium intybus): in vitro effects on swine nematodes and relationship to sesquiterpene lactone composition
- ANDREW R. WILLIAMS, MIGUEL A. PEÑA-ESPINOZA, ULRIK BOAS, HENRIK T. SIMONSEN, HEIDI L. ENEMARK, STIG M. THAMSBORG
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- Journal:
- Parasitology / Volume 143 / Issue 6 / May 2016
- Published online by Cambridge University Press:
- 03 March 2016, pp. 770-777
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Chicory is a perennial crop that has been investigated as a forage source for outdoor-reared ruminants and pigs, and has been reported to have anthelmintic properties. Here, we investigated in vitro anthelmintic effects of forage chicory-extracts against the highly prevalent swine parasites Ascaris suum and Oesophagostomum dentatum. Methanol extracts were prepared and purified from two different cultivars of chicory (Spadona and Puna II). Marked differences were observed between the anthelmintic activity of extracts from the two cultivars. Spadona extracts had potent activity against A. suum third (L3) and fourth (L4) – stage larvae, as well as O. dentatum L4 and adults, whereas Puna II extracts had less activity against A. suum and no activity towards O. dentatum L4. Transmission-electron microscopy of A. suum L4 exposed to Spadona extracts revealed only subtle changes, perhaps indicative of a specific anthelmintic effect rather than generalized toxicity. Ultra-high liquid chromatography-mass spectrometry analysis revealed that the purified extracts were rich in sesquiterpene lactones (SL), and that the SL profile differed significantly between cultivars. This is the first report of anthelmintic activity of forage chicory towards swine nematodes. Our results indicate a significant anthelmintic effect, which may possibly be related to SL composition.
Dendrimers, Dendrons, and Dendritic Polymers
- Discovery, Applications, and the Future
- Donald A. Tomalia, Jørn B. Christensen, Ulrik Boas
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- 05 November 2012
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- 18 October 2012
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Dendrimer science has exploded onto the polymer science scene as the fourth major class of polymer architecture. Capturing the history of dendrimer discovery to the present day, this book addresses all the essential information for newcomers and those experienced in the field, including:Fundamental theory, chemistry and physics of the 'dendritic state'Synthetic strategies (click chemistry, self-assembly, and so on)Dendron/dendrimer characterization techniquesArchitecturally driven 'dendritic effects' Developments in scientific and commercial applicationsConvergence with nanotechnology, including dendrimer-based nanodevices, nanomaterials, nanotoxicology and nanomedicine Dendrimers as a window to a new nano-periodic system. Including first-hand accounts from pre-1995 pioneers, progress in the dendrimer field is brought to life with anticipated developments for the future. This is the ideal book for researchers in both academia and industry who need a complete introduction to the 'dendritic state' with a special focus on dendrimer and dendron polymer science.
6 - Toxicology of dendrimers and dendrons
- Donald A. Tomalia, Jørn B. Christensen, University of Copenhagen, Ulrik Boas, Technical University of Denmark, Lyngby
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- Dendrimers, Dendrons, and Dendritic Polymers
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Summary
Introduction
Interest in pharmaceuticals, especially their benefits to human health and toxicology has a long history. Although the earliest activities were oriented toward benefits to health, it is also well known that there was substantial interest in the toxicology aspects of this field. As early as Roman times there was considerable political interest in design of certain potions as effective poisons for shortening life. Subsequent to this early history, legitimate pharmaceutical activities focused on preservation, remediation, and extension of life. These activities emerged in Europe as early as the twelfth century. One of the first pharmacies established in 1241 is still operational in Trier, Germany.
The pharmaceutical industry in the United States is much younger and its origins can be traced to the Philadelphia area. More than a half dozen fine chemical manufacturers founded as early as 1822 are still in existence today. This activity launched the beginning of the modern pharmaceutical industry as we know it. This movement manifested a shift from manufacturing of medicines in pharmacy laboratories to formal construction of manufacturing plants for this purpose. Throughout this period, drug reactions and benefits were documented as doctors and pharmacists compounded and administered medicines to patients.
Concurrent with the growth of this industry was an explosive growth and expansion of traditional small molecule chemistry. This parallel development of traditional chemistry led to the introduction of many small molecule inorganic/ organic therapies. Some of these therapies were beneficial while others were harmful to society and the industry. These early pharmaceutical candidates were both synthetic and natural in origin. They became the scientific platform and basis for the commercial activity of essentially all major pharmaceutical companies worldwide.
Frontmatter
- Donald A. Tomalia, Jørn B. Christensen, University of Copenhagen, Ulrik Boas, Technical University of Denmark, Lyngby
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- Dendrimers, Dendrons, and Dendritic Polymers
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Contents
- Donald A. Tomalia, Jørn B. Christensen, University of Copenhagen, Ulrik Boas, Technical University of Denmark, Lyngby
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- Dendrimers, Dendrons, and Dendritic Polymers
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4 - Characterization methodologies
- Donald A. Tomalia, Jørn B. Christensen, University of Copenhagen, Ulrik Boas, Technical University of Denmark, Lyngby
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- Dendrimers, Dendrons, and Dendritic Polymers
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Summary
The challenges of defining structures in a new, unprecedented polymer architecture
Characterization methodologies are a critical component for all the natural sciences. Appropriate protocols are required that both identify as well as define new entities within specific systems under investigation. Staudinger originally introduced the concept of polymers as covalent macromolecules [1, 2]. Shortly after his concept gained acceptance the important and seminal question arose: How does one characterize these new polymer entities? Traditional polymers at their inception were viewed as completely new classes of chemical structure and material. Unlike simple, monodisperse structures normally associated with traditional low molecular weight organic and inorganic compounds, these polymers were accessible only as polydisperse mixtures of macromolecular structures. Many traditional analytical/characterization methods developed for small molecules were of very limited use for these new materials. Polymers do not have boiling points. In many cases they were amorphous, not crystalline and were produced with variable compositions that were often dependent on the way they were synthesized. As a consequence, traditional characterization and elemental analyses were often meaningless. Methods developed for characterization of polymers not only reflected the fact that polymers are polydisperse mixtures of covalent compounds, but also that they are large molecules of unprecedented nanoscale dimensions.
In this context, both dendrimers and dendrons may be thought of as well-defined macromolecular compounds that exhibit features reminiscent of both small molecule and macromolecular regimes. More specifically, they are well-defined, quantized molecules in the classical sense of organic chemistry, yet they are also large polymeric, molecules of nanoscale dimensions. As a consequence, both small molecule and large molecule techniques are generally used in a convergent and collective fashion in order to characterize and define all dendrimers and dendrons. In the early, emerging days of the dendritic polymer field, substantial rejection was encountered concerning the very existence of these dendrimer and dendron structures.
7 - The dendritic effect
- Donald A. Tomalia, Jørn B. Christensen, University of Copenhagen, Ulrik Boas, Technical University of Denmark, Lyngby
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- Dendrimers, Dendrons, and Dendritic Polymers
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Summary
Introduction/definitions
The descriptor “dendritic effects” is a collective term widely used since the 1990s to describe unusual physico-chemical property patterns or trends observed for dendrons/dendrimers as a function of their generation level. These properties may be either maximized (i.e. a positive effect) or minimized (i.e. a negative effect) within a dendron/dendrimer series. A dendritic effect is referred to as either a positive or negative effect depending on whether it was accentuated or attenuated as a function of generation level. The term was generally used in an empirical sense to describe generation-dependent physico-chemical property patterns that were initially assumed to be dependent upon nanoscale sizes associated with the generation. However, accumulated evidence now reveals that these effects are dependent on more subtle parameters than mere size variations. The object of this chapter is to analyze these subtle dependences in an effort to gain insights into the cause–effect principles and predictive value of these dendritic effects. Understanding these nano-periodic property relationships should assist in dendrimer design optimization for both function and applications.
Some of the earliest dendritic effects were reported by Tomalia et al. [1–3], Astruc et al. [4] and Seebach et al. [5]. Undoubtedly, there are similar architecturally driven effects associated with the other three major polymer architectures (i.e. linear, crosslinked, and branched); however, they are generally less quantifiable due to their polydisperse structures. In any case, dendrons/dendrimers exhibit architecturally driven properties that are dramatically different to those observed for equivalent architectural isomeric types (i.e. linear, bridged (crosslinked), or branched) possessing common elemental compositions and molecular weights. In the context of a new emerging nano-periodic concept, described later in Chapter 8, dendritic effects may now be viewed as intrinsic and functional nano-periodic property patterns. In all cases they display a first-order dependency upon one of the critical nanoscale design parameters (CNDPs), namely, architecture. However, it must also be noted that dendritic effects are inextricably influenced by one or more interrelated CNDPs such as (a) size, (b) shape, (c) surface chemistry, (d) flexibility/rigidity, or (e) elemental composition, as illustrated in Figure 7.1 and 7.8. Both physical and chemical nanoscale properties are influenced by these well-defined CNDPs. This results in the manifestation of unique, intrinsic features, a few which are listed in the left and right hand columns in Figure 7.1. Many of these issues have been examined extensively elsewhere [73].
3 - Synthetic methodologies
- Donald A. Tomalia, Jørn B. Christensen, University of Copenhagen, Ulrik Boas, Technical University of Denmark, Lyngby
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- Dendrimers, Dendrons, and Dendritic Polymers
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Synthesis of dendritic polymers – a fourth major new architectural class
In traditional small molecule chemistry it is widely recognized that their structures may be categorized architecturally as: (I) linear, (II) bridged, and (III) branched types as shown in Figure 3.1. Seminal work by Vögtle and Buhleier [1] provided first examples of new non-traditional cascade type molecules. These structures are now recognized as small molecule examples of a fourth new architectural type, namely dendritic molecules. Since the introduction of Staudinger’s macromolecular hypothesis in the 1920s, three major polymer architectures have defined all traditional polymer types. Paralleling small molecule chemistry, all traditional macromolecular architectures were categorized into three major types, namely; (I) linear, (II) cross-linked (bridged) and (III) branched structures. Since the early 1980s these traditional polymer architectures have been joined by a fourth new major class of macromolecular architecture, namely dendritic macromolecules [2, 3]. This fourth class of dendritic polymers was distinguished from traditional polymer types, based on new intrinsic properties [2, 4–6]. These new properties are unlike any of those found in the three traditional architectural types and are often referred to as “dendritic effects” (see Chapter 7).
A multitude of synthetic strategies has been reported for preparation of dendritic materials since their discovery in the late 1970s-early 1980s and this has led to a broad range of methodologies and structures. Presently, this dendritic architectural class consists of four subclasses, namely: (IVa) random hyperbranched polymers, (IVb) dendrigraft polymers, (IVc) dendrons, and (IVd) dendrimers (Figure 3.2). The order of these subsets, Figure 3.2 from (a) to (d), reflects the polydispersity associated with the methodologies to produce each of these subsets and may be generally referred to as: (IVa) statistical, (IVb) semi-controlled and (IVc,d) controlled dendritic structures [7, 8].
5 - Nanomedical and advanced materials
- Donald A. Tomalia, Jørn B. Christensen, University of Copenhagen, Ulrik Boas, Technical University of Denmark, Lyngby
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Summary
Diagnostics
Immunoassays
The dense presentation of terminal functional groups found on the surface of dendrimers makes these nano-structures ideal for enhancement of signal amplification in diagnostic applications. For example, in solid-phase bioassays, dendrimers may be used as structural components to increase the density of immobilized detector molecules. This increases the ability to bind smaller amounts of target analytes in a biological sample, thereby increasing assay sensitivity. Furthermore, in monitoring of critical biological events during the assay, dendrimers are interesting candidates as unique scaffolds for fluorophore groups. This is important where the dense fluorophoric surface presentation of the dendrimer may lead to increased quantum yields (i.e. depending on Stokes’ shift), and in turn fluorescence intensity. For this reason, a broad range of assays involving dendrimers is being investigated as critical components in new more highly sensitive assays.
Dendrimers may be used to enhance both the covalent and non-covalent binding capacities of surfaces used for heterogeneous assays. For example, they are being considered in such enzyme-linked immuno-sorbent assays as ELISA, (polystyrene), microarray (glass) types as well as certain biosensor protocols involving gold surfaces and plasmon surface resonance spectroscopy. In all cases these protocols involve non-covalent binding of detection molecules to the surface; however, an alternative, covalent binding may be used to increase the stability and selectivity of the assay. In most cases, however, simply increasing the surface binding capacity markedly enhances the assay sensitivity. Therefore, by introducing higher concentrations of biological detector molecules at these surfaces one may generally expect to enhance both kinetics and analytical sensitivities for these assays. It is from this perspective that polyvalent nano-structures such as dendrimers with their dense multivalent surfaces are expected to be ideal candidates for this purpose.
1 - Introduction
- Donald A. Tomalia, Jørn B. Christensen, University of Copenhagen, Ulrik Boas, Technical University of Denmark, Lyngby
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- Dendrimers, Dendrons, and Dendritic Polymers
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Summary
Background/historical
Pervasive architecture and functional patterns found in nature
The Greek terms dendri-, dendrites, dendritic are root word descriptors for branching or treelike structures. These terms describe some of the most pervasive architectural patterns observed on our planet [1]. Before the early 1980s [2–4] all dendritic architectures and networks were known only as naturally occurring structures/entities found either in the abiotic world (e.g. snow crystals, lightning patterns, erosion/tributary river network fractals) or in the biological realm. In biological systems, these dendritic patterns are found at length scales ranging from meters (trees), millimeters/centimeters (vascular/circulatory systems in plants and animals, Golgi domains (organelles), fungi), microns (neurons) to nanometers (IgM antibodies, amylopectins and proteoglycans) as illustrated in Figure 1.1. Certain randomly branched, dendritic architectures were hypothesized by Nobel Laureate P. Flory as early as the 1940s to describe theoretical polymer intermediates in crosslinking events [5]. However, it was not until the late 1970s that the first examples of such dendritic architecture were intentionally synthesized and rigorously characterized in a laboratory. These first dendritic structures were synthesized both as core-shell-type, small molecules, and macromolecules. The widely recognized terms – dendrimers/dendrons (i.e. dendri [branched] and mer [part of] – were first coined and introduced by Tomalia in 1983 [6] to describe these compositionally broad and diverse categories of precisely defined core-shell, dendritic structures. A typical dendrimer family derived from a core and surrounded by radial shells (i.e. generations) of covalently connected branched monomers is illustrated in Figure 1.1.
It was soon realized that these newly discovered dendritic structures could be synthesized with a very wide range of diverse elemental compositions (i.e. both organic and inorganic). Furthermore, it was found that they could be obtained with unprecedented mono-dispersity and extraordinary structure control as a function of (a) size, (b) shape, (c) surface chemistry, (d) flexibility/rigidity, (e) architecture, and (f) composition. Unlike traditional synthetic polymers, these synthetic macromolecules were routinely synthesized with structure control normally associated only with highly precise biological polymers such as proteins, DNA, and RNA.
9 - The past, present, and future for dendrons and dendrimers
- Donald A. Tomalia, Jørn B. Christensen, University of Copenhagen, Ulrik Boas, Technical University of Denmark, Lyngby
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Summary
Pre-1980s
Before the early 1980s, the possibility of synthesizing and isolating discrete tree-like, macromolecular structures was considered to be an impossible challenge [1]. However, such hypothetical, tree-like entities were often visualized and proposed as transient intermediates by Flory to explain his pioneering concepts in the area of gelation theory during the early 1940s [2–4]. Flory’s seminal work ultimately led to recognition of the second major macromolecular polymer (architecture) after Staudinger’s linear architecture, namely, cross-linked polymers. The traditional polymer world during this era was quite simple. All synthetic polymers at that time were classified into two major categories based on physico-chemical properties. They were referred to as either (I) thermoplastics or (II) thermosets as described earlier (Chapter 1, Section 1.1.2, Figure 1.3). The very first examples of simple branched polymer architectures were just beginning to emerge. The notion of polymeric architecture consisting of “branches upon branches” was not in the vocabulary of polymer scientists at that time. However, it is noteworthy that Flory occasionally made references to “tree branching” polymeric architecture. He often used this architectural term as a visual for describing transient hyperbranched species that he hypothesized were involved in pathways to the “crosslinked” or “gelation state.” These vague but prophetic concepts were soon demonstrated experimentally toward the end of the 1970s, and led to the fourth major class of macromolecular architecture, namely; “dendritic polymers.”
Metaphorically speaking, dendrons are now referred to as “nanoscale molecular trees.” Anatomically, the tree root is the focal point (i.e. apex) of the dendron, whereas the interior consists of amplified branching layers growing from the root, and these are terminated by the molecular tree leaves (Z) or surface moieties of the dendron. As described in Chapter 1, the term dendrimer, coined by Tomalia et al. [5], is now a widely accepted scientific term or descriptor [6] for multiples or clusters of these nanoscale trees. More specifically, dendrimers are discrete, soft matter nano-building blocks.
2 - The dendritic state
- Donald A. Tomalia, Jørn B. Christensen, University of Copenhagen, Ulrik Boas, Technical University of Denmark, Lyngby
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- Dendrimers, Dendrons, and Dendritic Polymers
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- 18 October 2012, pp 25-112
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Summary
Introduction
Historically, each of the three traditional macromolecular architectural classes (i.e. I. Linear, II. Cross-linked, III. Branched) have opened very rich polymer science frontiers. The importance of each major architectural class is apparent from the recognition they have received based on named Nobel laureates and new emerging applications; as shown in Figure 2.1. These traditional polymer architecture discoveries have been characterized by the emergence of new syntheses, structures, properties, and products that have not only advanced polymer science but also dramatically improved the human condition during this past century [1, 2].
In the past decade, nanotechnology initiatives have created an international focus on new “bottom-up” synthesis strategies. These synthesis strategies are focused on new nanostructures, phenomena and properties associated with dimensional length scales residing between 1–100 nm [3–5]. These dimensions encompass many key biological building blocks (i.e. protein, DNA, RNA, etc.) and critical biological applications (i.e. nanomedicine, drug delivery, nano-pharmaceuticals), as well as abiotic application areas of interest (i.e. nano-photonics, nano-electronics). This chapter focuses on an emerging, fourth major class of polymer architecture, namely, the dendritic architectural state and the implications of its convergence with traditional polymer science and nanoscience [6, 7].
Index
- Donald A. Tomalia, Jørn B. Christensen, University of Copenhagen, Ulrik Boas, Technical University of Denmark, Lyngby
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- Dendrimers, Dendrons, and Dendritic Polymers
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8 - A quantized building block concept leading to a new nano-periodic system
- Donald A. Tomalia, Jørn B. Christensen, University of Copenhagen, Ulrik Boas, Technical University of Denmark, Lyngby
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- Dendrimers, Dendrons, and Dendritic Polymers
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- 18 October 2012, pp 293-377
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Summary
Introduction
The role of traditional chemistry as a scientific discipline and its impact on society and the human condition has been immeasurable. The central paradigm for this science is quite simply based on quantized atom building blocks and their discrete electron activity leading to bonding and assembly of these units. The ability to use intrinsic elemental periodic property patterns (i.e. the Mendeleev Periodic Table) for predicting physico-chemical properties, defining risk/benefit boundaries, and designing new molecular structures has rested solidly on the existence of a systematic scientific framework (i.e. central dogma) for the discipline. This systematic framework has not only served to unify and define traditional small molecule chemistry, but has also evolved into a platform of understanding for many related activities in physics, engineering, biology, and medicine. Although opinions may vary concerning the order of importance and content of such a framework, a general consensus usually includes the major discoveries and events set out in Table 8.1 [1–3].
First principles and central dogma for traditional chemistry
Building on A. Lavoisier’s reactive atom hypothesis and J. Proust’s proposal that atoms possess well-defined masses relative to each other, it was possible for J. Dalton to propose his atom/molecular theory, which is described in a simplified form below [3]. These statements are a modern paraphrase of Dalton’s revolutionary publication, A New System of Chemical Philosophy (1808), that launched traditional chemistry as it is recognized today.