Dendrimer as a versatile platform for biomedical application: A review

Modern chemistry is vastly fascinated by dendrimer chemistry, an area that is rapidly expanding and brimming with potential applications. Dendrimers are highly branched polymers that have multiple peripheral groups, interior cavities and they have many structural properties therefore Dendrimers play a crucial role in the fields of nanotechnology, pharmaceuticals, and medicinal chemistry. The terminal functional groups of dendrimers may be chemically linked to other moieties in order to adjust surface properties for applications such as biomimetic nanodevices. A variety of biologically active agents can be incorporated into dendrimers to create biologically active conjugates, including novel drug carriers, by utilizing the homogeneity of their three-dimensional architecture. The purpose of this review is to provide a brief overview of bio-inspired dendrimer applications, highlighting their use as drug and gene delivery agents, and biomedical diagnostic agents. In addition, the review mentions briefly some dendrimer applications in cosmetics, agrochemicals, and catalyst.     

A Review of Surface Functionalized Amine Terminated Dendrimers for Application in Biological and Molecular Sensing

Dendrimers are three dimensional nanosized synthetic molecules that have internal cavities and numerous surface groups. In recent times they have received increased attention in sensing applications. For dendrimers to be used as sensors, they most commonly require functionalization at their surface. This is because the surface is generally the first point of contact between the dendrimer and the outside world, hence surface functionalization serves to selectively home in on the target analyte. Further, sensor signals may be transmitted through surface functionalities e.g. fluorochromic molecules. It is therefore important to document surface functionalization approaches. Dendrimers with amine surface groups have the advantage of being able to be conjugated to other molecules via an amide linkage, which is one of the most fundamental and widespread chemical bonds in nature. In this paper we demonstrate the properties of dendrimers that make them so applicable to sensing. We review several methods for functionalizing dendrimers via an amide linkage, as well as present a review of surface functionalized polyamidoamine, polyamine, and polypeptide dendrimers that have been employed for biological, chemical and molecular sensing.     

Application of Dendrimers in Anticancer Diagnostics and Therapy

The application of dendrimeric constructs in medical diagnostics and therapeutics is increasing. Dendrimers have attracted attention due to their compact, spherical three-dimensional structures with surfaces that can be modified by the attachment of various drugs, hydrophilic or hydrophobic groups, or reporter molecules. In the literature, many modified dendrimer systems with various applications have been reported, including drug and gene delivery systems, biosensors, bioimaging contrast agents, tissue engineering, and therapeutic agents. Dendrimers are used for the delivery of macromolecules, miRNAs, siRNAs, and many other various biomedical applications, and they are ideal carriers for bioactive molecules. In addition, the conjugation of dendrimers with antibodies, proteins, and peptides allows for the design of vaccines with highly specific and predictable properties, and the role of dendrimers as carrier systems for vaccine antigens is increasing. In this work, we will focus on a review of the use of dendrimers in cancer diagnostics and therapy. Dendrimer-based nanosystems for drug delivery are commonly based on polyamidoamine dendrimers (PAMAM) that can be modified with drugs and contrast agents. Moreover, dendrimers can be successfully used as conjugates that deliver several substances simultaneously. The potential to develop dendrimers with multifunctional abilities has served as an impetus for the design of new molecular platforms for medical diagnostics and therapeutics.     

Starburst pamam dendrimers: Synthetic approaches,surface modifications,and biomedical applications

Dendrimers are having novel three dimensional, synthetic hyperbranched, nano-polymeric structure. Among all of the dendrimers, Poly-amidoamine (PAMAM) dendrimer are used enormously applying materials in supramolecular chemistry. This review described the structure, characteristic, synthesis, toxicity, and surface modification of PAMAM dendrimer. Various strategies in supramolecular chemistry of PAMAM for synthesizing it at commercial and laboratory scales along with their limitations and applications has also discussed. When compared to other nano polymers, the characteristics of supramolecular PAMAM dendrimers in nanopolymer science has shown significant achievement in transporting drugs for molecular targeted therapy, particularly in host–guest reaction. It also finds its applications in gene transfer devices and imaging of biological systems with minimum cytotoxicity. From that viewpoint, this review has elaborated the structural and safety aspect of PAMAM for targeted drug delivery with pharmaceuticals in addition to the biomedical application.     

手性树状分子膦配体在不对称催化氢化中的应用

树状大分子作为一类组成精确的超支化结构大分子,近十多年来引起了科学家们的广泛关注.作为一类新型可溶性载体应用于均相催化剂,尤其是手性均相催化剂的负载化研究是树状大分子的重要应用领域之一.本文主要介绍了手性树状大分子膦配体,包括膦配体位于树状分子核心、末端和表面的几种类型,重点对它们与金属配合物形成的催化剂在不对称催化氢化反应中的应用研究进行总结,同时对负载催化剂的分离与回收、树状分子载体的结构和体积对催化剂性能的影响进行了讨论.     

Interaction of polyamidoamine (PAMAM) succinamic acid dendrimers generation 4 with human serum albumin

Dendrimers, a relatively new group of highly branched three dimensional polymers, are intensively investigated to use them in biomedical and physicochemical sciences. Their specific architecture gives them the ability to interact with many different types of molecules. In our studies the interaction between PAMAM succinamic acid dendrimers generation 4 (PAMAM-SAH G4) and human serum albumin (HSA) was examined. Experiments showed that a single molecule of a HSA can bind approximately 6 particles of dendrimers. The fluorescence studies demonstrated that dendrimers lead to a decrease in protein fluorescence but changes in fluorescence anisotropy were not observed. Alterations in the spectrum of circular dichroism indicated changes in the secondary protein structure. The results clearly show that this generation of dendrimers possesses a strong ability to interact with human serum albumin.     

Synthetic strategy of dendrimers: A review

Dendrimer chemistry is a fascinating and growing area of modern chemistry. Dendrimers are macromolecular entities with unique three-dimensional topologies, multi-functionality, and unique chemical and physical properties. Because of these characteristics, they are particularly well suited for applications in nanotechnology, pharmaceuticals, and medicinal chemistry. The study of dendrimers and hyperbranched polymers is gaining widespread interest from researchers in academia and industry for their unique structure and properties. This review article focused on dendrimer structure and the different synthetic strategies employed at the laboratory and commercial levels. This review covers convergent and divergent approaches, as well as accelerated approaches to dendrimer synthesis.     

Design of biocompatible dendrimers for cancer diagnosis and therapy: current status and future perspectives

In the past decade, nanomedicine with its promise of improved therapy and diagnostics has revolutionized conventional health care and medical technology. Dendrimers and dendrimer-based therapeutics are outstanding candidates in this exciting field as more and more biological systems have benefited from these starburst molecules. Anticancer agents can be either encapsulated in or conjugated to dendrimer and be delivered to the tumour via enhanced permeability and retention (EPR) effect of the nanoparticle and/or with the help of a targeting moiety such as antibody, peptides, vitamins, and hormones. Imaging agents including MRI contrast agents, radionuclide probes, computed tomography contrast agents, and fluorescent dyes are combined with the multifunctional nanomedicine for targeted therapy with simultaneous cancer diagnosis. However, an important question reported with dendrimer-based therapeutics as well as other nanomedicines to date is the long-term viability and biocompatibility of the nanotherapeutics. This critical review focuses on the design of biocompatible dendrimers for cancer diagnosis and therapy. The biocompatibility aspects of dendrimers such as nanotoxicity, long-term circulation, and degradation are discussed. The construction of novel dendrimers with biocompatible components, and the surface modification of commercially available dendrimers by PEGylation, acetylation, glycosylation, and amino acid functionalization have been proposed as available strategies to solve the safety problem of dendrimer-based nanotherapeutics. Also, exciting opportunities and challenges on the development of dendrimer-based nanoplatforms for targeted cancer diagnosis and therapy are reviewed (404 references).     

Simplifying the synthesis of dendrimers: accelerated approaches

Dendrimers are highly branched and monodisperse macromolecules that display an exact and large number of functional groups distributed with unprecedented control on the dendritic framework. Based on their globular structure, compared to linear polymers of the same molecular weight, dendrimers are foreseen to deliver extraordinary features for applications in areas such as cancer therapy, biosensors for diagnostics and light harvesting scaffolds. Of the large number of reports on dendrimer synthesis only a few have reached commercial availability. This limitation can be traced back to challenges in the synthetic paths including a large number of reaction steps required to obtain dendritic structures with desired features. Along with an increased number of reaction steps come not only increased waste of chemical and valuable starting materials but also an increased probability to introduce structural defects in the dendritic framework. This tutorial review briefly covers traditional growth approaches to dendrimers and mainly highlights accelerated approaches to dendrimers. A special focus capitalizes on the impact of the click chemistry concept on dendrimer synthesis and the promise it has to successfully accomplish highly sophisticated dendrimers, both traditional as well as heterofunctional, in a minimum number of chemical steps. It is clear that accelerated synthetic approaches are of greatest importance as these will encourage the scientific community to synthesize and access dendrimers for specific applications. The final goal of accelerated synthesis is to deliver economically justified dendritic materials for future applications without compromising the environmental perspective.     

Multiscale modeling and simulation methods with applications to dendritic polymers

Dendrimers and hyperbranched polymers represent a novel class of structurally controlled macromolecules derived from a branches-upon-branches structural motif. The synthetic procedures developed for dendrimer preparation permit nearly complete control over the critical molecular design parameters, such as size, shape, surface/interior chemistry, flexibility, and topology. Dendrimers are well defined, highly branched macromolecules that radiate from a central core and are synthesized through a stepwise, repetitive reaction sequence that guarantees complete shells for each generation, leading to polymers that are mono-disperse. This property of dendrimers makes it particularly natural to coarsen interactions in order to simulate dynamic processes occurring at larger length and longer time scales. In this paper, we describe methods to construct 3-dimensional molecular structures of dendrimers (Continuous Configuration Boltzmann Biased direct Monte Carlo, CCBB MC) and methods towards coarse graining dendrimer interactions (NEIMO and hierarchical NEIMO methods) and representation of solvent dendrimer interactions through continuum solvation theories, Poisson–Boltzmann (PB) and Surface Generalized Born (SGB) methods. We will describe applications to PAMAM, stimuli response hybrid star-dendrimer polymers, and supra molecular assemblies crystallizing to A15 colloidal structure or Pm6m liquid crystals.     

Practical computational toolkits for dendrimers and dendrons structure design

Dendrimers and dendrons offer an excellent platform for developing novel drug delivery systems and medicines. The rational design and further development of these repetitively branched systems are restricted by difficulties in scalable synthesis and structural determination, which can be overcome by judicious use of molecular modelling and molecular simulations. A major difficulty to utilise in silico studies to design dendrimers lies in the laborious generation of their structures. Current modelling tools utilise automated assembly of simpler dendrimers or the inefficient manual assembly of monomer precursors to generate more complicated dendrimer structures. Herein we describe two novel graphical user interface toolkits written in Python that provide an improved degree of automation for rapid assembly of dendrimers and generation of their 2D and 3D structures. Our first toolkit uses the RDkit library, SMILES nomenclature of monomers and SMARTS reaction nomenclature to generate SMILES and mol files of dendrimers without 3D coordinates. These files are used for simple graphical representations and storing their structures in databases. The second toolkit assembles complex topology dendrimers from monomers to construct 3D dendrimer structures to be used as starting points for simulation using existing and widely available software and force fields. Both tools were validated for ease-of-use to prototype dendrimer structure and the second toolkit was especially relevant for dendrimers of high complexity and size.     

Transition Metal Catalysis Using Functionalized Dendrimers

Dendrimers are well-defined hyperbranched macromolecules with characteristic globular structures for the larger systems. These novel polymers have inspired many chemists to develop new materials and several applications have been explored, catalysis being one of them. The recent impressive strides in synthetic procedures increased the accessibility of functionalized dendrimers, resulting in a rapid development of dendrimer chemistry. The position of the catalytic site(s) as well as the spatial separation of the catalysts appears to be of crucial importance. Dendrimers that are functionalized with transition metals in the core potentially can mimic the properties of enzymes, their efficient natural counterparts, whereas the surface-functionalized systems have been proposed to fill the gap between homogeneous and heterogeneous catalysis. This might yield superior catalysts with novel properties, that is, special reactivity or stability. Both the core and periphery strategies lead to catalysts that are sufficiently larger than most substrates and products, thus separation by modern membrane separation techniques can be applied. These novel homogeneous catalysts can be used in continuous membrane reactors, which will have major advantages particularly for reactions that benefit from low substrate concentrations or suffer from side reactions of the product. Here we review the recent progress and breakthroughs made with these promising novel transition metal functionalized dendrimers that are used as catalysts, and we will discuss the architectural concepts that have been applied.     

Thermosensitive properties of poly(amidoamine) dendrimers with peripheral phenylalanine residues

Dendrimers are unique polymers with globular shapes and well-defined structures. We previously prepared poly(amidoamine) (PAMAM) dendrimers having phenylalanine (Phe) residues at every chain end of the dendrimer as efficient gene carriers. In this study, we found that Phe-derivatized PAMAM dendrimers change their water solubility depending on temperature. The dendrimers were soluble in aqueous solutions at low temperatures, but they became water-insoluble at temperatures above a specific threshold, which is termed the lower critical solution temperature (LCST). Although the LCST of Phe-modified dendrimers decreased with increasing dendrimer generation, these dendrimers exhibited an LCST of 20-30 degrees C under physiological conditions. In addition, the LCST of the dendrimers was controlled by introducing isoleucine (Ile) residues at chain ends of dendrimers at varying ratios with respect to Phe residues. The PAMAM dendrimers are known to encapsulate various drug molecules. For these reasons, temperature-sensitive dendrimers might be useful as efficient drug carriers with controlled size and temperature-responsive properties.     

Conformation and distribution of groups on the surface of amphiphilic polyether-co-polyester dendrimers: effect of molecular architecture

Amphiphilic polyester-co-polyether (PEPE) dendrimers synthesized from poly(ethylene glycol) (PEG) were examined to understand the influence of alterations in the architecture of dendrimers on their conformation at interfaces and distribution of various groups on their surface. Effect of changes in the number of branching points, type of terminal functional groups and generation of dendrimer was primarily evaluated. Dendrimers were deposited on mica by spin coating at 0.1 mg/mL. Tapping mode atomic force microscopy (AFM) was employed for the visualization of dendrimer topographies while, X-ray photoelectron spectroscopy (XPS), AFM phase and force imaging were used as the tools for characterization of their surfaces. Individual dendrimer molecules could be imaged by AFM, which showed that they are round or oval in topography. Dendrimers were also flattened on mica but the extent of flattening differed with the chemical structure; for instance, third generation dendrimers were more flattened than second generation dendrimers whereas, dendrimers with higher number of branches had greater height above the mica surface. Hydrophilic and hydrophobic groups present towards the aerial interface existed in distinct zones rather than being distributed randomly, except in dendrimer with higher number of branches. The percentage of various hydrophobic groups on the surface of dendrimer was enhanced by increase in the number of branches but, was lowered by the presence of hydroxyl groups as the pendant terminal groups. Furthermore, the core of dendrimers was not always located towards the centre, its position was found to be altered by the number of branching points, type of terminal functional groups and the generation of dendrimer.     

Solid-phase dendrimer synthesis: a promising approach to transform dendrimer construction

Dendrimers, by virtue of their unique well-defined dendritic structure and multivalent cooperativity, hold great promise for a wide variety of applications, ranging from healthcare to energy production and environmental sustainability. However, dendrimer synthesis suffers from two inherent problems which greatly handicap their development and limit their application: the formation of structural defects caused by incomplete or side reactions, and difficulties associated with purification. Solid-phase synthesis may overcome both these problems, firstly by enabling complete chemical reactions through the use of a large excess of reagents, secondly by facilitating purification through simple washing and filtering steps. The end result is the speeded up reactions producing the desired product in high yield, with simultaneous suppression of by-products. In this review, we present the challenges and current state of research in solid-phase dendrimer synthesis, and provide our perspectives on its future development. We start with a short introduction to solid-phase synthesis and specific considerations for dendrimer construction. We then present exemplary studies to highlight the potential of, and challenges faced by, solid-phase dendrimer synthesis. Finally, we describe efforts to deliver more effective and reliable methods that will transform the synthesis of dendrimers and permit exploitation of their full potential.     

树形大分子/金属配合物及其纳米复合材料的制备与性能研究进展

树形大分子是具有确定代数和末端基的蓬勃发展的新型合成高分子。大量具有不同的中心核、支链和末端基团的树形大分子已经被合成和应用于不同的领域,其功能化和应用是目前树形大分子研究领域的热点。本文综述了树形大分子/金属配合物及其纳米复合材料的制备与性能的研究进展,重点介绍了树形大分子/金属配合物材料和树形大分子/金属纳米复合材料的制备与性能研究的最新进展。     

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.     

The Design of Second-order Nonlinear Optical Dendrimers: From “Branch Only” to “Root Containing”

Dendrimers are considered as a promising family of organic second-order nonlinear optical (NLO) polymers because of their well-defined structures,easily modified peripheral functional groups,interior branches and central cores.In order to obtain NLO materials with high performance,dendrimer structures have been optimized in the past years,such as the "branch only" and the "root containing" type dendrimers.This feature article highlights the achievements in exploring the rational design of dendrimers,partially marked by their macroscopic NLO performance.     

Impact of PAMAM G2 and G6 dendrimers on bovine serum albumin (fatty acids free and loaded with different fatty acids)

Dendrimers are a new class of nanotechnological polymers suitable for drug targeting, microarray systems or detoxication. The present study is devoted to a detailed analysis of binding between PAMAM dendrimers and bovine serum albumin (fatty acid free or loaded with oleic, linoleic, oleic+linoleic or oleic+linoleic+arachodonic acids) by measuring zeta-potential, fluorescence quenching, fluorescence anisotropy and electron paramagnetic resonance. Addition of PAMAM G2 and G6 dendrimers to protein solutions resulted in attachment to the protein molecule. The PAMAM dendrimers also competed with BSA for fatty acids if two or three fatty acids were loaded per protein. This can lead to the extraction of fatty acids from BSA to the PAMAM dendrimer.     

Supramolecular catalysts by encapsulating palladium complexes within dendrimers

Dendrimers are well-defined and highly branched macromolecules. By utilizing their capsular architectures, dendrimers encapsulating various catalytically active species can be prepared, which often bring about unique catalysis. Treatment of the alkylated PPI dendrimer with 4-diphenylphosphinobenzoic acid and [PdCl(C3H5)]2 afforded the dendrimer-encapsulated Pd complex using ionic interactions. The dendrimers encapsulating Pd complexes acted as unique supramolecular catalysts for the Heck reaction and allylic amination. The specific nanoenvironment created by the dense amino groups inside the dendrimers can provide high catalytic activity and stability for the Pd complexes. Facile recovery of the dendritic catalysts could be achieved by thermomorphic systems.