Small Dendrimers Research Articles

Targeting the phosphatidylglycerol lipid: An amphiphilic dendrimer as a promising antibacterial candidate.

The rapid emergence and spread of multidrug-resistant bacterial pathogens require the development of antibacterial agents that are robustly effective while inducing no toxicity or resistance development. In this context, we designed and synthesized amphiphilic dendrimers as antibacterial candidates. We report the promising potent antibacterial activity shown by the amphiphilic dendrimer AD1b, composed of a long hydrophobic alkyl chain and a tertiary amine-terminated poly(amidoamine) dendron, against a panel of Gram-negative bacteria, including multidrug-resistant Escherichia coli and Acinetobacter baumannii. AD1b exhibited effective activity against drug-resistant bacterial infections in vivo. Mechanistic studies revealed that AD1b targeted the membrane phospholipids phosphatidylglycerol (PG) and cardiolipin (CL), leading to the disruption of the bacterial membrane and proton motive force, metabolic disturbance, leakage of cellular components, and, ultimately, cell death. Together, AD1b that specifically interacts with PG/CL in bacterial membranes supports the use of small amphiphilic dendrimers as a promising strategy to target drug-resistant bacterial pathogens and addresses the global antibiotic crisis.

Core-size and geometry versus toxicity in small amino terminated PAMAM dendrimers.

A series of 6 small PAMAM dendrimers (G0-dendrimers) differing in the size, polarity and flexibility has been synthesized. The toxicity has been investigated in three different human cancer cell lines (HeLa, MCF-7, THP-1) and the endothelial skin cell line HMEC-1 in order to evaluate their potential as vehicles for drug delivery.

A size shrinkable dendrimer-lipid hybrid nanoassembly for reversing tumor drug resistance

Drug resistance is a major obstacle in tumor therapy. One effective approach to overcoming this issue is by improving the penetration of drugs into the lesions. Here, we report size shrinkable dendrimer-lipid hybrid nanoassemblies (PATU-lipid-PEG/DOX). The PATU-lipid-PEG/DOX have initial sizes of ∼92 nm, which are ideal for blood circulation and tumor vascular penetration. Once PATU-lipid-PEG/DOX at tumor sites, they will disassemble and release small dendrimers (∼3 nm) to realize deep tumor penetration. As a result, Doxorubicin (DOX) can be delivered intracellularly, thereby reversing tumor multidrug resistance. The efficacy of PATU-lipid-PEG/DOX was validated in drug-resistant tumor mice. This study provides a versatile drug delivery platform to address the challenges of tumor drug resistance.

The novel HS-mimetic, Tet-29, regulates immune cell trafficking across barriers of the CNS during inflammation

BackgroundDisruption of the extracellular matrix at the blood–brain barrier (BBB) underpins neuroinflammation in multiple sclerosis (MS). The degradation of extracellular matrix components, such as heparan sulfate (HS) proteoglycans, can be prevented by treatment with HS-mimetics through their ability to inhibit the enzyme heparanase. The heparanase-inhibiting ability of our small dendrimer HS-mimetics has been investigated in various cancers but their efficacy in neuroinflammatory models has not been evaluated. This study investigates the use of a novel HS-mimetic, Tet-29, in an animal model of MS.MethodsNeuroinflammation was induced in mice by experimental autoimmune encephalomyelitis, a murine model of MS. In addition, the BBB and choroid plexus were modelled in vitro using transmigration assays, and migration of immune cells in vivo and in vitro was quantified by flow cytometry.ResultsWe found that Tet-29 significantly reduced lymphocyte accumulation in the central nervous system which, in turn, decreased disease severity in experimental autoimmune encephalomyelitis. The disease-modifying effect of Tet-29 was associated with a rescue of BBB integrity, as well as inhibition of activated lymphocyte migration across the BBB and choroid plexus in transwell models. In contrast, Tet-29 did not significantly impair in vivo or in vitro steady state-trafficking under homeostatic conditions.ConclusionsTogether these results suggest that Tet-29 modulates, rather than abolishes, trafficking across central nervous system barriers.

Mechanistic Studies for the Rational Design of Multivalent Glycodendrimers.

We have synthesized B-antigen-displaying dendrimers (16-mers) with different sizes and evaluated their affinity to their IgM antibody in order to investigate which design features lead to effective multivalency. Unexpectedly, the smallest dendrimer, which cannot chelate the multiple binding sites of IgM, clearly exhibited multivalency, together with an affinity similar to or higher than those of the larger dendrimers. These results indicate that the statistical rebinding model, which involves the rapid exchange of clustered glycans, significantly contributes to the multivalency of glycodendrimers. Namely, in the design of glycodendrimers, high-density glycan presentation to enhance statistical rebinding should be considered in addition to the ability to chelate multiple binding sites. This notion stands in contrast to the currently prevailing scientific consensus, which prioritizes the chelation model. This study thus provides new and important guidelines for molecular design of glycodendrimers.

Amphiphilic Dendritic Nanomicelle-Mediated Delivery of Gemcitabine for Enhancing the Specificity and Effectiveness

PurposeGemcitabine is the first line and the gold standard drug for pancreatic cancer. However, the anticancer efficacy is severely limited by its instability and poor cellular uptake. To enhance the clinical efficacy of gemcitabine, we constructed a novel nanodrug delivery system based on amphiphilic dendrimers and aliphatic gemcitabine prodrug.MethodsAn aliphatic gemcitabine prodrug and a small amphiphilic dendrimer were synthesized and characterized by high resolution mass spectrometry (HRMS) as well as nuclear magnetic resonance (NMR). Then the aliphatic gemcitabine prodrug was encapsulated into the small amphiphilic dendrimer by film dispersion method, resulting in a novel nanodrug delivery system. Subsequently, the size, morphology, drug loading, stability, drug release profiles, cell uptake, toxicity, the anticancer activity and in vivo distribution of the new developed gemcitabine delivery system were systematically evaluated by different technical methods, including transmission electron microscopy (TEM), dynamic light-scattering (DLS), ultraviolet spectrophotometer, flow cytometry, in vivo imaging system etc.ResultsWe developed a novel nanodrug delivery system of gemcitabine using amphiphilic dendrimer. This dendrimer-based gemcitabine nanoformulation reported here possess a high drug loading of 33%. With the features of small size, stable formulation and pH-responsive drug release, the obtained gemcitabine nanoformulation could effectively accumulate in tumor site and rapid uptake in cells. Finally, the gemcitabine nanoformulation displayed more potent anticancer activity compared to free gemcitabine both in vitro and in vivo. Moreover, the nanodrug displayed greatly reduced adverse effects and satisfactory biocompatibility.ConclusionBenefiting the advantageous features of both amphiphilic dendrimers and nanotechnology-based drug delivery, this gemcitabine nanosystem constitutes a promising therapeutic candidate for pancreatic cancer treatment. This study also underlines the potential use of self-assembling amphiphilic dendrimer-based nanotechnology for improving drug efficacy as well as reducing drug toxicity.

Fluorescent dendrimer-based probes for cell membrane imaging: Zebrafish epidermal labeling-based toxicity evaluation

Visualizing the plasma membrane of living mammalian cells both in vitro and in vivo is crucial for tracking their cellular activities. However, due to the complex and dynamic nature of the plasma membrane, most commercial dyes for membrane staining can only realize very limited imaging performance. Thus, precise and stable plasma membrane imaging remains technically challenging. Here, by taking advantage of the small, well-defined, and amine-rich dendrimers, we prepared poly(ethylene glycol)-cholesterol (PEG-Chol)-conjugated and cyanine dye (e.g., cyanine2, cyanine3, and cyanine5)-labeled dendrimer nanoprobes (termed DPC-Cy2, DPC-Cy3, and DPC-Cy5 NPs). It was revealed that these probes enabled universal, wash-free, long-term (at least 8 h), and multicolor (green, yellow, and red) plasma membrane labeling of a variety of live mammalian cells. Further, we confirmed that the nanoprobes (using DPC-Cy5 as a representative) could achieve high-quality, wash-free, and stable cell surface labeling of live zebrafish embryos. More importantly, we demonstrated that our probes could act as biosensors to visualize the toxicity of metal–organic frameworks (MOFs) toward the epidermal cells of zebrafish embryos, and thus they hold great potential for identifying the toxic effect of drugs/materials at the single-cell scale or in live animals. The present work highlights the advantages of utilizing dendrimers for constructing functional imaging materials, and it is also believed that the fluorescent dendrimer nanoprobes developed in this work may find wide applications like cell imaging, drug toxicity evaluation, and cellular state monitoring.

Toward Electrically Pumped Organic Lasers: A Review and Outlook on Material Developments and Resonator Architectures

Organic lasers have undergone decades of development. A myriad of materials with excellent optical gain properties, including small molecules, dendrimers, and polymers, have been demonstrated. Various resonator geometries have also been applied. While sharing the advantages of the solution processability and mechanical flexibility features of organic materials, organic optical gain media also offer interesting optical properties, such as emission tunability through chemical functionalization and inherent large optical gain coefficients. They offer prospects for different applications in the fields of bioimaging, medicine, chemo‐ and biosensing, anticounterfeit applications, or displays. However, the realization of electrically pumped organic lasers still remains a challenge due to the inherent drawbacks of organic semiconductors, e.g., modest carrier mobility, long‐lived excited‐state absorption, and extra losses which originate in the device (e.g., absorption from metal electrodes). Herein, the past developments of organic lasers are discussed, highlighting the importance of materials and cavities with regard to the goal of electrically pumped organic lasers. The latest progress and the possible ways to address the challenge are discussed.

Self-Assembling Supramolecular Dendrimers for Biomedical Applications: Lessons Learned from Poly(amidoamine) Dendrimers.

Dendrimers, notable for their well-defined radial structures with numerous terminal functionalities, hold great promise for biomedical applications such as drug delivery, diagnostics, and therapeutics. However, their translation into clinical use has been greatly impeded by their challenging stepwise synthesis and difficult purification.To circumvent these obstacles, we have pioneered a self-assembly approach to constructing noncovalent supramolecular dendrimers using small amphiphilic dendrimer building units which can be easily synthesized and purified. By virtue of their amphipathic nature, the small amphiphilic dendrimers are able to self-assemble and generate large supramolecular dendrimers via noncovalent weak interactions such as van der Waals forces, H bonds, and electrostatic interactions. The so-created noncovalent dendrimers can mimic covalent dendrimers not only in terms of the radial structural feature emanating from a central core but also in their capacity to deliver drugs and imaging agents for biomedical applications. The noncovalent supramolecular dendrimers can be easily synthesized and modulated with regard to size, shape, and properties by varying the nature of the hydrophobic and hydrophilic entities as well as the dendrimer generation and terminal functionalities, ensuring their adaptability to specific applications. In particular, the dendritic structure of the amphiphilic building units permits the creation of large void spaces within the formed supramolecular dendrimers for the physical encapsulation of drugs, while the large number of surface functionalities can be exploited for both physical and chemical conjugation of pharmaceutic agents for drug delivery.Poly(amidoamine) (PAMAM) dendrimers are the most intensively studied for biomedical applications by virtue of their excellent biocompatibility imparted by their peptide-mimicking amide backbones and numerous interior and terminal amine functionalities. We present a short overview of our self-assembly strategy for constructing supramolecular PAMAM dendrimers for biomedical applications. Specifically, we start with the introduction of dendrimers and their synthesis, focusing on the innovative self-assembly synthesis of supramolecular dendrimers. We then detail the representative examples of the noncovalent supramolecular PAMAM dendrimers established in our group for the delivery of anticancer drugs, nucleic acid therapeutics, and imaging agents, either within the dendrimer interior or at the dendrimer terminals on the surface. Some of the supramolecular dendrimer nanosystems exhibit outstanding performance, excelling the corresponding clinical anticancer therapeutics and imaging agents. This self-assembly approach to creating supramolecular dendrimers is completely novel in concept yet easy to implement in practice, offering a fresh perspective for exploiting the advantageous features of dendrimers in biomedical applications.

An ionizable supramolecular dendrimer nanosystem for effective siRNA delivery with a favorable safety profile

Gene therapy using small interfering RNA (siRNA) is emerging as a novel therapeutic approach to treat various diseases. However, safe and efficient siRNA delivery still constitutes the major obstacle for clinical implementation of siRNA therapeutics. Here we report an ionizable supramolecular dendrimer vector, formed via self-assembly of a small amphiphilic dendrimer, as an effective siRNA delivery system with a favorable safety profile. By virtue of the ionizable tertiary amine terminals, the supramolecular dendrimer has a low positively charged surface potential and no notable cytotoxicity at physiological pH. Nonetheless, this ionizable feature imparted sufficient surface charge to the supramolecular dendrimer to enable formation of a stable complex with siRNA via electrostatic interactions. The resulting siRNA/dendrimer delivery system had a surface charge that was neither neutral, thus avoiding aggregation, nor too high, thus avoiding cytotoxicity, but was sufficient for favorable cellular uptake and endosomal release of the siRNA. When tested in different cancer cell lines and patient-derived cancer organoids, this dendrimer-mediated siRNA delivery system effectively silenced the oncogenes Myc and Akt2 with a potent antiproliferative effect, outperforming the gold standard vector, Lipofectamine 2000. Therefore, this ionizable supramolecular dendrimer represents a promising vector for siRNA delivery. The concept of supramolecular dendrimer nanovectors via self-assembly is new, yet easy to implement in practice, offering a new perspective for supramolecular chemistry in biomedical applications.

Straightforward synthesis of gold nanoparticles by adding water to an engineered small dendrimer.

A small water-soluble phosphorus-containing dendrimer was engineered for the complexation of gold(I) and for its reduction under mild conditions. Gold nanoparticles were obtained as colloidal suspensions simply and only when the powdered form of this dendrimer was dissolved in water, as shown by transmission electron microscopy (TEM) and energy dispersive X-ray spectroscopy (EDX) analyses. The dendrimers acted simultaneously as mild reducers and as nanoreactors, favoring the self-assembly of gold atoms and promoting the growth and stabilization of isolated gold nanoparticles. Thus, an unprecedented method for the synthesis of colloidal suspensions of water-soluble gold nanoparticles was proposed in this work.

Ir(0) and Pt(0) nanoparticle-triazine dendrimer composites

The formation of M@dendrimer composites (M = platinum, iridium) is reported, at room temperature, by mechanical milling of commercially available metallic precursors, sodium borohydride and small generation triazine-based dendrimers. After impurity removal, the composites are characterized by TEM showing spherical, worm-like or agglomerated nanoparticles depending upon the macromolecule stabilizer used. As a test of the surface activity of the metallic nanoparticles, the study of activity of the composites on the catalytic reduction of 4-nitrophenol show differences for each metal employed and suggest that surface of the NPs is not passivated by the presence of the stabilizer dendrimers.

Intratumor Performance and Therapeutic Efficacy of PAMAM Dendrimers Carried by Clustered Nanoparticles.

In recent years, small nanoparticles (NPs) with a diameter ofless than 10 nm have aroused considerable interest in biomedical applications. However, their intratumor performance, as well as the antitumor efficacy, has not been well understood due to their size-dependent pharmacokinetics, which presents a formidable challenge for delivering a comparable amount of different small NPs to tumor tissues. Utilizing the multistage delivery strategy, we construct G3-, G5-, and G7-iCluster delivery systems by using poly(amidoamine) (PAMAM) dendrimers of different generations (G3-, G5-, and G7-PAMAM) as building blocks. The iCluster nanoparticles showed comparable pharmacokinetics and similar initial tumor deposition due to their similarity in size and surface chemistry. After accumulating at a tumor site, individual small dendrimers were released, and thus, their intratumor performance was comparatively investigated. Our results indicated that a subtle change in generation markedly affects their intratumor activities. G5-iCluster outperformed G3-iCluster and G7-iCluster in the treatment efficacy in an orthotopic pancreatic tumor model. The mechanistic study revealed that G3-PAMAM showed reduced particle retention in tumor tissue due to its small size and weak cell internalization, while G7-PAMAM was much less penetrative because of its relatively large size and strong particle-cell interaction. In contrast, G5-PAMAM exhibited balanced tumor penetration, cell internalization, and tumor retention. Our finding highlights the huge influence of the subtle difference of small NPs in their intratumor performance.

Tumor Uptake of Triazine Dendrimers Decorated with Four, Sixteen, and Sixty-Four PSMA-Targeted Ligands: Passive versus Active Tumor Targeting.

Various glutamate urea ligands have displayed high affinities to prostate specific membrane antigen (PSMA), which is highly overexpressed in prostate and other cancer sites. The multivalent versions of small PSMA-targeted molecules are known to be even more efficiently bound to the receptor. Here, we employ a well-known urea-based ligand, 2-[3-(1,3-dicarboxypropyl)-ureido] pentanedioic acid (DUPA) and triazine dendrimers in order to study the effect of molecular size on multivalent targeting in prostate cancer. The synthetic route starts with the preparation of a dichlorotriazine bearing DUPA in 67% overall yield over five steps. This dichlorotriazine reacts with G1, G3, and G5 triazine dendrimers bearing a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) group for 64Cu-labeling at the core to afford poly(monochlorotriazine) intermediates. Addition of 4-aminomethylpiperidine (4-AMP) and the following deprotection produce the target compounds, G1-(DUPA)4, G3-(DUPA)16, and G5-(DUPA)64. These targets include 4/16/64 DUPA groups on the surface and a DOTA group at the core, respectively. In vitro cell assay using PC3-PIP (PSMA positive) and PC3-FLU (PSMA negative) cells reveals that G1-(DUPA)4 has the highest PC3-PIP to PC3-FLU uptake ratio (10-fold) through the PSMA-mediated specific uptake. While G5-(DUPA)64 displayed approximately 12 times higher binding affinity (IC50 23.6 nM) to PC3-PIP cells than G1-(DUPA)4 (IC50 282.3 nM) as evaluated in a competitive binding assay, the G5 dendrimer also showed high non-specific binding to PC3-FLU cells. In vivo uptake of the 64Cu-labeled dendrimers was also evaluated in severe combined inmmunodeficient (SCID) mice bearing PC3-PIP and PC3-FLU xenografts on each shoulder, respectively. Interestingly, quantitative imaging analysis of positron emission tomograph (PET) displayed the lowest tumor uptake in PC3-PIP cells for the midsize dendrimer G3-(DUPA)16 (19.4 kDa) (0.66 ± 0.15%ID/g at 1 h. p.i., 0.64 ± 0.11%ID/g at 4 h. p.i., and 0.67 ± 0.08%ID/g at 24 h. p.i.). Through the specific binding of G1-(DUPA)4 to PSMA, the smallest dendrimer (5.1 kDa) demonstrated the highest PC3-PIP to muscle and PC3-PIP to PC3-FLU uptake ratios (17.7 ± 5.5 and 6.7 ± 3.0 at 4 h p.i., respectively). In addition, the enhanced permeability and retention (EPR) effect appeared to be an overwhelming factor for tumor uptake of the largest dendrimer G5-(DUPA)64 as the uptake was at a similar level irrelevant to the PSMA expression.

Design Strategy for Solution‐Processable Thermally Activated Delayed Fluorescence Emitters and Their Applications in Organic Light‐Emitting Diodes

AbstractSolution‐processable thermally activated delayed fluorescence (TADF) emitters have received tremendous attentions in recent years due to their intrinsic merits of theoretical 100% exciton harvesting capability and excellent compatibility to low‐cost and easily scalable solution processes. Herein, a comprehensive review of solution‐processable TADF emitters is presented, including small molecules, dendrimers, and polymers. Their molecular design, optoelectronic properties, and device performances are summarized, and specific emphasis is placed on the structure–property relationships of these emitters. This review not only offers a guideline for designing highly efficient TADF emitters compatible with solution‐processed organic light‐emitting diodes, but also paves further directions for the development of solution‐processable TADF emitters.

Synthesis and properties of carbosilane dendrimers with perfluorohexyl groups in the outer layer of the molecular structure

Branched perfluorohydrosiloxane with CF3CF2CF2C(CF3)2(CH2)3 groups at the silicon atom was synthesized by a sequence of chemical reactions. The resulting compound was used as a modifying agent for carbosilane dendrimers of the 3rd and 6th generations. Dendrimers with perfluorohexyl terminal groups in surface layer are characterized by a complex of physicochemical methods. It is demonstrated that due to the branching of perfluoroalkyl terminal groups, obtained carbosilane dendrimers are soluble in organic and inorganic media. Differences in the solubility of small and large dendrimers are caused by the formation of the outer fluoride shell of different densities.

Recent progress in solution processable TADF materials for organic light-emitting diodes

Molecular design and recent progress on solution-processed TADF materials in OLEDs, including small molecules, polymers and dendrimers, is reviewed.

Study of non-covalent interactions on dendriplex formation: Influence of hydrophobic, electrostatic and hydrogen bonds interactions

The interaction of a double stranded small interference RNA (siRNA Nef) with cationic carbosilane dendrimers of generations 1–3 with two different ammonium functions at the periphery ([−NMe2R]+, R=Me, (CH2)2OH) has been studied by experimental techniques (zeta potential, electrophoresis, single molecule pulling experiments) and molecular dynamic calculations. These studies state the presence of different forces on dendriplex formation, depending on generation and type of ammonium group. Whilst for higher dendrimers electrostatic forces mainly drive the stability of dendriplexes, first generation compounds can penetrate into siRNA strands due to the establishment of hydrophobic interactions. Finally, in the particular case of first generation dendrimer [G1O3(NMe2(CH2)2OH))6]6+; the presence of hydroxyl groups reinforces dendriplex stability by hydrogen bonds formation. However, since these small dendrimers do not cover the RNA, only higher generation derivatives protect RNA from degradation.

Rapid Synthesis of Functionalized High-Generation Polyester Dendrimers via Strain-Promoted Alkyne–Azide Cycloaddition

Preparation of structurally perfect high-generation dendrimer libraries with different peripheral groups is challenging as divergent synthesis introduces peripheral defects and convergent synthesis leads to low yields. Here, we prepare a third-generation polyester dendron based on the bisMPA monomer structure, having eight peripheral azide functionalities, as an “inner” dendron. We also prepare a series of low-generation “outer” dendrons (G2 and G3) with various peripheral groups, including aromatic, aliphatic, and polar structures, each having a single dibenzoazacyclooctyne (DIBAC) at the core. Efficient strain-promoted azide–alkyne cycloaddition (SPAAC) enables quantitative coupling between the outer and inner dendrons, producing high-generation (G5 and G6) dendrimers in a single coupling step. Characterization by NMR and mass spectrometry shows that the coupling products are structurally perfect. Using this strategy, we prepared a small dendrimer library that includes the first high-generation monodisp...

Improved large-scale synthesis and characterization of small and medium generation PAMAM dendrimers

Dendrimers are promising polymers for biomedical applications; however, most dendrimer formulations have failed to move from laboratory science to upscaled products for preclinical testing or GMP production. This publications reports on an improved large-scale PAMAM dendrimer synthesis that is suitable to manufacture large amounts of highly pure and monodisperse dendrimers of generations G0–G5. Furthermore, an extended analytical guideline how to characterize PAMAM dendrimers with NMR, HPLC, SEC-MALS, ESI, MALDI, UV–vis, fluorescence, and IR spectroscopy is provided.