Current Topics in Medicinal Chemistry - Volume 8, Issue 14, 2008

There is no doubt that in science in the 21st century, developments in the field of the so-called Nanosciences will feature widely. Nanosciences deal with nanomolecules and their applications, particularly those in materials science and biomedicine. Biomedical applications of nanomolecules can be said to have originated with the development of polymer chemistry and these applications have now been extended with the appearance of dendrimers, the hyperbranched nanomolecules that are considered to be a fourth class of polymers. It is now almost 30 years since the groups of D. Tomalia in the laboratories of Dow Chemicals, F. Vögtle at the University of Bonn and G. Newkome at the University of Louisiana prepared hyperbranched macromolecules that, from the point of view of their structure, exhibited substantial differences from known conventional polymers. These were originally given various names but the term “dendrimer” given by Tomalia to describe these molecules has now become universally accepted. From the beginning of their appearance in the scientific literature, dendritic compounds, due to their unique architecture, have been a very attractive subject for further investigation for many researchers all over the world. The possibility to control their physicochemical properties, as well as other characteristics such as size and shape, by manipulating their chemical composition gave rise initially to a great number of studies related to the development of synthetic methodologies of this new category of chemical compounds and then, very soon afterwards, to the study of their properties and the ways these molecules might be usefully applied. In recent years, research in the field of dendrimers has experienced an exponential development both at an academic and at a technological level and this is a result of the wide range of applications that have been foreseen for them in areas ranging from biomedical to material science. For biomedical applications in particular, the interest in the development of dendrimers as diagnostic and therapeutic tools can be related to their precise architecture which gives them a significant advantage over other generally polydisperse nanoparticles in that there is the possibility of stricter control of their pharmacodynamic profile, while in addition dendrimers are also characterized by their surface multifunctionality which offers the opportunity for multivalent interactions with biological substrates. The present issue of Current Topics in Medicinal Chemistry deals with some of the unique aspects associated with recent results regarding the Biomedical Applications of Dendrimers. As an introduction to this collection of articles, Helmut Ringsdorf (Institut fur Organische Chemie, Universität Mainz) and Maria Micha-Screttas (Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, Athens, Greece) have undertaken a historical review of the application of nanomolecules, starting with polymers and then dendrimers, to the area of Life Sciences. They present some thoughts and concerns regarding the development of new scientific fields, while at the same time correlating decisive research achievements in the area of chemistry and biology with the subsequent development and application of synthetic macromolecules in the field of biomedicine. The effectiveness of cancer therapeutic approaches depends mainly on diagnosis at an early stage and the specificity of therapeutics agents. In their review, Istvan J. Majoros, Christopher R. Williams, and James R. Baker, Jr. (Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, USA) describe all the new dendrimerbased technologies for diagnosis and therapeutic approaches in the field of oncology. Michelle Longmire, Peter L. Choyke and Hisataka Kobayashi (Molecular Imaging Program, National Cancer Institute, National Institutes of Health, Maryland, USA) provide an account of the contribution of dendrimers science to the development of more effective contrast agents for optical, magnetic resonance, computer tomography and radionuclide imaging. They also describe how their physicochemical characteristics affect their biological profile and how, by maximizing the possibilities of their unique structure, it could be possible to develop agents for multi-modality imaging.........

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In recent years, medicinal chemists have begun to realize that dendrimers may be a keystone in the future of medicine. The field of oncology will soon be revolutionized by novel strategies for diagnosis and therapy employing dendrimer-based nanodevices. In the near future, cancer diagnosis via MRI will be improved by the incorporation of dendrimers as advanced contrast agents. Novel dendrimer-based contrast agents can not only be targeted specifically to cancer cells but may also incorporate a cytotoxic function to induce apoptosis on said cells as well. Dendrimers are being applied to a variety of cancer therapies to improve the safety and effectiveness of many common therapeutics. Investigations into the applicability of dendrimers in photodynamic therapy, boron neutron capture therapy, and gene transfection are also being undertaken. This review will cover the fundamentals of cutting-edge research utilizing dendrimers for cancer diagnosis and therapy. An objective review of these new technologies will detail how dendrimerbased nanodevices are advantageous over conventional medicine.

The extensive adaptability of dendrimer-based contrast agents is ideal for the molecular imaging of organs and other target-specific locations. The ability of literally atom-by-atom modification on cores, interiors, and surface groups, permits the rational manipulation of dendrimer-based agents in order to optimize their physical characteristics, biodistribution, receptor-mediated targeting, and controlled release of the payload. Such modifications enable agents to localize preferentially to areas or organs of interest for facilitating target-specific imaging as well as assume excretion pathways that do not interfere with desired applications. Recent innovations in dendrimer research have increased agent directibility and new synthetic chemistry approaches have increased efficiency of production as well as led to the creation of novel dendrimer-based contrast agents. In addition, by taking advantage of the numerous attachment sites available on the surface of a single dendrimer molecule, new synthetic chemistry techniques have led to the development of multimodality magnetic resonance, radionuclide, and fluorescence imaging agents for molecular imaging. Herein we discuss advances in dendrimer-based contrast agents for molecular imaging focusing mainly on the chemical design as applied to optical, magnetic resonance, computer tomography, radionuclide, and multi-modality imaging.

This article focuses on the ability of dendritic molecules to interact with nucleic acids and hence deliver them into cells. Dendritic molecules have branched structures which are made by an iterative, layer-by-layer synthesis. The control applied in their synthesis means that dendrimers are well-defined nanoscale molecular species - ideal for interacting with nanoscale bio-targets such as DNA/RNA. Binding and delivery of genetic material into cells in vivo holds out the prospect of gene therapy, and we will consider the potential advantages of dendritic vectors in this field of nanomedicine. As this article illustrates, the synthetic versatility of dendritic molecules has enabled the synthesis of a wide array of DNA binders and delivery vehicles, with different advantages. This versatility forms the basis for optimism that the dendritic approach may well yield active, highly targeted delivery vectors, suitable for in vivo application in gene therapy

This review describes the strategy for the development of multifunctional dendrimeric and hyperbranched polymers, collectively named dendritic polymers, aiming at their application as drug and gene delivery systems. Employing well-characterized and mainly commercially available dendritic polymers, the functionalization of these polymers is aimed at providing drug carriers of low toxicity, high encapsulating capacity, specificity to certain type of cells and transport ability through their membranes. Following a step-wise functionalization strategy of the starting dendritic polymers one has the option to prepare products that fulfill one or more of these requirements. In particular, in addition to polyvalency which is a common feature of the dendritic polymers, these carriers bearing a number of targeting ligands exhibit specificity to certain cells, another type of groups secures stability in biological milieu and prolonged circulation, while other moieties facilitate their transport through cell membranes. Furthermore, dendritic polymers applied for gene delivery should be or become cationic in the biological environment for the formation of complexes with the negatively charged genetic material.

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.

Carbohydrate protein interactions are at the front of several biological interactions spanning from cell growth and differentiation, cell signaling, apoptosis, cancer, and microbial infections. Classical medicinal glycochemistry has so far concentrated on designing glycosyl transferase and glycohydrolase inhibitors for which only handful candidates have emerged. Added to the complexity of drug resistances, drugs in development have rapidly witnessed this limitation as well. New approaches are therefore highly encouraged. Amongst these, blocking pathogen adhesions to host tissues as an early preventive mechanism is a foreseeable potentiality. It has the clear advantage that the pathogens are unlikely to mutate their anchoring motifs without upsetting their own binding to host tissues. An added dilemma is that these binding interactions are usually too weak to provide suitable drug candidates. As a consequence, the community has successfully come up with multivalent glycoconjugates having greatly enhanced avidity. An alternative strategy in which both monovalent ligands as well as the multivalent scaffolds undergoing QSAR improvement is thus suggested. This review will highlight recent trends toward the design of multivalent glycodendrimers and their biological applications.

Combinatorial libraries of peptide dendrimers bearing two and four copies of C-fucosyl residues were screened for binding to fucose specific lectins leading to potent ligands for Ulex europaeus lectin UEA-I (IC50 = 11 μM). The dendrimers also show high affinity for the lectin PA-IIL (IC50 = 0.14 μM) from the pathogenic bacteria Pseudomonas aeruginosa. The dendrimers described are the first multivalent ligands for these lectins. In our system, glycopeptide dendrimer-protein binding is modulated by the nature of the amino acid residues present in the dendritic structure instead of depending solely on the number of sugars attached to the scaffold. Studies of colchicine-glycopeptide dendrimer conjugates with improved selectivity for cancer cells in comparison to colchicine are also described.

Two general aspects which need to be considered for the successful application of dendrimers for biomedical purposes are their availability at an acceptable cost and their suitability as regards their pharmacodynamic and pharmacokinetic properties. These two aspects are covered in this review. In the first part, synthetic strategies for the preparation of dendrimers are outlined and emphasis is given to recent work on methodologies whose aim is the development of more efficient routes to dendrimers in terms of the materials used for their synthesis as well as in terms of the procedures required for their purification. These include procedures involving double-stage and double exponential synthesis, orthogonal coupling strategies, self-assembly and solid-phase approaches, as well as particularly useful synthetic protocols such as those used in “click chemistry”. The second part of the review deals with the way in which the size, chemical constitution and physicochemical properties of dendrimers used for drug delivery may affect pharmacodynamic and pharmacokinetic parameters which are important considerations for drug bioavailability. This is illustrated by an overview of examples from recent work involving non-steroidal anti-inflammatory drugs, anticancer drugs and antibacterials.

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