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Dendrons are an important class of macromolecules that can be used for a broad range of applications. Recent studies have indicated that mixtures of oligoglycerol detergent (OGD) regioisomers are superior to individual regioisomers for protein extraction. The origin of this phenomenon remains puzzling. Here we discuss the synthesis and characterization of dendritic oligoglycerol regioisomer mixtures and their implementation into detergents. We provide experimental benchmarks to support quality control after synthesis and investigate the unusual utility of OGD regioisomer mixtures for extracting large protein quantities from biological membranes. We anticipate that our findings will enable the development of mixed detergent platforms in the future., (© 2020 The Authors. Published by Wiley-VCH GmbH.)

The synthetic compound dendritic polyglycerol sulfate (dPGS) is a pleiotropic acting molecule but shows a high binding affinity to immunological active molecules as L-/P-selectin or complement proteins leading to well described anti-inflammatory properties in various mouse models. In order to make a comprehensive evaluation of the direct effect on the innate immune system, macrophage polarization is analyzed in the presence of dPGS on a phenotypic but also metabolic level. dPGS administered macrophages show a significant increase of MCP1 production paralleled by a reduction of IL-10 secretion. Metabolic analysis reveals that dPGS could potently enhance the glycolysis and mitochondrial respiration in M0 macrophages as well as decrease the mitochondrial respiration of M2 macrophages. In summary the data indicate that dPGS polarizes macrophages into a pro-inflammatory phenotype in a metabolic pathway-dependent manner., (© 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Fluorescent nanomaterials are expected to revolutionize medical diagnostic, imaging, and therapeutic tools due to their superior optical and structural properties. Their inefficient water solubility, cell permeability, biodistribution, and high toxicity, however, limit the full potential of their application. To overcome these obstacles, a water-soluble, fluorescent, cytocompatible polymer-single-walled carbon nanotube (SWNT) complex is introduced for bioimaging applications. The supramolecular complex consists of an alkylated polymer conjugated with neutral hydroxylated or charged sulfated dendronized perylene bisimides (PBIs) and SWNTs as a general immobilization platform. The polymer backbone solubilizes the SWNTs, decorates them with fluorescent PBIs, and strongly improves their cytocompatibility by wrapping around the SWNT scaffold. In photophysical measurements and biological in vitro studies, sulfated complexes exhibit superior optical properties, cellular uptake, and intracellular staining over their hydroxylated analogs. A toxicity assay confirms the highly improved cytocompatibility of the polymer-wrapped SWNTs toward surfactant-solubilized SWNTs. In microscopy studies the complexes allow for the direct imaging of the SWNTs' cellular uptake via the PBI and SWNT emission using the 1st and 2nd optical window for bioimaging. These findings render the polymer-SWNT complexes with nanometer size, dual fluorescence, multiple charges, and high cytocompatibility as valuable systems for a broad range of fluorescence bioimaging studies., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Dendritic polyglycerols (dPG), particularly dendritic polyglycerol sulfates (dPGS), have been intensively studied due to their intrinsic anti-inflammatory activity. As related to brain pathologies involving neuroinflammation, the current study examined if dPG and dPGS can (i) regulate neuroglial activation, and (ii) normalize the morphology and function of excitatory postsynaptic dendritic spines adversely affected by the neurotoxic 42 amino acid amyloid-β (Aβ 42 ) peptide of Alzheimer disease (AD). The exact role of neuroglia, such as microglia and astrocytes, remains controversial especially their positive and negative impact on inflammatory processes in AD. To test dPGS effectiveness in AD models we used primary neuroglia and organotypic hippocampal slice cultures exposed to Aβ 42 peptide. Overall, our data indicate that dPGS is taken up by both microglia and astrocytes in a concentration- and time-dependent manner. The mechanism of action of dPGS involves binding to Aβ 42 , i.e., a direct interaction between dPGS and Aβ 42 species interfered with Aβ fibril formation and reduced the production of the neuroinflammagen lipocalin-2 (LCN2) mainly in astrocytes. Moreover, dPGS normalized the impairment of neuroglia and prevented the loss of dendritic spines at excitatory synapses in the hippocampus. In summary, dPGS has desirable therapeutic properties that may help reduce amyloid-induced neuroinflammation and neurotoxicity in AD.

The development of effective nonviral vectors for gene therapy is still a challenge in research, due to the high toxicity of many existing polycationic nanocarriers. In this paper, the development of two pH-cleavable polyglycerol-amine-based nanocarriers is described. The benz-acetal bond represents the pH-sensitive cleavage site between dendritic polyglycerol (dPG) and glycerol-based 1,2-diamines that can complex genetic material. Due to the acid lability of the acetal moiety, the cleavable dPG-amines are less toxic in vitro. Cell-mediated degradation results in non-toxic dPG with low amine functionalization and low molecular weight cleavage products (cp). The genetic material is released because of the loss of multivalent amine groups. Interestingly, the release kinetics at the endosomal pH could be controlled by simple chemical modification of the acetals. In vitro experiments demonstrate the ability of the cleavable dPG-amine to transfect HeLa cells with GFP-DNA, which resulted in cell-compatible cleavage products., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The emerging field of nanomedicine provides new approaches for the diagnosis and treatment of diseases, for symptom relief and for monitoring of disease progression. One route of realizing this approach is through carefully constructed nanoparticles. Due to the small size inherent to the nanoparticles a proper characterization is not trivial. This review highlights the application of time-resolved fluorescence spectroscopy and fluorescence lifetime imaging microscopy (FLIM) for the analysis of nanoparticles, covering aspects ranging from molecular properties to particle detection in tissue samples. The latter technique is particularly important as FLIM allows for distinguishing of target molecules from the autofluorescent background and, due to the environmental sensitivity of the fluorescence lifetime, also offers insights into the local environment of the nanoparticle or its interactions with other biomolecules. Thus, these techniques offer highly suitable tools in the fields of particle development, such as organic chemistry, and in the fields of particle application, such as in experimental dermatology or pharmaceutical research.

Drug loaded dendritic core-multishell (CMS) nanocarriers are of especial interest for the treatment of skin diseases, owing to their striking dermal delivery efficiencies following topical applications. CMS nanocarriers are composed of a polyglycerol core, connected by amide-bonds to an inner alkyl shell and an outer methoxy poly(ethylene glycol) shell. Since topically applied nanocarriers are subjected to biodegradation, the application of conventional amide-based CMS nanocarriers (10-A-18-350) has been limited by the potential production of toxic polyglycerol amines. To circumvent this issue, three tailored ester-based CMS nanocarriers (10-E-12-350, 10-E-15-350, 10-E-18-350) of varying inner alkyl chain length were synthesized and comprehensively characterized in terms of particle size, drug loading, biodegradation and dermal drug delivery efficiency. Dexamethasone (DXM), a potent drug widely used for the treatment of inflammatory skin diseases, was chosen as a therapeutically relevant test compound for the present study. Ester- and amide-based CMS nanocarriers delivered DXM more efficiently into human skin than a commercially available DXM cream. Subsequent in vitro and in vivo toxicity studies identified CMS (10-E-15-350) as the most biocompatible carrier system. The anti-inflammatory potency of DXM-loaded CMS (10-E-15-350) nanocarriers was assessed in TNFα supplemented skin models, where a significant reduction of the pro-inflammatory cytokine IL-8 was seen, with markedly greater efficacy than commercial DXM cream. In summary, we report the rational design and characterization of tailored, biodegradable, ester-based CMS nanocarriers, and their subsequent stepwise screening for biocompatibility, dermal delivery efficiency and therapeutic efficacy in a top-down approach yielding the best carrier system for topical applications., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Successful application of gene silencing approaches critically depends on systems that are able to safely and efficiently deliver genetic material such as small interfering RNA (siRNA). Due to their beneficial well-defined dendritic nanostructure, self-assembling dendrimers are emerging as promising nanovectors for siRNA delivery. However, these kinds of vectors are plagued with stability issues, especially when considered for in vivo applications. Therefore, in the present study, disulfide-based temporarily fixed micelles are developed that can degrade upon reductive conditions, and thus lead to efficient cargo release. In detail, lipoic acid-derived crosslinked micelles are synthesized based on small polymerizable dendritic amphiphiles. Particularly, one candidate out of this series is able to efficiently release siRNA due to its redox-responsive biodegradable profile when exposed to simulated intracellular environments. As a result, the reduction-triggered disassembly leads to potent gene silencing. In contrast, noncrosslinkable, structurally related constructs fails under the tested assay conditions, thereby confirming the applied rational design approach and demonstrating its large potential for future in vivo applications., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A stable polymeric network that mimics the highly polyanionic extracellular cartilage matrix still remains a great challenge. The main aim of this study is to present the synthesis of dendritic polyglycerol sulfate (dPGS)-based in situ forming hydrogels using strain promoted azide-alkyne cycloaddition reactions. A real time rheological study has been used to characterize the hydrogel properties. The viability of encapsulated human chondrocytes in the different hydrogels are monitored using live-dead staining. Furthermore, type I and II collagen gene have been analyzed. Hydrogels with elastic moduli ranging from 1 to 5 kPa have been prepared by varying the dPGS amount. The chondrocyte viability in dPGS hydrogels is found to be higher than in pure PEG and alginate-based hydrogels after 21 d. The higher cell viability in the dPGS engineered hydrogels can be explained by the fact that dPGS can interact with different proteins responsible for cell growth and proliferation., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Dendritic core-multi shell (CMS) particles are polymer based systems consisting of a dendritic polar polyglycerol polymer core surrounded by a two-layer shell of nonpolar C18 alkyl chains and hydrophilic polyethylene glycol. Belonging to nanotransport systems (NTS) they allow the transport and storage of molecules with different chemical characters. Their amphipihilic character CMS-NTS permits good solubility in aqueous and organic solutions. We showed by multifrequency electron paramagnetic resonance (EPR) spectroscopy that spin-labeled 5-doxyl stearic acid (5DSA) can be loaded into the CMS-NTS. Furthermore, the release of 5DSA from the carrier into the stratum corneum of porcine skin was monitored ex vivo by EPR spectroscopy. Additionally, the penetration of the CMS-NTS into the skin was analyzed by fluorescence microscopy using indocarbocyanine (ICC) covalently bound to the nanocarrier. Thereby, no transport into the viable skin was observed, whereas the CMS-NTS had penetrated into the hair follicles down to a depth of 340 μm ± 82 μm. Thus, it could be shown that the combined application of fluorescence microscopy and multi-frequency EPR spectroscopy can be an efficient tool for investigating the loading of spin labeled drugs to nanocarrier systems, drug release and penetration into the skin as well as the localization of the NTS in the skin., (Copyright © 2016 Elsevier B.V. All rights reserved.)

One approach to further improve the therapeutic efficacy of nanoparticles is employment of active targeting strategies. Bispecific antibodies (bsAbs) that bind to both tumor specific antigens on the cell surface and to haptens such as digoxigenin (Dig) can direct digoxigeninylated payloads to tumor cells. In this study, we investigate the potential of dendritic polyglycerol (dPG) conjugates, which consist of a doxorubicin (DOX) prodrug, Dig moiety, and a poly (ethylene glycol) (PEG) shell, in combination with bsAb, as a novel approach for targeted prodrug delivery. We could show successful binding of the bsAbs to dPGDigMal- DOX-PEG conjugates, as well as binding of these complexes to the cell surface of Lewis Y (LeY) expressing MCF-7 cells. Using flow cytometry, we could show the preferential binding of the targeting complex over the complex of control conjugate lacking Dig moieties. At concentrations that are usually applied for drug delivery, antibodycomplexed nanoparticles (independent of antibody specificity) released cytotoxic compounds into cells to the same degree as unmodified nanoparticles. This indicates that antibody-attachment does not interfere with the inherent cell binding and drug delivery properties of nanoparticles. At low doxorubicin concentrations and short incubation times, however, we were able to see a slightly increased target specific cytotoxicity in vitro which is mediated by complexation of the digoxigeninylated NP with the Dig-binding moiety of a bsAb that in turns direct the complexed bsAb to target cells. This study demonstrates the potential of digoxigeninylated dPG prodrug conjugates in combination with bsAbs as a new platform for targeted prodrug delivery into cancerous tissues. However the nanoparticle design needs to be further optimized for significant targeted delivery.

Interactions of nanoparticles with biomaterials determine the biological activity that is key for the physiological response. Dendritic polyglycerol sulfates (dPGS) were found recently to act as an inhibitor of inflammation by blocking selectins. Systemic application of dPGS would present this nanoparticle to various biological molecules that rapidly adsorb to the nanoparticle surface or lead to adsorption of the nanoparticle to cellular structures such as lipid membranes. In the past, fluorescence lifetime measurements of fluorescently tagged nanoparticles at a molecular and cellular/tissue level have been proven to reveal valuable information on the local nanoparticle environment via characteristic fluorescent lifetime signatures of the nanoparticle bound dye. Here, we established fluorescence lifetime measurements as a tool to determine the binding affinity to fluorescently tagged dPGS (dPGS-ICC; ICC: indocarbocyanine). The binding to a cell adhesion molecule (L-selectin) and a human complement protein (C1q) to dPGS-ICC was evaluated by the concentration dependent change in the unique fluorescence lifetime signature of dPGS-ICC. The apparent binding affinity was found to be in the nanomolar range for both proteins (L-selectin: 87 ± 4 nM and C1q: 42 ± 12 nM). Furthermore, the effect of human serum on the unique fluorescence lifetime signature of dPGS-ICC was measured and found to be different from the interactions with the two proteins and lipid membranes. A comparison between the unique lifetime signatures of dPGS-ICC in different biological environments shows that fluorescence lifetime measurements of unique dPGS-ICC fluorescence lifetime signatures are a versatile tool to probe the microenvironment of dPGS in cells and tissue.

Background: Anti-inflammatory nanoparticular compounds could represent a strategy to diminish osteoarthritis (OA) progression. The present study was undertaken to prove the uptake of nanoparticular dendritic polyglycerol sulfates (dPGS) by rat-derived articular chondrocytes and to answer the question of whether dPGS could modulate knee joint cartilage degradation in a rat OA model and whether complications could arise., Methods: dPGS uptake and cytotoxicity was assessed in cultured primary rat-derived articular chondrocytes. Subsequently, OA was induced in the right knee joints of 12 male Wistar rats by medial collateral ligament and meniscus transection. Unoperated left knees remained as controls. Six weeks post surgery six rats were either treated daily (14 days) with 30 mg/kg dPGS (s.c.) or a similar volume of physiological saline. Animals were analyzed clinically for gait alterations. Explanted knee joints were studied histologically using OA scores according to Mankin (1971), Glasson et al., (2010) and the synovitis score according to Krenn et al., (2006). Liver, spleen and kidneys were analyzed for degenerative changes due to dPGS accumulation., Results: dPGS was taken up after 2 hours by the chondrocytes. Whereas no significant clinical signs of OA could be detected, at the histological level, all operated rat knee joints revealed features of OA in the medial compartment. The values produced by both OA score systems were lower in rats treated with dPGS compared with saline-treated animals. Synovitis score did not significantly differ between the groups. The analyzed organs revealed no degenerative changes., Conclusions: dPGS presented overall cyto- and biocompatibility, no accumulation in metabolizing organs and chondroprotective properties in the osteoarthritic knee joint.

The development of safe and effective delivery vectors is a great challenge for the medicinal application of RNA interference (RNAi). In this study, we aimed to develop new synthetic transfection agents based on dendritic polyglycercol (dPG), which has shown great biocompatibility in several biomaterial applications. Histidine and aromatic amino acids were conjugated to the amine-terminated dPGs through amide bonds. We systematically tuned the amino acid combination, functionalization ratio, ligand density, and dPG core size to find optimal vectors. It was found that histidine-tryptophan-functionalized dPGs exhibited improved delivery efficiency and greatly reduced toxicity over simple amine-terminated dPGs. Furthermore, the optimized vectors exhibited strong siRNA binding and high transfection efficiency in serum containing media. The results indicate that the current amino acid-functionalized dPG system is a promising candidate for in vivo siRNA delivery applications.

Polyglycerol dendrimers as an important class of polymeric materials especially attractive for covalent attachment to therapeutic proteins as a useful alternative to traditional PEGylation procedures. Herein, we combine in vivo noncanonical amino acid (ncAA) incorporation and chemoselective conjugation in vitro to produce novel hybrid protein-dendrimer conjugates with the defined architectures. We incorporated Azidohomoalanine (Aha) as methionine substitute in vivo into various protein scaffolds to allow non-invasive dendrimer conjugations (dendronylation). Our approach makes recombinant proteins accessible for the design of multivalent dendrimer conjugates since it enables the preparation of many sequences with various positions for regioselective dendronylation., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Inflammatory processes driven by cytokines play a crucial role during osteoarthritis (OA) progression. Dendritic polyglycerol sulfate (dPGS) was analyzed in vitro for its effects on articular chondrocytes, cartilage and cytokines involved in the OA process., Methods: The metabolic activity of cultured human articular chondrocytes stimulated for 24 h with dPGS (10(-3)-10(-6) mol/L) was monitored using AlamarBlue(®) assay. The dPGS uptake was studied using fluorescence labeled nanoparticles. Further, chondrocytes were either treated with 10(-6) M dPGS, TNFα (10 ng/mL) alone or with a combination of both. The influence on extracellular matrix components, pro- and anti-inflammatory cytokines, matrix metalloproteinase (MMP)1 and the anaphylatoxin receptor C3aR was analyzed by RTD-PCR, flow cytometry and ELISA., Results: Even at higher dosages (10(-3) mol/L), dPGS did not influence chondrocytes viability. Uptake of dPGS was successfully monitored in human articular chondrocytes and synovial fibroblasts, penetration into cartilage chips was up to ~50 µm. Cellular treatment with dPGS had no effect on synthesis of pro-inflammatory cytokines TNFα and IL-6, but expression of the anti-inflammatory IL-10 was upregulated. Cotreatment with TNFα and dPGS reduced the TNFα level, while IL-1β, IL-6 and IL-10 expression did not change. Collagen type II gene expression was significantly reduced after preincubating cells with dPGS, but remained unaffected at the protein level., Conclusion: Results indicate that dPGS could play a role in regulation of cytokines associated with the inflammatory aspect of OA progression.

Unimolecular micelles are covalently bound molecular architectures and therefore highly stable which makes them particularly attractive for drug delivery. Accordingly, many reports in the literature emphasize the importance of these molecular architectures for nanomedicine. This conceptual review will present some of the recent advances in the application of these dendritic core-shell systems for drug delivery. Unimolecular micelles based on hyperbranched and dendritic cores will be discussed and sorted by the nature of their core and structure., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Engineering nanostructures of defined size and morphology is a great challenge in the field of self-assembly. Herein we report on the formation of supramolecular nanostructures of defined morphologies with subtle structural changes for a new series of dendritic amphiphiles. Subsequently, we studied their application as nanocarriers for guest molecules.

Dendritic polyglycerol sulfate (dPGS) is a biocompatible, bioactive polymer which exhibits anti-inflammatory activity in vivo and thus represents a promising candidate for therapeutic and diagnostic applications. To investigate the in vivo pharmacokinetics in detail, dPGS with a molecular weight of approx. 10 kDa was radiolabeled with (3)H and (64)Cu, and evaluated by performing biodistribution studies and small animal positron emission tomography (PET). (3)H-labeling was accomplished by an oxidation-reduction process with sodium periodate and [(3)H]-borohydride. (64)Cu-labeling was achieved by conjugation of isothiocyanate- or maleimide-functionalized copper(II)-chelating ligands based on 1,4-bis(2-pyridinylmethyl)-1,4,7-triazacyclononane (DMPTACN) to an amino functionalized dPGS scaffold, followed by reaction with an aqueous solution containing (64)CuCl2. Independent biodistribution by radioimaging and PET imaging studies with healthy mice and rats showed that the neutral dPG was quantitatively renally eliminated, whereas the polysulfated analogues accumulated mainly in the liver and spleen. Small amounts of the dPGS derivatives were slowly excreted via the kidneys. The degree of uptake by the reticuloendothelial system (RES) was similar for dPGS with 40% or 85% sulfation, and surface modification of the scaffold with the DMPTACN chelator did not appear to significantly affect the biodistribution profile. On the basis of our data, the applicability of bioactive dPGS as a therapeutic agent might be limited due to organ accumulation even after 3 weeks. The inert characteristics and clearance of the neutral polymer, however, emphasizes the potential of dPG as a multifunctional scaffold for various nanomedical applications.

Near-infrared (NIR) fluorescent dyes are gaining increased attention due to their potential to serve as molecular probes for in vivo imaging. Here, we demonstrate that oligoglycerol dendrons effectively enhance the fluorescence properties of an NIR dye by increasing the solubility in water and the prevention of aggregate formation. First- and second-generation oligoglycerol dendrons were conjugated to an NIR dye via a dipolar-cycloaddition (click) reaction. The two new dye conjugates exhibited enhanced NIR fluorescent emission and considerably higher fluorescent quantum yields than the dye alone. The high photostability measured for one of the oligoglycerol-linked dyes, in comparison to commonly used fluorogenic dyes such as Cy5 and Cy7, was validated using fluorescence microscopy of macrophages.

The synthesis of water-soluble dyes, which absorb and emit in the range between 650 and 950 nm and display high extinction coefficients (ε) as well as high fluorescence quantum yields (Φf), is still a demand for optical imaging. We now present a synthetic route for the preparation of a new group of glycerol-substituted cyanine dyes from dendronized indole precursors that have been functionalized as N-hydroxysuccinimide (NHS) esters. High Φf values of up to 0.15 and extinction coefficients of up to 189 000 L mol(-1) cm(-1) were obtained for the pure dyes. Furthermore, conjugates of the new dendronized dyes with the antibody cetuximab (ctx) that were directed against the epidermal growth factor receptor (EGFR) of tumor cells could be prepared with dye to protein ratios between 0.3 and 2.2 to assess their potential as imaging probes. For the first time, ctx conjugates could be achieved without showing a decrease in Φf and with an increasing labeling degree that exceeded the value of the pure dye even at a labeling degree above 2. The incorporation of hydrophilically and sterically demanding dendrimers into cyanines prevented dimer formation after covalent conjugation to the antibody. The binding functionality of the resulting ctx conjugates to the EGFR was successfully demonstrated by cell microscopy studies using EGFR expressing cell lines. In summary, the combination of hydrophilic glycerol dendrons with reactive dye labels has been established for the first time and is a promising approach toward more powerful fluorescent labels with less dimerization.

To gain insight into the factors that affect stability and transport efficiency under dilution conditions, dendronized and hyperbranched multifunctional amphiphilic polymers are synthesized by following the "grafting to" approach using varied amounts of propargylated alkyl chain with perfect and hyperbranched polyglycerol dendrons on the base copolymer of PEG (Mn: 1000 g mol(-1)) diethylester and 2-azidopropane-1,3-diol following the "bio-catalytic method" and "click approach". The dendronized and hyperbranched polymeric systems form supramolecular aggregates and exhibit an efficient transport potential for the model dye "Nile red" in the low μm range in the core-shell-type architecture provided with distinct amphiphilicity as required for encapsulation. Cytotoxicity studies show the polymeric systems to be non-toxic over a wide concentration range. The cellular internalization of Nile-red-encapsulated supramolecular micellar structures is also studied using cellular fluorescence micro-scopy and fluorescence-activated cell sorting (FACS) measurements. A comparison of the data for the dendronized polymers (PEG Mn: 600/1000 g mol(-1)) with the respective low-molecular-weight amphiphile reveal that these polymeric systems are excellent nanotransporters., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This work describes the formation of a new dendritic polyglycerol-poly(ethylene glycol)-based 3D polymer network as a matrix for immobilization of the redox enzyme periplasmatic aldehyde oxidoreductase to create an electrochemical biosensor. The novel network is built directly on the gold surface, where it simultaneously stabilizes the enzyme for up to 4 days. The prepared biosensors can be used for amperometric detection of benzaldehyde in the range of 0.8-400 μM.

In this study, the extent to which the scaffold architecture of polyglycerol sulfates affects inflammatory processes and hemocompatibility is investigated. Competitive L-selectin binding assays, cellular uptake studies, and blood compatibility readouts are done to evaluate distinct biological properties. Fully glycerol based hyperbranched polyglycerol architectures are obtained by either homopolymerization of glycidol (60% branching) or a new copolymerization strategy of glycidol with ethoxyethyl glycidyl ether. Two polyglycerols with 24 and 42% degree of branching (DB) are synthesized by using different monomer feed ratios. A perfectly branched polyglycerol dendrimer is synthesized according to an iterative two-step protocol based on allylation of the alcohol and subsequent catalytic dihydroxylation. All the polyglycerol sulfates are synthesized with a comparable molecular weight and degree of sulfation. The DB make the different polymer conjugates perform different ways. The optimal DB is 60% in all biological assays., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In this review, we outline the concept and applicability of self-assembling dendrimers for gene-delivery applications. Low-molecular-weight, well-defined cationic dendritic arrays which have been modified with hydrophobic domains can form self-organized multivalent systems that have significant advantages over nonassembling, high-molecular-weight/polymeric gene vectors. Particular structural variations have been highlighted with respect to the individual components of the displayed dendritic amphiphiles, namely, the employed amine termini, the hydrophobic segment, the size of the dendritic array, and the integration of special features such as targeting ability and cleavability/degradability, which can all have a crucial effect on gene-transfection efficiencies. Accordingly, the scientific efforts to create new synthetic gene-delivery vectors to act as promising in vivo transfection agents in the future will be presented and discussed here.

The development of effective polymer-based nanocarriers which are able to target diseased tissues still remains a great challenge in current research. Dendritic polyglycerols have emerged as novel polymeric scaffolds that have demonstrated a great potential for diverse biomedical applications. These architectures have already proven their usefulness in therapeutic approaches related to multivalency, given by the synergy between the nanosized dimensions combined with the high density of functional groups. However, a continuous effort is necessary to modify and tailor polyglycerol architectures to fit the future demands of biomedical applications. The present work deals with the development of a general synthetic strategy that allows the linkage of low molecular weight dendritic polyglycerols to fluorescent dyes and cell targeting ligands. The receptor mediated cellular uptake of the polyglycerol conjugates highlight their potential to acts as new targeted nanocarriers that should be able to decrease non-specific cellular uptake.

Herein we describe a platform technology for the synthesis and characterization of partially aminated, (35)S-labeled, dendritic polyglycerol sulfate (dPG(35)S amine) and fluorescent dPGS indocarbocyanine (ICC) dye conjugates. These polymer conjugates, based on a biocompatible dendritic polyglycerol scaffold, exhibit a high affinity to inflamed tissue in vivo and represent promising candidates for therapeutic and diagnostic applications. By utilizing a one-step sequential copolymerization approach, dendritic polyglycerol (Mn ≈ 4.5 kDa) containing 9.4% N-phthalimide protected amine functionalities was prepared on a large scale. Sulfation and simultaneous radio labeling with (35)SO3 pyridine complex, followed by cleavage of the N-phthalimide protecting groups, yielded dPG(35)S amine as a beta emitting, inflammation specific probe with free amino functionalities for conjugation. Furthermore, efficient labeling procedures with ICC via iminothiolane modification and subsequent "Michael" addition of the maleimide functionalized ICC dye, as well as by amide formation via NHS derivatized ICC on a dPGS amine scaffold, are described. The dPGS-ICC conjugates were investigated with respect to their photophysical properties, and both the radiolabeled and fluorescent compounds were comparatively visualized in histological tissue sections (radio detection and fluorescence microscopy) of animals treated with dPGS. Furthermore, cellular uptake of dPGS-ICC was found in endothelial cord blood (HUVEC) and the epithelial lung cells (A549). The presented synthetic routes allow a reproducible, controlled synthesis of dPGS amine on kilogram scale applying a one-pot batch reaction process. dPGS amine can be used for analysis via radioactivity or fluorescence, thereby creating a new platform for inflammation specific, multimodal imaging purposes using other attachable probes or contrast agents.

Development of effective polymer-based nanocarriers for the successful application in cancer therapy still remains a great challenge in current research. In the present study we present a dendritic polyglycerol-based multifunctional drug immunoconjugate that specifically targets and kills cancer cell lines expressing epidermal growth factor receptor (EGFR). The nanocarrier was provided with a dendritic core as a multifunctional anchoring point, doxorubicin (Doxo) coupled through a pH-sensitive linker, a fluorescence marker, poly(ethylene glycol), as solubilizing and shielding moiety, and a scFv antibody conjugated through the SNAP-Tag technology. The study provides the proof of principle that SNAP-tag technology can be used to generate drug-carrying nanoparticles efficiently modified with single-chain antibodies to specifically target and destroy cancer cells.

In this paper we report a novel approach to generate biodegradable polyglycerol nanogels on different length scales. We developed a mild, surfactant free inverse nanoprecipitation process to template hydrophilic polyglycerol nanoparticles. In situ crosslinking of the precipitated nanoparticles by bioorthogonal copper catalyzed click chemistry allows us to obtain size defined polyglycerol nanogels (100-1000nm). Biodegradability was achieved by the introduction of benzacetal bonds into the net points of the nanogel. Interestingly, the polyglycerol nanogels quickly degraded into low molecular weight fragments at acidic pH values, which are present in inflamed and tumor tissues as well as intracellular organelles, and they remained stable at physiological pH values for a long time. This mild approach to biodegradable polyglycerol nanogels allows us to encapsulate labile biomacromolecules such as proteins, including the therapeutic relevant enzyme asparaginase, into the protein resistant polyglycerol network. Enzymes were encapsulated with an efficacy of 100% and after drug release, full enzyme activity and structural integrity were retained. This new inverse nanoprecipitation procedure allows the efficient encapsulation and release of various biomacromolecules including proteins and could find many applications in polymer therapeutics and nanomedicine., (Copyright © 2012 Elsevier B.V. All rights reserved.)

A new class of non-ionic dendronized multiamphiphilic polymers is prepared from a biodegradable (AB)n-type diblock polymer synthesized from 2-azido-1,3-propanediol (azido glycerol) and polyethylene glycol (PEG)-600 diethylester using Novozym-435 (Candida antarctica lipase) as a biocatalyst, following a well-established biocatalytic route. These polymers are functionalized with dendritic polyglycerols (G1 and G2) and octadecyl chains in different functionalization levels via click chemistry to generate dendronized multiamphiphilic polymers. Surface tension measurements and dynamic light scattering studies reveal that all of the multiamphiphilic polymers spontaneously self-assemble in aqueous solution. Cryogenic transmission electron microscopy further proves the formation of multiamphiphiles towards monodisperse spherical micelles of about 7-9 nm in diameter. The evidence from UV-vis and fluorescence spectroscopy suggests the effective solubilization of hydrophobic guests like pyrene and 1-anilinonaphthalene-8-sulfonic acid within the hydrophobic core of the micelles. These results demonstrate the potential of these dendronized multiamphiphilic polymers for the development of prospective drug delivery systems for the solubilization of poorly water soluble drugs., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A new amphiphilic membrane marker based on a water-soluble dendritic polyglycerol perylene imido dialkylester has been designed, synthesized, and its optical properties characterized. In water it forms fluorescently quenched micellar self-aggregates, but when incorporated into a lipophilic environment, it monomerizes, and the highly fluorescent properties of the perylene core are recovered. These properties make it an ideal candidate for the imaging of artificial and cellular membranes as demonstrated by biophysical studies.

The ability of self-assembling multivalent DNA-binding dendrons to interact with biological targets is modified by co-assembly with two novel low-molecular-weight cholesterol-functionalised PEG units, one based on triethylene glycol (Chol-PEG-3) and one on an octaethylene glycol (Chol-PEG-8). The addition of either PEG lipid affected the co-assembled nanostructure surface charge and size in different ways depending on the structure of the self-assembling DNA-binding dendron. Co-assembly with Chol-PEG-8 enhanced DNA binding, while Chol-PEG-3 inhibited it. Insertion of Chol-PEG-8 into the aggregates modified their ability to cross a model mucus layer, the details of which can be understood in terms of a balance between the mucoadhesivity due to the surface charge of the nanoscale aggregates and that due to the PEG groups. This study demonstrates that the interaction of nanoscale assemblies with biological systems depends on a number of different factors in a sometimes unpredictable way. Given how simply multiple building blocks can be combined by self-assembly, we conclude that self-assembled multivalent systems have great potential for optimisation to maximise their biological and clinical activity.

Development of nonviral vectors for the successful application of gene therapy through siRNA/DNA transfection of cells is still a great challenge in current research. (1, 2) In the present study, we have developed multivalent polyglycerol dendron based amphiphiles with well-defined molecular structures that express controlled glycine arrays on their surfaces. The structure-activity relationships with respect to the siRNA complexation, toxicity, and transfection profiles were studied with synthesized amphiphilic polycations. Our findings revealed that a second-generation amphiphilic dendrimer (G2-octaamine, 4) that has eight amine groups on its surface and a hydrophobic C-18 alkyl chain at the core of the dendron, acts as an efficient vector to deliver siRNA and achieve potent gene silencing by investigating the knockdown of luciferase and GAPDH gene activity in HeLa cells. Interestingly, the amphiphilic vector is nontoxic even at higher ratio of N/P 100. To the best of our knowledge this is the first example of successful in vitro siRNA transfection using dendritic amphiphiles. We believe that this supramolecular complex may serve as a new promising alternative for nonviral siRNA delivery systems and will be investigated for in vivo siRNA delivery in the future.

Among the various polymeric architectures, dendritic polymers have received a substantial scientific focus for their highly branched, multifunctional, and well-defined structures. Dendritic scaffolds have found many applications for designing nanoscale drug/gene delivery carriers and constructing diagnostic and biosensor devices, and protein-resistant surfaces. A significant number of research groups across Europe share the common objective, yet in conspicuously individual ways, of utilizing such polymers for devising innovative biomedical tools and techniques. This review describes the European effort of finding the application of dendritic polymers as advanced generation therapeutics within the purview of nanomedicine., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Nanotechnology has resulted in materials that have greatly improved the effectiveness of drug delivery because of their ability to control matter on the nanoscale. Advanced forms of nanomedicine have been synthesized for better pharmacokinetics to obtain higher efficacy, less systemic toxicity, and better targeting. These criteria have long been the goal in nanomedicine, in particular, for systemic applications in oncological disorders. Now, the "holy grail" in nanomedicine is to design and synthesize new advanced macromolecular nanocarriers and to translate them from lab to clinic. This review describes the current and future perspectives of nanomedicine with particular emphasis on the clinical targets in cancer and inflammation. The advanced forms of liposomes and polyethylene glycol (PEG) based nanocarriers, as well as dendritic polymer conjugates will be discussed with particular attention paid to designs, synthetic strategies, and chemical pathways. In this critical review, we also report on the current status and perspective of dendritic polymer nanoconjugate platforms (e.g. polyamidoamine dendrimers and dendritic polyglycerols) for cellular localization and targeting of specific tissues (192 references).

We present a highly selective approach for the targeting of inflammation with a multivalent polymeric probe. Dendritic polyglycerol was employed to synthesize a polyanionic macromolecular conjugate with a near-infrared fluorescent dye related to Indocyanine Green (ICG). On the basis of the dense assembly of sulfate groups which were generated from the polyol core, the resulting polyglycerol sulfate (molecular weight 12 kD with ~70 sulfate groups) targets factors of inflammation (IC(50) of 3-6 nM for inhibition of L-selectin binding) and is specifically transported into inflammatory cells. The in vivo accumulation studied by near-IR fluorescence imaging in an animal model of rheumatoid arthritis demonstrated fast and selective uptake which enabled the differentiation of diseased joints (score 1-3) with a 3.5-fold higher fluorescence level and a signal maximum at 60 min post injection. Localization in tissues using fluorescence histology showed that the conjugates are deposited in the inflammatory infiltrate in the synovial membrane, whereas nonsulfated control was not detected in association with disease. Hence, this type of polymeric imaging probe is an alternative to current bioconjugates and provides future options for targeted imaging and drug delivery.

A versatile route for the synthesis of highly functionalized, polyanionic macromolecules based on dendritic polyglycerol was applied by means of the Huisgen-Sharpless-Meldal 1,3-dipolar cycloaddition ("click-reaction") of polyglycerolazide precursors and alkyne-functionalized anions such as sulfonates, carboxylates, phosphonates, and bisphosphonates. In addition, the corresponding polyglycerol phosphate has been synthesized via direct hydroxyl interconversion of polyglycerol to the corresponding phosphate with a degree of functionalization >80% by analogy to the synthesis of previously reported polyglycerol sulfates (dPGS). On the basis of the finding that dPGS exhibits high affinity for L- and P-selectin, the potential of these novel polyanionic, multivalent macromolecules of varying anionic nature as L-selectin inhibitors has been evaluated in vitro by means of a competitive concentration dependent binding assay. Affinity of all polyanions toward L-selectin was demonstrated with distinct IC(50) values ranging from the low nanomolar to the high micromolar range. The efficiency of L-selectin inhibition increases in the order carboxylate < phosphate < phosphonate ≈ sulfonate < bisphosphonate < sulfate. Additional DLS and ζ-potential measurements of these polyanions were performed to correlate their binding affinity toward L-selectin with their anionic nature. However, a direct correlation of effective charge and particle size with the determined IC(50) values turned out to require further in-depth studies on the microstructure of the polyanions but clearly indicate an exceptional position of dPGS among the studied dendritic polyelectrolytes.

The synthesis and aggregation behavior of photo-switchable, nonionic dendritic amphiphiles was investigated with regard to transport and release of guest molecules. The correlation between the critical micelle concentration and the switching ability is shown., (This journal is © The Royal Society of Chemistry 2011)

In an attempt to explore the potential of dendritic systems for the development of effective anticancer drug delivery systems, we explored a simple modular approach of preparing polyglycerol doxorubicin prodrugs, with flexibility for drug loading using an acid-sensitive hydrazone linker and further post-modification with poly(ethylene glycol) shell. The resulting drug polymer conjugates showed optimal properties for in vitro and in vivo applications because of their high water solubility, an appropriate size for passive tumor targeting, a high stability at physiological conditions, pronounced acid-sensitive properties, cellular internalization, and a favorable toxicity profile. Doxorubicin polyglycerol conjugates with a high drug loading ratio showed clearly improved antitumor efficacy over doxorubicin in an ovarian xenograft tumor model (A2780) inducing transient complete remissions thus demonstrating the potential of developing efficient multifunctional dendritic drug delivery using our modular approach., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Polymeric nanocarriers possess advanced physicochemical properties that improve bioavailability, enhance cellular dynamics, and control target ability in drug delivery. In particular, dendritic polyglycerol is a promising new biocompatible scaffold for drug delivery. The present study explores the chemo-enzymatic modifications on dendritic hyperbranched polyglycerol (dPG) leading to amphiphilic polymeric architectures with easily hydrolysable ester linkages. Furthermore, these architectures were studied for nile red solubilization with capacity up to 5.6 mg/L at 0.1 wt % polymer conc. This corresponds to an ~10 fold increase in solubility of nile red. The release of nile red from these polymers was observed with a half life of 8 hours at pH 5.0, while no release was found at pH 7.4. The cell viability studies of our polymeric architectures showed them to be relatively nontoxic and to have the potential for future drug delivery applications.

Adhesive interactions of leukocytes and endothelial cells initiate leukocyte migration to inflamed tissue and are important for immune surveillance. Acute and chronic inflammatory diseases show a dysregulated immune response and result in a massive efflux of leukocytes that contributes to further tissue damage. Therefore, targeting leukocyte trafficking may provide a potent form of anti-inflammatory therapy. Leukocyte migration is initiated by interactions of the cell adhesion molecules E-, L-, and P-selectin and their corresponding carbohydrate ligands. Compounds that efficiently address these interactions are therefore of high therapeutic interest. Based on this rationale we investigated synthetic dendritic polyglycerol sulfates (dPGS) as macromolecular inhibitors that operate via a multivalent binding mechanism mimicking naturally occurring ligands. dPGS inhibited both leukocytic L-selectin and endothelial P-selectin with high efficacy. Size and degree of sulfation of the polymer core determined selectin binding affinity. Administration of dPGS in a contact dermatitis mouse model dampened leukocyte extravasation as effectively as glucocorticoids did and edema formation was significantly reduced. In addition, dPGS interacted with the complement factors C3 and C5 as was shown in vitro and reduced C5a levels in a mouse model of complement activation. Thus, dPGS represent an innovative class of a fully synthetic polymer therapeutics that may be used for the treatment of inflammatory diseases.

RNA interference provides great opportunities for treating diseases from genetic disorders, infection, and cancer. The successful application of small interference RNA (siRNA) in cells with high transfection efficiency and low cytotoxicity is, however, a major challenge in gene-mediated therapy. Several pH-responsive core shell architectures have been designed that contain a nitrogen shell motif and a polyglycerol core, which has been prepared by a two-step protocol involving the activation of primary and secondary hydroxyl groups by phenyl chloroformate and amine substitution. Each polymer was analyzed by particle size and ζ potential measurements, whereas the respective polyplex formation was determined by ethidium bromide displacement assay, atomic force microscopy (AFM), and surface charge analysis. The in vitro gene silencing properties of the different polymers were evaluated by using a human epithelial carcinoma cell (HeLaS3) line with different proteins (Lamin, CDC2, MAPK2). Polyplexes yielded similar knockdown efficiencies as HiPerFect controls, with comparably low cytotoxicity. Therefore, these efficient and highly biocompatible dendritic polyamines are promising candidates for siRNA delivery in vivo.

Stimuli-responsive polymer architectures are molecular systems which evolve with an external signal. The observed changes are mainly decomposition, isomerization, polymerization, activation, supramolecular aggregation, and structural modifications of these molecules. The external stimuli, which can be combined in order to provoke these molecular changes, are numerous. In this review, we have chosen to present an overview on different mechanisms to impart responsiveness to dendritic polymers, with the particular aim of delivery and release of bioactive molecules., (Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.)

New targets for RNA interference (RNAi)-based cancer therapy are constantly emerging from the increasing knowledge on key molecular pathways that are paramount for carcinogenesis. Nevertheless, in vivo delivery of small interfering RNA (siRNA) remains a crucial challenge for therapeutic success. siRNAs on their own are not taken up by most mammalian cells in a way that preserves their activity. Moreover, when applied in vivo, siRNA-based approaches are all limited by poor penetration into the target tissue and low silencing efficiency. To circumvent these limitations, we have developed novel polymerized polyglycerol-based dendrimer core shell structures to deliver siRNA to tumors in vivo. These cationic dendrimers can strongly improve the stability of the siRNA, its intracellular trafficking, its silencing efficacy, and its accumulation in the tumor environment owing to the enhanced permeability and retention effect. Here, we show that our dendritic nanocarriers exhibited low cytotoxicity and high efficacy in delivering active siRNA into cells. With use of human glioblastoma and murine mammary adenocarcinoma cell lines as model systems, these siRNA-dendrimer polyplexes silenced the luciferase gene, ectopically overexpressed in these cells. Importantly, significant gene silencing was accomplished in vivo within 24 h of treatment with our luciferase siRNA-nanocarrier polyplexes, as measured by noninvasive intravital bioluminescence imaging. Moreover, our siRNA-nanocarriers show very low levels of toxicity as no significant weight loss was observed after intravenous administration of the polyplexes. We show a proof of concept for siRNA delivery in vivo using a luciferase-based model. We predict that in vivo silencing of important cell growth and angiogenesis regulator genes in a selective manner will justify this approach as a successful anticancer therapy.

In this paper we report on the synthesis of a new family of nonionic dendritic amphiphiles that self-assemble into defined supramolecular aggregates. Our approach is based on a modular architecture consisting of different generations of hydrophilic polyglycerol dendrons [G1-G3] connected to hydrophobic C(11) or C(16) alkyl chains via mono- or biaromatic spacers, respectively. All amphiphiles complex hydrophobic compounds as demonstrated by solubilization of Nile Red or pyrene. The structure of the supramolecular assemblies as well as the aggregation numbers are strongly influenced by the type of the dendritic headgroup. While the [G1] amphiphiles form different structures such as ringlike and fiberlike micelles, the [G2] and [G3] derivatives aggregate toward spherical micelles of low polydispersity clearly proven by transmission electron microscopy (TEM) measurements. In the case of the biaromatic [G2] derivative, the structural persistence of the micelles allowed a three-dimensional structure determination from the TEM data and confirmed the aggregation number obtained by static light scattering (SLS) measurements. On the basis of these data, molecular packing geometries indicate a drastic mass deficit of alkyl chains in the hydrophobic core volume of spherical micelles. It is noteworthy that these highly defined micelles contain as little as 15 molecules and possess up to 74% empty space. This behavior is unexpected as it is very different from classical detergent micelles such as sodium dodecyl sulfate (SDS), where the hydrophobic core volume is completely filled by alkyl chains.

Nanocarriers possess advanced physicochemical properties that improve bioavailability, enhance cellular dynamics, and control targetability in drug delivery. In particular, dendritic polyglycerol is a promising new biocompatible scaffold for drug delivery. The present explores the structure-biocompatibility relationship of dendritic polyglycerol (dPG) derivatives possessing neutral, cationic, and anionic charges. The effect of solution pH on the surface charge was studied in buffered aqueous solution between pH 4.8 and 7.4. Surface charge properties of dPG derivatives are discussed in terms of surface functionalities and compared with amine and hydroxyl terminated polyamidoamine (PAMAM) dendrimers. Zeta potential measurements and fluorescence quenching studies address the binding interactions of dPGs to bovine serum albumin in order to explore the applicability of dPG derivatives for systemic delivery. Cellular entry of dPG-dye conjugate was evaluated using A549 lung epithelial cells, while in vitro toxicity was studied for various dPGs and compared to PAMAM dendrimers, polyethyleneimine (PEI), dextran, and linear polyethylene glycol (PEG) using human hematopoietic cell line U-937. Cellular uptake studies of dye labelled dPGs inferred that the charged derivatives (dPG-sulfate and dPG-amine) are more rapidly internalized primarily inside the cytosol of A549 cells compared to the neutral dPG. The cell compatibility results show that the dendritic polyglycerols are as safe as linear PEG polymer or dextran, which indicates the suitability of dPG derivatives in delivering therapeutic agents systemically., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

The purpose of this study was to investigate dendritic glycerol-based amphiphiles as novel solubilizers using poorly water-soluble anticancer drug Sagopilone. The effect of different core structures on the solubilization, formulation stability, and cytotoxicity using human umbilical vein endothelial cells (HUVECs) were investigated and compared to standard excipients. Structurally, all amphiphiles were composed of 2nd generation polyglycerol (PG[G2]) as the hydrophilic part and a single C(18)-chain (PG[G2]-C(18)), a C(18)-chain coupled by a diaromatic spacer (PG[G2]-DiAr-C(18)), a C(18)-chain with a naphthyl or bisphenyl end group (PG[G2]-C(18)-Naph/-BiP), or two C(18)-chains (PG[G2]-(C(18))(2)) as the hydrophobic part. They formed small (7-10 nm), monodisperse (PDI 0.04-0.20) micelles with the exception of PG[G2]-(C(18))(2). The amphiphiles revealed a 2-3-fold higher solubilization of Sagopilone than Cremophor ELP and polysorbate 80 independent of the core structure. PG[G2]-DiAr-C(18) exhibited the highest solubilization capacity (56.7+/-1.3 mg/g) compared to Cremophor ELP (18.5+/-0.1 mg/g). The micellar dispersions were stable in drug content over 3 days (> or = 97%). In contrast to polysorbate 80, dilutions did not show any precipitation after 3 days at 37 degrees C (remaining drug content: > 95%). They did not induce significant cytotoxicity at a concentration of 0.01 g/L after 24 h, and PG[G2]-C(18)-Naph was the least cytotoxic structure after 72 h with values comparable to Cremophor ELP and polysorbate 80. Overall, these amphiphiles possess superior solubilization properties compared to standard excipients used in parenteral formulations with an excellent formulation stability profile and comparable cytotoxicity., (2010 Elsevier B.V. All rights reserved.)

The application of nanotechnology in medicine and pharmaceuticals is a rapidly advancing field that is quickly gaining acceptance and recognition as an independent area of research called "nanomedicine". Urgent needs in this field, however, are biocompatible and bioactive materials for antifouling surfaces and nanoparticles for drug delivery. Therefore, extensive attention has been given to the design and development of new macromolecular structures. Among the various polymeric architectures, dendritic ("treelike") polymers have experienced an exponential development due to their highly branched, multifunctional, and well-defined structures. This Review describes the diverse syntheses and biomedical applications of dendritic polyglycerols (PGs). These polymers exhibit good chemical stability and inertness under biological conditions and are highly biocompatible. Oligoglycerols and their fatty acid esters are FDA-approved and are already being used in a variety of consumer applications, e.g., cosmetics and toiletries, food industries, cleaning and softening agents, pharmaceuticals, polymers and polymer additives, printing photographing materials, and electronics. Herein, we present the current status of dendritic PGs as functional dendritic architectures with particular focus on their application in nanomedicine, in drug, dye, and gene delivery, as well as in regenerative medicine in the form of non-fouling surfaces and matrix materials.