Amphiphilic Dendron Research Articles

On the edge between organic solvent nanofiltration and ultrafiltration: Characterization of regenerated cellulose membrane with aspect on dendrimer purification and recycling

The performance of commercial cellulose membranes with pore size on the border between ultra- and nanofiltration in selected organic solvents was studied focusing on rejection of small solutes and applicability for dendrimer purification. Organic markers in the MW range 100 – 700 Da and polarity range from nonpolar to polar protic compounds (aliphatics, aromatics, ethers, esters and alcohols) were used for membrane characterization. Transmission experiments in mixtures of methanol and dichloromethane of variable ratio showed the suitability of tested membranes for intended purpose, bringing information on structural factors affecting the rejection. Besides solute molar volume, its polarity type, or affinity, most conveniently expressed by Hansen solubility parameters, was found to be a crucial factor; with increasing size of solute molecule the spatial arrangement becomes also important. Solvent composition influences not only the behavior of solutes, but it also affects the membrane structure: poor solvation of cellulose by less polar solvents causes partial pore collapse, resulting in a decrease of membrane molecular weight cutoff. This effect can be used to improve the retention of a target product, as was shown for the first generation amphiphilic dendron. In addition, a simple mathematical model, allowing to estimate the course of nanofiltration and to optimize its conditions in a semicontinuous dead-end setup, is presented.

Amphiphilic Phosphorus Dendrons Associated with Anti-inflammatory siRNA Reduce Symptoms in Murine Collagen-Induced Arthritis.

Small interfering RNA (siRNA) holds promise for treating rheumatoid arthritis by inhibiting major cytokines such as tumor necrosis factor-α (TNF-α). We developed original cationic amphiphilic phosphorus dendrons to produce dendriplexes associated with TNF-α siRNA. The dendrons were made of 10 pyrrolidinium end groups and a C17 aliphatic chain. The dendriplexes demonstrated the ability to protect siRNA from nuclease degradation and to promote macrophage uptake. Moreover, they led to potent inhibition of TNF-α expression in the lipopolysaccharide-activated mouse macrophage cell line RAW264.7 in vitro model. A significant anti-inflammatory effect in the murine collagen-induced arthritis model was observed through arthritis scoring and histological observations. These results open up essential perspectives in using this original amphiphilic dendron to reduce the disease burden and improve outcomes in chronic inflammatory diseases.

Amphiphilic phosphorous dendron micelles co-deliver microRNA inhibitor and doxorubicin for augmented triple negative breast cancer therapy.

Combined chemo/gene therapy of cancer through different action mechanisms has been emerging to enhance the therapeutic efficacy towards cancer, and still remains a challenging task due to the lack of highly effective and biocompatible nanocarriers. In this work, we report a new nanosystem based on amphiphilic phosphorus dendron (1-C12G1) micelles to co-deliver microRNA-21 inhibitor (miR-21i) and doxorubicin (DOX) for combination therapy of triple negative breast cancer. The amphiphilic phosphorus dendron bearing a long linear alkyl chain and ten protonated pyrrolidine surface groups was prepared and was demonstrated to form micelles in water solution and have a hydrodynamic size of 103.2 nm. The micelles are shown to be stable, enable encapsulation of an anticancer drug DOX with optimal loading content (80%) and encapsulation efficiency (98%), and can compress miR-21i to form polyplexes to render it with good stability against degradation. The co-delivery system of 1-C12G1@DOX/miR-21i polyplexes has a pH-dependent DOX release profile, and can be readily phagocytosed by cancer cells to inhibit them due to the different anticancer mechanisms, which was further validated after intravenous injection to treat an orthotopic triple-negative breast tumor model in vivo. With the proven biocompatibility under the studied doses, the developed amphiphilic phosphorus dendron micelles could be developed as an effective nanomedicine formulation for synergistic cancer therapy.

Engineered Stable Bioactive Per Se Amphiphilic Phosphorus Dendron Nanomicelles as a Highly Efficient Drug Delivery System To Take Down Breast Cancer In Vivo.

Conventional small molecular chemical drugs always have challenging limitations in cancer therapy due to their high systemic toxicity and low therapeutic efficacy. Nanotechnology has been applied in drug delivery, bringing new promising potential to realize effective cancer treatment. In this context, we develop here a new nanomicellar drug delivery platform generated by amphiphilic phosphorus dendrons (1-C17G3.HCl), which could form micelles for effective encapsulation of a hydrophobic anticancer drug doxorubicin (DOX) with a high drug loading content (42.4%) and encapsulation efficiency (96.7%). Owing to the unique dendritic rigid structure and surface hydrophilic groups, large steady void space of micelles can be created for drug encapsulation. The created DOX-loaded micelles with a mean diameter of 26.3 nm have good colloidal stability. Strikingly, we show that the drug-free micelles possess good intrinsic anticancer activity and act collectively with DOX to take down breast cancer cells in vitro and the xenografted tumor model in vivo through upregulation of Bax, PTEN, and p53 proteins for enhanced cell apoptosis. Meanwhile, the resulting 1-C17G3.HCl@DOX micelles significantly abolish the toxicity relevant to the free drug. The findings of this study demonstrate a unique nanomicelle-based drug delivery system created with the self-assembling amphiphilic phosphorus dendrons that may be adapted for chemotherapy of different cancer types.

Cationic Amphiphilic Dendrons with Anticancer Activity.

Cancer has become the leading cause of human death worldwide, and there is an urgent need to design and develop new oncology drugs. In this study, we report series of cationic amphiphilic dendrons with different hydrophobic alkyl chains (Cn) and different generations (Gx) and demonstrate their use for anticancer applications. The results revealed that lower-generation dendrons (G1) with a longer hydrophobic alkyl chain (C12 and C18) have stronger antitumor activity. Among these dendrons, a lead candidate C12-G1 was identified that demonstrated excellent broad-spectrum antitumor activity in 7 cancer cell lines including highly metastatic tumor cells, while simultaneously, hemolysis was negligible. Mechanistic studies showed that C12-G1 could lead to cytoplasmic leakage and induce cancer cell necrosis through membrane disruption. In addition, C12-G1 showed potent inhibition of tumor growth in a B16-F10 melanoma model. In conclusion, these findings demonstrate that the cationic amphiphilic dendron might be a promising agent for anticancer application.

Phosphorus dendron nanomicelles as a platform for combination anti-inflammatory and antioxidative therapy of acute lung injury.

Rationale: Development of novel nanomedicines to inhibit pro-inflammatory cytokine expression and reactive oxygen species (ROS) generation for anti-inflammatory therapy of acute lung injury (ALI) remains challenging. Here, we present a new nanomedicine platform based on tyramine-bearing two dimethylphosphonate sodium salt (TBP)-modified amphiphilic phosphorus dendron (C11G3) nanomicelles encapsulated with antioxidant drug curcumin (Cur).Methods: C11G3-TBP dendrons were synthesized via divergent synthesis and self-assembled to generate nanomicelles in a water environment to load hydrophobic drug Cur. The created C11G3-TBP@Cur nanomicelles were well characterized and systematically examined in their cytotoxicity, cellular uptake, intracellular ROS elimination, pro-inflammatory cytokine inhibition and alveolar macrophages M2 type repolarization in vitro, and evaluated to assay their anti-inflammatory and antioxidative therapy effects of ALI mice model through pro-inflammatory cytokine expression level in bronchoalveolar lavage fluid and lung tissue, histological analysis and micro-CT imaging detection of lung tissue injury in vivo.Results: The nanomicelles with rigid phosphorous dendron structure enable high-capacity and stable Cur loading. Very strikingly, the drug-free C11G3-TBP micelles exhibit excellent cytocompatibility and intrinsic anti-inflammatory activity through inhibition of nuclear transcription factor-kappa B, thus causing repolarization of alveolar macrophages from M1 type to anti-inflammatory M2 type. Taken together with the strong ROS scavenging property of the encapsulated Cur, the developed nanomicelles enable effective therapy of inflammatory alveolar macrophages in vitro and an ALI mouse model in vivo after atomization administration.Conclusion: The created phosphorus dendron nanomicelles can be developed as a general nanomedicine platform for combination anti-inflammatory and antioxidative therapy of inflammatory diseases.

Comparison of the effects of dendrimer, micelle and silver nanoparticles on phospholipase A2 structure

The interaction of nanoparticles (NP) with proteins (the so-called 'protein corona') is a huge challenge in attempting to apply them in personalized nanomedicine. We have analyzed the interaction between A) two 'soft' NPs (a cationic phosphorus dendrimer of generation 3; a cationic phosphorus amphiphilic dendron of generation 2), and B) one 'hard' nanoparticle (silver NP covered with cationic carbosilane dendritic moieties); and membrane-bound protein phospholipase A2 from bovine pancreas. The hard and soft NPs have differences in the nature of their interactions with phospholipase A2. This enzyme surrounds hard AgNP, whereas dendrimer and amphiphilic dendron form aggregates/micelles with phospholipase A2. There is a difference in action of phospholipase A2 bound to the core of dendrimer, and of micelles formed from non-covalent interactions between the amphiphilic dendron. These data are important in understanding the nature of interaction between different kinds of nanoparticles and proteins.

Facile Synthesis of Amphiphilic Fluorescent Phosphorus Dendron-Based Micelles as Antiproliferative Agents: First Investigations.

We designed and synthesized several families of novel amphiphilic fluorescent phosphorus dendron-based micelles showing relevant antiproliferative activities for use in the field of theranostic nanomedicine. Based on straightforward synthesis pathways, 12 amphiphilic phosphorus dendrons bearing 10 protonated cyclic amino groups (generation one), or 20 protonated amino groups (generation two), and 1 hydrophobic chain carrying 1 fluorophore moiety were created. The amphiphilic dendron micelles had the capacity to aggregate in solution using hydrophilic/hydrophobic interactions, which promoted the formation of polymeric micelles. These dendron-based micelles showed moderate to high antiproliferative activities against a panel of tumor cell lines. This paper presents for the first time the synthesis and our first investigations of new phosphorus dendron-based micelles for cancer therapy applications.

Optically active quantum dots with induced circularly polarized luminescence in amphiphilic peptide dendron hydrogel.

In this study, water-soluble semiconductor quantum dots (QDs) showing induced circularly polarized luminescence (CPL) in an organic–inorganic coassembled hydrogel were demonstrated. Achiral QDs could be encapsulated into a chiral peptide dendron hydrogel through cogelation. These cogels displayed intense induced circularly polarized emission. In addition, the direction of the CPL property of QD cogels could be regulated by the supramolecular chirality of hydrogels. Our findings reveal that the emergence of CPL achiral QDs can be triggered by the chirality transfer in a multiple-component dendron hydrogel system. This study has given a new understanding into the design of functional chiroptical materials.

Photodegradable coumarin-derived amphiphilic dendrons for DNA binding: Self-assembly and phototriggered disassembly in water and air-water interface.

In this article, we demonstrate the self-assembly and photoresponive behavior of a novel coumarin-based amphiphilic dendron in both aqueous solution and air-water interface. The dendritic structure, namely C-IG1, was composed of a lipophilic cholesterol and hydrophilic poly(amido amine) (PAMAM) dendron, and the amphiphilic counterpart is interconnected by a photolabile coumarin carbonate ester, enabling the photoinduced degradation of the amphiphiles in protic solvents via SN1-like mechanism. A Nile red solubilization fluorescence assay suggests a low critical aggregation concentration for the micelle formation of C-IG1 in aqueous solutions (3.9 × 10-5 M); the Langmuir analysis further indicates that C-IG1 possesses significant compressibility in air-water interface, eventually forming homogeneous monolayers with a final molecular area (A0) of 36 Å2. Notably, the micelles and Langmuir monolayer are quite stable until photo-triggered dissociation based on the photocleavage of C-IG1 amphiphile activated by 365-nm incident light. Moreover, the transition in interfacial morphology of the Langmuir monolayer during the assembly and photodegradation processes also can be visually analyzed by incorporating Nile red probes with in situ monitoring through fluorescence microscopy. The thin film deposited on a glass substrate by the Langmuir-Blodgett technique also shows a photoresponsive behavior based on the change in the contact angles of a water droplet on the surface upon light stimulation. The binding affinity of C-IG1 and cyclic DNA determined by the fluorescence quenching analysis of the coumarin reporter suggests a ground-state macromolecular complexation process occurring through polyvalent interactions between the pseudodendrimers and biomacromolecules. The ethidium bromide displacement assay further indicates thus dendriplex formation at low nitrogen-to-phosphorous value (N/P < 1) and confirms that the decomplexation accompanied by DNA release can be achieved through an active phototriggered route under spatiotemporal control.

Reversible Plasmonic Circular Dichroism via Hybrid Supramolecular Gelation of Achiral Gold Nanorods

The fabrication of chiroptical plasmonic nanomaterials such as chiral plasmonic gold nanorods (GNRs) has been attracting great interest. Generally, in order to realize the plasmonic circular dichroism (PCD) from achiral GNRs, it is necessary to partially replace the surface-coated cetyltrimethylammonium bromide with chiral molecules. Here, we present a supramolecular approach to generate and modulate the PCD of GNRs through the hybrid gelation of GNRs with an amphiphilic chiral dendron gelator. Upon gelation, the PCD could be produced and further regulated depending on the ratio of the dendrons to GNRs. It was revealed that the wrapping of the self-assembled nanofibers around the GNRs is crucial for generating the PCD. Furthermore, the hybrid gel underwent a thermotriggered gel-sol and sol-gel transformation, during which the PCD can disappear (solution) and reappear (gel), respectively, and such process can be repeated many times. In addition, the hybrid gel could also undergo shrinkage upon addition of a slight amount of Mg2+ ions, during which the PCD disappeared also. Thus, through the gel formation and subsequent metal ion- or temperature-triggered phase transition, PCD can be reversibly modulated. The results not only clarified the generation mechanism of PCD from the achiral GNRs without the chiral modification on the surface but also offered a simple and efficient way to modulate the PCD.

Supra-dendron Gelator Based on Azobenzene-Cyclodextrin Host-Guest Interactions: Photoswitched Optical and Chiroptical Reversibility.

A novel amphiphilic dendron (AZOC8 GAc) with three l-glutamic acid units and an azobenzene moiety covalently linked by an alkyl spacer has been designed. The compound formed hydrogels with water at very low concentration and self-assembled into chiral-twist structures. The gel showed a reversible macroscopic volume phase transition in response to pH variations and photo-irradiation. During the photo-triggered changes, although the gel showed complete reversibility in its optical absorptions, only an incomplete chiroptical property change was achieved. On the other hand, the dendron could form a 1:1 inclusion complex through a host-guest interaction with α-cyclodextrin (α-CD), designated as supra-dendron gelator AZOC8 GAc/α-CD. The supra-dendron showed similar gelation behavior to that of AZOC8 GAc, but with enhanced photoisomerization-transition efficiency and chiroptical switching capacity, which was completely reversible in terms of both optical and chiroptical performances. The self-assembly of the supra-dendron is a hierarchical or multi-supramolecular self-assembling process. This work has clearly illustrated that the hierarchical and multi-supramolecular self-assembling system endows the supramolecular nanostructures or materials with superior reversible optical and chiroptical switching.

Role of Aromatic Interactions in Temperature-Sensitive Amphiphilic Supramolecular Assemblies.

Aromatic interactions were found to greatly influence the temperature-dependent dynamic behavior within supramolecular assemblies. Using an amphiphilic dendron, we systematically changed the hydrophobic groups introducing increasing levels of aromaticity while keeping the hydrophilic part constant. We show that the supramolecular assemblies become less sensitive to temperature changes when aromatic interactions in the aggregate are increased. Conversely, the absence of aromaticity in the hydrophobic moieties produces temperature-sensitive aggregates. These results show that subtle molecular-level interactions can be utilized to control temperature-sensitive behavior in the nanoscale. These findings open up new design strategies to rationally tune the behavior of stimuli-responsive supramolecular assemblies on multiple spatiotemporal scales.

A dual thermal and photo-switchable shrinking-swelling supramolecular peptide dendron gel.

A supramolecular dendron gel was fabricated through the co-assembly of an L-glutamic acid terminated amphiphilic dendron and a positively charged azobenzene derivative, which showed a dual thermal and photo-switched reversible volume phase transition or shrinking/swelling.

Self-assembled thermosensitive nanoparticles based on oligoethylene glycol dendron conjugated doxorubicin: preparation, and efficient delivery of free doxorubicin

An amphiphilic dendron–drug conjugate was synthesized via oligoethylene glycol (OEG) dendrons coupled with anticancer drug doxorubicin (DOX).

Photodegradable self-assembling PAMAM dendrons for gene delivery involving dendriplex formation and phototriggered circular DNA release

Photoresponsive amphiphilic dendron bearing a photolabile o-nitrobenzyl group possesses self-assembly, DNA binding and photo-induced release.

Amphiphilic Polymerizable Porphyrins Conjugated to a Polyglycerol Dendron Moiety as Functional Surfactants for Multifunctional Polymer Particles.

An amphiphilic polyglycerol dendron (PGD) conjugated porphyrin (PGP) bearing a polymerizable group was successfully synthesized. The PGP was used as an effective surfactant in emulsion and microsuspension polymerization systems to prepare styrene and methacrylate polymer particles, and the use of PGP provided the simple polymer particles with fluorescence derived from the metalloporphyrin and high colloidal stability due to the PGD. Furthermore, based on confocal laser scanning microscopy, we observed that the particles spontaneously formed a core-shell morphology with the PGP localized in the shell region during the polymerization and demonstrated drug loading in the shell region using rhodamine B as a model drug. The results indicate that the use of the functional surfactant PGP led to the preparation of multifunctional polymer particles from simple monomer species, and the resulting particles possessed high colloidal stability, fluorescence, and drug loading capability.

Interfacial assembly and host–guest interaction of anthracene-conjugated l-glutamate dendron with cyclodextrin at the air/water interface

The interfacial assembly of photo-induced dimerization of atypical anthracene-containing amphiphilic dendron and host–guest interaction with γ-cyclodextrin has been investigated. It has been proved that even without long alkyl chain the amphiphilic dendron could still form stable Langmuir monolayer at the air/water interface. Through the host–guest interaction, γ-cyclodextrin can be used to encapsulate two headgroups of amphiphilic dendron in the antiparallel direction. However, the formed host–guest complex was sensitive to the surface pressure. Slight compression of surface pressure led amphiphilic dendron to reassemble into nanofibers through the strong π–π stacking between headgroups. On the other hand, under in situ irradiation, the amphiphilic dendron was stabilized in the cavity of γ-cyclodextrin through headgroup dimerization and the host–guest complex further irregularly aggregated to nanoparticles. Meanwhile, γ-cyclodextrin, as a silencer, blocked the supramolecular chirality transfer. Our conclusion was demonstrated through UV/vis, FT-IR, CD spectrum and AFM images, respectively.

Synthesis of Novel Amphiphilic Dendron–Coil Macromonomer and Rheological Behavior of Its Acrylate Copolymer Emulsion

A novel amphiphilic dendron–coil macromonomer, 3,5-di(n-hexadecyloxy)benzoyloxy polyoxyethylene methacrylate [(3,5)16G1-CO2PEG1000MA, 6], was synthesized by esterification of polyoxythylene (molecular weight M = 1000) with 3,5-di(n-hexadecyloxy)benzoyl chloride followed by methacrylate chloride. The compound was then characterized by means of NMR and FT-IR. Moreover, a new kind of dendron hydrophobically modified alkali-soluble emulsion (DHASE) polymer was synthesized by emulsion copolymerization of macromonomer 6 with mathacrylic acid and ethyl acrylate. The rheological behavior of a series of DHASE was tested. It has been found that, during alkalization, while the value of pH reached to 6.5, all the samples of DHASE had a significant increase in terms of viscosity and obvious shear-thinning behavior. Besides, the solution viscosity increased with increasing the macromonomer 6 content and the polymer concentration. Moreover, the mechanism of the association process was discussed by examining the changes of G′ and G″ in the angular frequency range of 10–2–102 rad/s. The results illustrate the potential of this novel amphiphilic dendron–coil macromonomer in hydrophobically modified alkali-soluble emulsion polymers and associative thickeners for the first time.

A metal ion triggered shrinkable supramolecular hydrogel and controlled release by an amphiphilic peptide dendron

Divalent metal ions were found to trigger the shrinkage of a supramolecular hydrogel based on a peptide dendron, and the shrinkable gel could be further used to control the release of vitamin B1.