Use Of Dendrimers Research Articles

Dendrimer a versatile polymer in drug delivery

Dendrimers are a unique class of synthetic macromolecules having highly branched, three-dimensional, nanoscale architecture with very low polydispersity and high functionality. Structural advantages allow dendrimers to play an important role in the fields of nanotechnology, pharmaceutical and medicinal chemistry. This review discusses several aspects of dendrimers, including preparation, dendrimer-drug coupling chemistry, structural models of dendrimer-based drug delivery systems, and physicochemical and toxicological properties. Dendrimers have emerged as one of the most interesting themes for researchers as a result of their unique architecture and macromolecular characteristics. Several groups are involved in exploring their potential as versatile carriers in drug delivery. The use of dendrimers in drug delivery has been reviewed extensively. The increasing relevance of the potential of dendrimers in drug delivery emphasizes the need to explore the routes by which they can be administered. The high level of control possible over the architectural design ofdendrimers; their size, shape, branching length/density, and their surface functionality clearly distinguish these structures as unique and optimum carriers in those applications. The bioactive agents may be encapsulated into the interior of the dendrimers or chemically attached/physically adsorbed onto the dendrimer surface, with the option of tailoring the carrier to the specific needs of the active material and its therapeutic applications. This review clearly demonstrates the potential of this new fourth major class of polymer architecture and indeed substantiates the high hopes for the future of dendrimers.

Changes in gene expression pattern of human primary macrophages induced by carbosilane dendrimer 2G-NN16.

The use of dendrimers for biomedical applications has emerged with promising results. 2G-NN16 is a carbosilane dendrimer with sixteen positive charges per molecule tested to be capable to bind and release antisense oligonucleotides (ODNs) and small interference RNA (siRNA) in vitro. In spite of low cytotoxicity observed for these dendrimers, little is known about cellular changes they produce in cells in general and in immune cells in particular. Genomic technologies allow us to identify global gene expression profile changes in macrophages exposed to a non-toxic concentration (5 microM) of 2G-NN16, alone or complexed with a random siRNA (dendriplex). Results were confirmed by quantitative real-time RT-PCR. Exposing macrophages to this dendrimer or dendriplex causes multiple gene expression changes, but no specific action of random siRNA was detected. Pathway analysis of differentially expressed genes shows the altered functions to be immune response, proliferation and transcription regulation. Interleukin 17F (IL17F) was the most regulated gene. Global gene expression profiles are a highly sensitive method to measure the toxicity degree of a gene delivery vehicle. The strong repression of IL17F, IL23R and IL23A, all of which are involved in autoimmune disease, by this particular dendrimer suggests a potential pharmacological application.

Applications of Dendrimers in Tissue Engineering

Despite the wide-spread use of dendrimers in biomedical applications, their use in the fabrication of tissue engineering scaffolds has been limited. The highly branched, multivalent nature of dendrimers makes them ideal candidates for a variety of tissue engineering applications, including as crosslinking agents, modulators of surface charge and surface chemistry, and as primary components in scaffolds that mimic natural extracellular matrices. Compared to linear polymers, the multiple end groups of dendrimers may potentially offer more control over factors such as cell proliferation rates and biodegradation profiles through systematic variation of generation size, concentration, and end group chemistry. The combination of dendrimers and other traditional scaffold polymers, such as proteins, carbohydrates, and linear synthetic polymers has led to the creation of hybrid scaffolds with new physical, mechanical, and biochemical properties. This review describes examples where dendritic macromolecules have been incorporated into scaffolds for the regeneration of a variety of tissues and cell types and highlights areas where dendrimers have yet to be utilized.

Dendrimeric phosphines in asymmetric catalysis

Dendrimers are hyperbranched nanosized and precisely defined molecules, attracting increasing attention each year due to their numerous properties in catalysis, materials science, and biology. This tutorial review concerns the use of dendrimers as catalysts and focuses more precisely on their properties as enantioselective catalysts. Emphasis is put on chiral phosphine complexes constituting the core or the end groups of various types of dendrimers. The effect of the location of the catalytic entities, the effect of the size (generation) and the nature of the dendritic skeleton on the enantiomeric excesses are discussed.

Design, Synthesis and Potent Pharmaceutical Applications of Glycodendrimers:A Mini Review

Dendrimers are a new class of artifical macromolecules with well-defined hyperbranched structures which endue these promising materials with a wide variety of applications. They are useful tools in drug discovery and allow bio-active molecules to be presented in a highly multi-valent fashion on the surface. Recently, the use of dendrimers as scaffolds of carbohydrates to synthesize glycodendrimers with high and specific affinities to various receptors has made it possible for these dendritic materials to participate in extracellular and intracellular biochemical processes. References on synthesis and biological applications of glycodendrimers in the literatures demonstrate that dendrimers are suitable candidates as scaffolds of these bioactive carbohydrates. In this mini-review, different approaches to construct glycodendrimers as well as their promising applications in biological systems are fully discussed.

Design and construction of nickel hexacyanoferrate – Starburst PAMAM dendrimer modified gold electrodes for the potentiometric detection of potassium in aqueous media

Potentiometric sensors for potassium detection were prepared by chemical modification of polycrystalline gold electrodes with sub-monolayers of 3-mercaptopropionic acid or 2-aminoethanethiol (SC and SA, respectively) followed by the covalent attachment of PAMAM dendrimers (generation 4.0, DA, and 3.5, DC, respectively) in order to obtain films suitable for further electrostatic adsorption of nickel hexacyanoferrate (NiHCF) complexes. The characterization of the resulting electroactive layers by cyclic voltammetry (CV) experiments showed that the use of dendrimers in the synthesis of the films not only enhances the surface coverage of NiHCF when compared to thiol modified electrodes, but also the electroanalytic performance of the modified surfaces for the detection and quantification of potassium in aqueous medium under controlled ionic strength ( I) conditions.

Dendrimer-Based Prodrugs: Design, Synthesis, Screening and Biological Evaluation

Dendrimers are a new class of artificial macromolecules with well-defined hyperbranched structures which enable bio-active molecules such as drugs to be presented in a highly multi-valent fashion. Covalent conjugation of drugs to the surface of dendrimers can be easily achieved either by direct chemical reactions between dendrimers and drug molecules including esterification and amidation or through cleavable linkers, depending on the functional groups on the surface of dendrimers. The pharmacological properties of these dendrimer-based prodrugs such as biocompatibility, biodistribution, biostability, bioadhesion and biopermeability can be modulated by further modifying dendrimers with specific functional molecules to fit a specific medicinal purpose. In this mini-review, recent advances on the use of dendrimers as prodrug nano-scaffolds were briefly demonstrated. The design and synthesis of dendrimer-based prodrugs as well as screening their intrinsic properties in biological systems were fully discussed.

Molecular design and photophysical criteria for lanthanide emission enhancement in erbium(III)-cored complexes based on dendritic ligands for information technology

Recently, luminescent lanthanide complexes have considerable interest because of their academic interests and potential utility in a wide variety of photonic applications, such as planar waveguide amplifiers, plastic lasers, lightemitting diodes, and luminescent probes. The 4f electrons in lanthanide (Ln) ions are slightly perturbed by the effects of lattice phonons and static strain fields in the coordination environment of ions, since the f-electrons are shielded by the outer 5s and 5p electrons. It leads to the sharp spectral line-like emission bands. Also, the forbidden 4f -4f n electronic transitions renders the low absorption and emission cross-section of lanthanide ions, while luminescent lifetime is relatively long. To overcome these shortcomings, recently, luminescent ligands are being used to excite Ln ions via an energy transfer from the luminescent ligands to the Ln ions. In most cases, the luminescent Ln ions are usually coordinated to the organic luminescent ligands, acting as sensitizers or antenna chromophores, which efficiently absorb and transfer light to excite Ln ions via energy transfer process. This sensitization process is much more effective than the direct excitation of Ln ions, since the absorption coefficients of organic chromophores are many orders of magnitude larger than the intrinsically low molar absorption coefficients (typically 1-10 M cm) of Ln ions. Recently, several research groups have focused on developing the efficient artificial light-harvesting (LH) lanthanide complexes, in which the use of dendrimers for light harvesting systems has been widely demonstrated. The encapsulation of luminescent Ln ions into a luminescent dendrimer can lead to a system capable of shielding central Ln ion from nonradiative environment and efficiently transferring excited energy from the peripheral chromophores to the focal point of the dendrimer. For example, Frechet et al. have reported the site isolation and antenna effects on luminescent properties of spherical lanthanide(III)-cored dendrimer complexes. Although its spectral overlap integral (J) between the emission band of peripheral antenna and the absorption band of Ln ions was not satisfactorily large to obtain the effective energy transfer, the Frechet arylether typed dendrons were widely used as light-harvesting antenna. Moreover, very recently, to enhance the near-infrared (NIR) emission intensity and maintain the effective energy transfer process, our research efforts have been focused on developing stable and inert Er(III)-encapsulated complexes with artificial light-harvesting systems using dendritic luminescent ligands based on metalloporphyrins, naphthalenes, and anthracenes bearing the Frechet aryl-ether dendrons, namely, (Er3+-[Gn-Pt-Por]3(terpy), Er 3+-[Gn-Naph]3(terpy) and Er3+-[Gn-An]3(terpy)). We observed that the NIR emission intensity of the lanthanide complexes was dramatically enhanced with increasing the generation number (n) of the Frechet aryl-ether dendrons, due to the site-isolation and light-harvesting effects. Two possible energy transfer (ET) pathways for the sensitized emission in luminescent Ln(III) complexes have been suggested, as schematically illustrated in Scheme I. It is well-believed that in general only energy transfer from the

Dendrimers as drug delivery vehicles: non-covalent interactions of bioactive compounds with dendrimers.

This mini review highlights issues associated with the use of dendrimers as drug delivery vehicles. The review introduces dendrimers and summarizes findings on their use in vivo and in vitro. Specifically, this review is limited to examples wherein the drug is non-covalently associated with the dendrimer. Examples wherein the drug is covalently attached to the dendrimer are not discussed.

Dendrimer Based Anti-Infective and Anti-Inflammatory Drugs

Alternatives to traditional antibiotics and to antiviral and anti-inflammatory drugs are much in need and the molecular design and development of anti-infective compounds constitute a pivotal area in modern medicinal research. Dendrimers are a relatively new class of structurally well-defined, i.e. monodisperse, synthetic polymers with hyperbranched structures which enable a given molecular motif to be presented in a highly multivalent fashion. Several types of dendrimers with various structural elements and molecular dimensions are commercially available at an affordable price. The surface of dendrimers can be modified relatively easily and, depending on the surface motif, the pharmacological properties of the dendrimer such as cytotoxicity, bacteriocidal and virucidal effect, biodistribution and biopermeability may be modulated to fit a specific medicinal purpose. Dendrimers are thus highly suitable tools in drug discovery and they allow the synthesis of molecules with high and specific binding affinities to a wide variety of receptors, viruses and bacteria. Hence the use of dendrimers for the development of antiviral or antibacterial drugs, destroying the infective agent or disrupting multivalent binding interactions between the infective agent and cells of the host organism has become a highly active research field. The wide range of applications reported for the use of dendrimers as anti-infective and anti-inflammatory drugs in the patent literature demonstrates the general applicability of these molecules as drug candidates. The present review will briefly treat the intrinsic properties of dendrimers in biological systems, as well as general concerns regarding the treatment of infective diseases. The use of dendrimers as anti-infective and anti-inflammatory drugs will be based on a thorough review of the recent patent literature.

Dendrimers As Drugs: Discovery, Preclinical and Clinical Development of SPL7013 Gel (VivaGel™), a Dendrimer Based Microbicide for HIVand STI Prevention

Starpharma focuses on the use of dendrimers as drugs in their own right – in contrast to dendrimers as drug delivery vehicles or diagnostics. Dendrimers offer a unique platform for exploring chemical diversity on the nanoscale and the production of dendrimer libraries covering a diverse array of macromolecular structures can be used in drug discovery and development. One pharmaceutical application of dendrimers that Starpharma is pursuing is the development of microbicides for the prevention of HIV and sexually transmitted infections (STIs). This presentation will describe the dendrimer drug discovery and lead candidate selection process from which SPL7013 emerged as a microbicide development candidate. Pivotal preclinical data will be presented that lead to Starpharma submitting an Investigational New Drug application (IND) for SPL7013 gel (VivaGelTM) to the United States Food and Drug Administration (FDA) in June 2003, the first such submission for a dendrimer based drug. Finally, results of the first clinical trial under this IND will presented. from 2005 International Meeting of The Institute of Human Virology Baltimore, USA, 29 August – 2 September 2005

Dendrimers and Antivirals: A Review

In response to the need for antiviral agents, dendrimers, hyper-branched, well-defined, and chemically versatile molecules, have been found to have a number of potential uses. How they are used is based on knowledge of 1) how a virus interacts with its target cells, 2) how it replicates, and 3) which viral components are recognized by the immune response of the host. Many viral-host cell interactions are initiated by viral proteins binding to specific cell surface carbohydrates. Dendrimers offer an efficient means of presenting multiple ligands, or sites of contact, on a single molecule. Derivatized with carbohydrate residues, the multivalent ligands have been shown to inhibit viral binding. Dendrimers derivatized with peptides or anionic groups have also been found to inhibit infection. The availability of a number of different types of dendrimers permits synthesis of potential inhibitors of viral binding to be tailored to meet the dimensions needed for optimum adherence by the virus. Future directions should see increased studies of the use of dendrimers as carriers of 1) multiple indicators on a viral probe to increase diagnostic sensitivity, 2) multiple peptides for use as immunogens or as inhibitors of viral binding, and 3) inhibitors of viral enzymes. While the field of dendrimer chemistry is relatively young, promising results indicate that dendrimers may provide the scaffolding needed for development of effective antivirals.

En Route to Complete Design of Heterogeneous Catalysts

AbstractFor Abstract see ChemInform Abstract in Full Text.

Dendrimers as Drugs: Discovery and Preclinical and Clinical Development of Dendrimer-Based Microbicides for HIV and STI Prevention

Starpharma focuses on the use of dendrimers as drugs in their own right, in contrast to dendrimers as drug delivery vehicles or diagnostics. This contextual review describes how dendrimers offer a unique platform for exploring chemical diversity on the nanoscale and how the production of dendrimer libraries covering a diverse array of macromolecular structures can be used in drug discovery and development. Using Starpharma's work on the prevention of HIV and sexually transmitted infections (STIs) through the development of microbicide candidates as an example, the process from which SPL7013 emerged as a development candidate is described. Following a range of preclinical studies, Starpharma submitted an investigational new drug application (IND) for SPL7013 gel (VivaGel) to the United States Food and Drug Administration (FDA) in June 2003, the first such submission for a dendrimer-based drug. The first clinical trial under this IND was completed in 2004.

Dendritic NanoTechnologies, Inc.

At recent FDA conferences focused on the potential of nanotechnology, Tomalia gave a presentation on the significance of dendrimers as fundamental nanoscale building blocks and their unique applications as a function of generation. For example, generation-7, -8, or -9 dendrimers may have applications as nano-scaffolding for gene vectors; generation-4, -5, or -6 dendrimers may be useful as nanocontainers in small-molecule drug delivery. The FDA’s Center for Drug Evaluation and Research (CDER), in particular, takes an active position in educating scientists about the unique regulatory issues nanomedicine presents.DNT is also pursuing the scaffolding idea to improve diagnostic imaging. In 1994, Tomalia, in collaboration with 2003 Nobel laureate and magnetic resonance imaging (MRI) researcher Paul C. Lauterbur, PhD at the University of Illinois and others co-published the first paper showing the importance of dendrimer scaffolding by demonstrating that conjugating high multiples of a gadolinium chelate contrast agent on the surface of a dendrimer produced the highest relaxivity measurements known. Relaxivity is a technical process used to improve the contrast of MRI images. The higher the relaxivity, the better the contrast. The dendrimer-based imaging product achieved relaxivity ratings between 40 and 50. By comparison, Magnevist, a commercial chelated gadolinium contrast agent, has a relaxivity rating of approximately 4.0–5.0. “With these enhanced contrast properties, we have the potential to detect disease at a much earlier stage,” says Tomalia. The past 11 years have seen the publication of dozens of papers that used dendrimers as scaffolding to present MRI contrast agents. “They have allowed entirely new in vivo diagnostics of vascular systems, ischemia, tumor diagnostics (primary and metastatic) at incredibly high resolutions,” explains Tomalia. “You can image things never possible before.” In September 2004, an NCI/NIH examination of the 10-year preclinical research history of dendrimer-based contrast agents suggested that these materials are ready for IND approval consideration.DNT, in collaboration with the MIT Institute for Soldier Nanotechnologies and a consortium of other nanotechnology-inclusive companies such as Carbon Nanotechnologies, Inc., Triton Biosystems, Nomadics, Inc., and Dow Corning are also investigating the use of dendrimer nanotechnology innovations to protect U.S. soldiers in the field. Tomalia’s former colleague James Baker also started NanoProtect, a commercial venture with similar goals. Baker also founded two other nanotechnology-based entities, NanoBio Corporation and NanoCure Corporation. NanoCure, in particular, pursues product pipeline similar to that of DNT and also applies dendrimer technology.Though dendrimers represent only one approach to nanotechnology, they appear to hold significant potential as fundamental building blocks for nanoscale synthesis for biological and industrial applications. And DNT, although still a small, 20-person, privately held venture, is well positioned to offer new contributions to the field.

En route to complete design of heterogeneous catalysts

Achieving complete control in the synthesis of the active center of a heterogeneous catalyst, which includes the active site, environment around the active site, and the access path is highly desirable but not attainable yet. However, there has been significant progress in recent years that permits a level of control of these properties that are unachievable before. Some illustrative examples are described to demonstrate this in the synthesis of active sites in metal and oxide catalysts and their surroundings. For the active site synthesis, examples include using polynuclear metal complexes as precursors, cluster beam deposition, and use of dendrimers to generate metallic active sites, protection of coordination unsaturation in the synthesis of oxide active sites, and employing silsesquioxane, and unit-by-unit approach. Exfoliation, use of inverse micelles, molecular and macromolecular templating as techniques to exert control of the environment of the active center are also discussed. The limitations of these synthetic methods and remaining challenges are examined.

Dendrimers in Drug Research

AbstractFor Abstract see ChemInform Abstract in Full Text.

Dendrimers in drug research.

Dendrimers are versatile, derivatisable, well-defined, compartmentalised chemical polymers with sizes and physicochemical properties resembling those of biomolecules e.g. proteins. The present critical review (citing 158 references) briefly describes dendrimer design, nomenclature and divergent/convergent dendrimer synthesis. The characteristic physicochemical features of dendrimers are highlighted, showing the effect of solvent pH and polarity on their spatial structure. The use of dendrimers in biological systems are reviewed, with emphasis on the biocompatibility of dendrimers, such as in vitro and in vivo cytotoxicity, as well as biopermeability, biostability and immunogenicity. The review deals with numerous applications of dendrimers as tools for efficient multivalent presentation of biological ligands in biospecific recognition, inhibition and targeting. Dendrimers may be used as drugs for antibacterial and antiviral treatment and have found use as antitumor agents. The review highlights the use of dendrimers as drug or gene delivery devices in e.g. anticancer therapy, and the design of different host-guest binding motifs directed towards medical applications is described. Other specific examples are the use of dendrimers as 'glycocarriers' for the controlled multimeric presentation of biologically relevant carbohydrate moieties which are useful for targeting modified tissue in malignant diseases for diagnostic and therapeutic purposes. Finally, the use of specific types of dendrimers as scaffolds for presenting vaccine antigens, especially peptides, for use in vaccines is presented.

Evaluations of Unformulated and FormulatedDendrimer-Based Microbicide Candidates in Mouse and Guinea PigModels of GenitalHerpes

Prevention of sexually transmitted infections is a priority in developed and developing countries. One approach to prevention is the use of topical microbicides, and one promising approach is the use of dendrimers, highly branched macromolecules synthesized from a polyfunctional core. Three new dendrimer products developed to provide stable and cost-efficient microbicides were initially evaluated in vitro for anti-herpes simplex virus activity and then in vivo by using a mouse model of genital herpes. From these experiments one product, SPL7013, was chosen for further evaluation to define the dose and duration of protection. Unformulated SPL7013 provided significant protection from genital herpes disease and infection at concentrations as low as 1 mg/ml and for at least 1 h following topical (intravaginal) administration of 10 mg/ml. This compound was then formulated into three vehicles and further evaluated in mouse and guinea pig models of genital herpes infection. In the murine evaluations each of the formulations provided significant protection at concentrations of 10 and 50 mg/ml. Formulated compounds provided protection for at least 1 h at a concentration of 10 mg/ml. From these experiments formulation 2V was chosen for dose ranging experiments using the guinea pig model of genital herpes. The guinea pig evaluations suggested that doses of 30 to 50 mg/ml were required for optimal protection. From these studies a lead compound and formulation (2V of SPL7013) was chosen for ongoing evaluations in primate models of simian immunodeficiency virus and Chlamydia trachomatis infection.

Towards dendrimers as biomimetic macromolecules

Dendrimers can be obtained in precise molecular weights even at high generations. This feature, as well as the inherent globular shape of high generation dendrimers, makes them ideal candidates for macromolecular biomimetics. In this account, we discuss the synthesis and use of dendrimers that are reminiscent of macromolecular architectures present in nature. In particular, we focus the use of dendrimers in the areas of encapsulation, functionalization, and sequencing. To cite this article: S. Thayumanavan et al., C. R. Chimie 6 (2003).