Dendrimers In Solution Research Articles

Formation of soluble complexes of cationic polypyridylphenylene dendrimers with DNA

The complexation of DNA with a dendrimer with the successive addition of the dendrimer solution to the solution of DNA leads to the appearance and accumulation of compact particles with a diameter of Dh = 100 ± 10 nm that coexist with particles whose dimensions coincide with those of free DNA molecules (Dh = 450 ± 50 nm). The fraction of large particles decreases regularly; moreover, when the equimolar ratio of charged groups of interacting components is achieved, these particles disappear. The coexistence of practically free DNA molecules and a compact soluble negatively charged complex is confirmed by a sedimentation assay. Further addition of the dendrimer up to a certain ratio of charged groups of the components, much higher than unity, brings about phase separation, while at a large excess of charge groups of the dendrimer (above fivefold), the system turns out to be fully single-phase and composed of compact (110 ± 10 nm) cationic soluble complexes. Owing to the positive charge and small size of complex particles no greater than a critical value of 150 nm, the particles possess an important ability to interact with a positively charged cell membrane and to enter a living cell via endocytosis.

Size‐Tunable Micron‐Bubbles Based on Fluorous–Fluorous Interactions of Perfluorinated Dendritic Polyglycerols

This paper describes the behavior of various generations of polyglycerol dendrimers that contain a perfluorinated shell. The aggregation in organic solvents is based on supramolecular fluorous-fluorous interactions, which can be described by means of (19)F NMR spectroscopy. In order to study the interaction and aggregation phenomena of dendrimers with perfluorinated shell and perfluoro-tagged guest molecules we investigated [G3.5]-dendrimer with a perfluorinated shell in the presence of perfluoro-tagged disperse red. Noteworthy, the interaction intensities varied in an unexpected manner depending on the equivalents of perfluoro-tagged guest molecules added to the dendrimers in solution which then formed supramolecular complexes based on fluorous-fluorous interactions. We found that these complexes aggregated around residual air in the solvent to form stable micron-sized bubbles. Their sizes correlated with the interaction intensities measured for certain dendrimer-guest molecule ratios. Degassing of the solutions led to a quasi phase separation between organic and fluorous phase, whereby the dendrimers formed the fluorous phases. Regassing the sample with air afforded bubbles of the initial size again.

Host−Guest Chemistry of Dendrimer−Drug Complexes. 5. Insights into the Design of Formulations for Noninvasive Delivery of Heparin Revealed by Isothermal Titration Calorimetry and NMR Studies

The host-guest chemistry of dendrimer-biomacromolecule complexes is of great significance to both design and optimization of dendrimer-based drug delivery and host-guest systems. Here, we characterized the interactions between dendrimer and heparin by isothermal titration calorimetry (ITC), (1)H nuclear magnetic resonance ((1)H NMR), pulsed-field gradient (PFG) NMR, nuclear Overhauser effect spectroscopy (NOESY), and atomic force microscopy (AFM) studies. The calorimetric results suggest that miscellaneous aggregates are formed at different stages when heparin was titrated into a dendrimer solution: dendrimer-heparin "necklace" structures, followed by the formation of larger and more stable aggregates, and then macroscopic complexes which precipitate from the solution. The binding process is significantly influenced by dendrimer generation, surface functionality, and ion strength, indicating that the formation of dendrimer-heparin aggregates is predominantly driven by electrostatic interactions. The NMR results confirm the dendrimer-heparin binding models established by calorimetric measurement and present a new type of dendrimer-heparin aggregates at higher heparin/dendrimer molar ratios. Formulations containing generation 5 (G5) PAMAM dendrimers with a heparin/G5 molar ratio of 0.5-1.2 are proposed as effective ones for the treatment of thrombosis in noninvasive delivery routes such as nasal, pulmonary, transdermal, and oral routes. The combination of ITC and NMR in this study provides new insight into the interactions between globular and linear polymers and the delivery of macromolecular therapeutics such as heparin by dendrimers.

Cyclam‐Cored Dendrimers Appended with Four Dendrons of Two Different Types: Intradendrimer Energy Transfer

We have synthesized two cyclam-cored dendrimers appended with dendrons of two different types by proper protection/deprotection of the cyclam unit. The resulting dendrimers contain six naphthyl and two dansyl units (N6 D2) or two dansyl and six naphthyl units (N2 D6) at the periphery. Their photophysical properties have been compared to those of a dendrimer containing 8 dansyl units (D8) and a previously investigated dendrimer containing 8 naphthyl units (N8). The absorption spectra are those expected on the basis of the number of chromophores, demonstrating that no ground state interaction takes place. The emission spectra of N2 D6 and N6 D2 show naphthalene localized and naphthalene excimer emission similar to those observed in the case of N8, together with a much stronger dansyl emission with maximum at 525 nm. Addition of CF(3)SO(3)H to dendrimer solutions in CH(3)CN/CH(2)Cl(2) 1:1 (v/v) leads to protonation of the aliphatic amine units of the cyclam core at first and then of the aromatic amine of each dansyl chromophores. Cyclam can be diprotonated and this affects dansyl absorption and, most significantly, emission bands by a charge perturbation effect. Each dansyl unit is independently protonated in both dendrimers. The most interesting photophysical feature of these heterofunctionalized cyclam-cored dendrimers is the occurrence of an intradendrimer photoinduced energy transfer from naphthyl to dansyl chromophores of two different dendrons (interdendron mechanism). The efficiency of this process is 50 % for N6 D2 and it can be increased up to 75 % upon protonation of the cyclam core and formation of N6 D2(2H(+)). This arises from the fact that protonation of the amine units of the cyclam prevents formation of exciplexes upon naphthyl excitation, thus shutting down one of the deactivation processes of the fluorescent naphthyl excited state.

X-ray computed tomography contrast agents prepared by seeded growth of goldnanoparticles in PEGylated dendrimer

Gold nanoparticles (Au NPs) are a potential x-ray computed tomography (CT) contrastagent. A biocompatible and bioinactive surface is necessary for application of goldnanoparticle to CT imaging. Polyethylene glycol (PEG)-attached dendrimers have beenused as a drug carrier with long blood circulation. In this study, the Au NPs weregrown in the PEGylated dendrimer to produce a CT contrast agent. The AuNPs were grown by adding gold ions and ascorbic acid at various equivalentsto the Au NP-encapsulated dendrimer solution. Both size and surface plasmonabsorption of the grown Au NPs increased with adding a large number of gold ions.The x-ray attenuation of the Au NPs also increased after the seeded growth.The Au NPs grown in the PEG-attached dendrimer at the maximum under ourconditions exhibited a similar CT value to a commercial iodine agent, iopamidol,in vitro. The Au NP-loaded PEGylated dendrimer and iopamidol were injectedinto mice and CT images were obtained at different times. The Au NP-loadedPEGylated dendrimer achieved a blood pool imaging, which was greater thana commercial iodine agent. Even though iopamidol was excreted rapidly, thePEGylated dendrimer loading the grown Au NP was accumulated in the liver.

New Insights into Interactions between Dendrimers and Surfactants. 4. Fast-Exchange/Slow-Exchange Transitions in the Structure of Dendrimer−Surfactant Aggregates

The interactions between poly(amidoamine) (PAMAM) dendrimer and surfactant (sodium dodecyl sulfate, SDS) in aqueous solutions were investigated by a combination of (1)H NMR, diffusion measurements (PFG NMR), and NOE techniques. The diffusion studies suggested that different types of dendrimer-surfactant aggregates are formed by varying surfactant concentrations in the dendrimer solution. The (1)H NMR analysis proved that the presence of fast-exchange/slow-exchange transitions in the dendrimer-surfactant aggregates. The supramolecular structure of the aggregate was based on the hydrophobic interactions between the dendrimer scaffold and the surfactant aliphatic chain, as well as electrostatic/hydrogen-bond interactions between dendrimers and SDS monomers, bilayers, or globular micelles. In comparison with previous investigations, the present study provides a new insight into interactions between dendrimers and surfactants, which may be helpful for the design of dendrimer-based microreactors or nanovehicles.

Intramolecular Structural Change of PAMAM Dendrimers in Aqueous Solutions Revealed by Small-Angle Neutron Scattering

Small-angle neutron scattering (SANS) experiments were carried out to investigate the structure of aqueous (D(2)O) G4 PAMAM dendrimer solutions as a function of molecular protonation and dendrimer concentration. Our results indicate unambiguously that, although the radius of gyration R(G) remains nearly invariant, the dendrimer radial density profile rho(r) decreases in the dendrimer core with a continuous increase in protonation. This discovery also suggests that R(G), which is commonly adopted by numerous simulation and experimental works in describing the global dendrimer size, is not suitable as the index parameter to characterize the dendrimer conformation change. We also found that R(G) and rho(r), for dendrimers dissolved in both neutral and acidified solutions, remain nearly constant over the studied concentration range. We further demonstrate that the outcome of the widely used Guinier method is questionable for extracting R(G) in the concentration range studied. Our results reveal the polymer colloid structural duality as benchmarks for future experimental and theoretical studies and provide a critical step toward understanding drug encapsulation by ionic bonds.

Internal Dynamics and Energy Transfer in Dansylated POPAM Dendrimers and Their Eosin Complexes

Internal dynamics of dansylated poly(propyleneamine) dendrimers (POPAM, G1-G4) in solution and excitation energy transfer from dansyls to eosin in POPAM-eosin complexes have been studied by time-resolved fluorescence spectroscopy and molecular dynamics (MD) simulations. Combining the results from fluorescence anisotropy and the MD simulation studies suggests three time domains for the internal dynamics of the G3 and G4 generations, about 60 ps for motions of the outer-sphere dansyls, 500-1000 ps for restricted motions of back-folded dansyls, and 1500-2600 ps for the overall rotation. For the smaller generations, the contribution from the restricted motions was not entirely evident. Eosin binding hinders fast rotation of the dansyl fragments in the largest G4 dendrimer, but the motion of back-folded dansyls is more hindered in the pure dendrimer. Both fluorescence anisotropy and MD results for the G4 dendrimer support the "soft" dendrimer picture with almost free mobility and substantial back-folding of the dansyls of the dendrimers in solution. Analysis of time-dependent spectral shifts of fluorescence reveals 20-30 ps excited-state solvation relaxation around a single dansyl of a dendrimer. Dendrimer-independent excitation energy transfer from 4 to 8 ps from dansyls to eosins in POPAM-eosin complexes G2-G4 was observed.

Self-assembly of l-glutamate based aromatic dendrons through the air/water interface: morphology, photodimerization and supramolecular chirality

A series of dendrimers containing focal aromatic rings, ranged from phenyl, naphthyl, anthryl to pyrenyl, and the l-glutamate peripheral groups were designed and their self-assembly through the air/water interface was investigated. It has been found that although these dendrimers have no long alkyl chains, some of the dendrimers could form stable monolayers at the air/water interface due to an appropriate balance between the hydrophobic core and the hydrophilic peripheral group. Nanofibers were observed for the monolayers of the dendrimer containing a 2-anthryl group, while nanostrips were observed for that containing a pyrenyl group. In contrast to the dendrimers in solution, the molecular chirality at the chiral center of l-glutamate was transferred to the supramolecular assemblies in the films, indicating the effect of the interfacial assembly. For the dendrimers containing an anthryl core, photodimerization occurred. The photoirradiation was carried out under different conditions such as in solution, in a floating monolayer and in the transferred LB films. Different morphologies were obtained. These results indicated that the photoreaction of an anthryl dendrimer can be regulated through the interfacial organization, which leads to different packing as well as the subsequent photoreaction.

A simple model for the anomalous intrinsic viscosity of dendrimers

The intrinsic viscosity of dendrimers in solution shows several anomalous behaviors that have hitherto not been explained within the existing theoretical frameworks of either Zimm or Rouse. Here we propose a simple two-zone model based on the radial segmental density profile of the dendrimers and combine a non-draining core with a free-draining outer region description, to arrive at a simple formula that captures most of the main features in the intrinsic viscosity data obtained in experiments.

Swelling and rheology of thermoresponsive gradient copolymer micelles

Poly(laurylmethacrylate-block-styrene-block-laurylmethacrylate) gradient copolymers (PLMA-PS-PLMA) in a selective solvent for PLMA, self-assemble into spherical colloidal micelles. The structure and the dynamics of the solutions are investigated as a function of temperature and concentration using small angle X-ray scattering (SAXS) and rheology. When the temperature is increased, the micellar cores shrink and the coronas increase due to the gradual solubilization of the domains where S and LMA segments are mixed. The swelling of the micelles is perfectly correlated to the increase of the viscosity. The variations of the low-shear viscosity over a wide range of concentrations and temperatures are rescaled onto a universal curve and compared to those for other soft colloidal systems like star polymers, hairy particles and dendrimer solutions.

Synthesis of polyglutamine conjugates of lysine dendrimers in solution and polymer gel

The synthesis of polyglutamine conjugates of lysine dendrimers, in which carboxyl groups of polyglutamine chains are linked via one point to the amino groups of N-terminal lysine fragments of dendrimers, is studied. Lysine dendrimers of third, fourth, and fifth generations are preliminarily prepared via the solid-phase synthesis on a polymer support, crosslinked p-methylbenzohydrylaminopolystyrene. The first approach to the synthesis of polyglutamine conjugates of dendrimers consisted in that, after the synthesis of lysine dendrimers, their removal from the polymer support, their full unblocking, and their purification, γ-benzyl glutamate N-carboxyadhydride is involved in solution polymerization at the amino groups of lysine of the outer sphere of dendrimers. The second approach includes the polymerization of γ-benzyl glutamate N-carboxyadhydride on the amino groups of N-terminal lysine residues of lysine dendrimers performed before dendrimer removal from the polymer support. The structural study of star-shaped conjugate of lysine dendrimers makes it possible to for the first time estimate the similarities and differences in these two approaches to the synthesis of polyglutamine conjugates of lysine dendrimers.

Molecular Dynamics Simulations of a Charged Dendrimer in Multivalent Salt Solution

The multivalent salt dependent behaviors of a charged dendrimer in solution are investigated by molecular dynamics simulations with explicit free ions. We find that the charged dendrimers show a dense-core conformation together with the back-folding of terminal monomers to the interior under all the conditions studied. We also observe an interesting ion exchange phenomenon, the replacement of the condensed monovalent counterions by multivalent salt ions due to a strong electrostatic attraction. Furthermore, we find that the dendrimer adopts an extended conformation in the absence of salt. Upon addition of salt, the dendrimer collapses as a result of a drop in the osmotic pressure inside the dendrimer. With an additional increase in the salt concentration, the dendrimer weakly swells due to an enhanced excluded volume effect of the adsorbed salt ions. The overcharge phenomenon also appears in our system. Consequently, our findings show a strong dependence of the conformation of charged dendrimers on salt concentration and give valuable insight into their behaviors at various salt concentrations at the molecular level.

Dendrimers in solution can have their remote catalytic groups folded back into the core: Enantioselective transaminations by dendritic enzyme mimics-II

PAMAM dendrimers with double thioether arms have been synthesized with a pyridoxamine core and terminal chiral amino groups. Transamination to afford natural isomers of phenylalanine and alanine induced enantioselectivity by the peripheral chiral caps, supporting a computer model that indicates folding of dendrimer chains back into the core.

Surface Hydrophobic Modification of Fifth-Generation Hydroxyl-Terminated Poly(amidoamine) Dendrimers and Its Effect on Biocompatibility and Rheology

Water-soluble, commercially-available poly(amidoamine) (PAMAM) dendrimers are highly-branched, well-defined, monodisperse macromolecules having an ethylenediamine core and varying surface functional groups. Dendrimers are being employed in an increasing number of biomedical applications. In this study, commercially obtained generation 5 hydroxyl-terminated (G5OH) PAMAM dendrimers were studied as potential proteomimetics for ophthalmic uses. To this end, the surface of G5OH PAMAM dendrimers were hydrophobically modified with varying amounts of dodecyl moieties, (flexible long aliphatic chains), or cholesteryl moieties (rigid lipid found in abundance in biological systems). Dendrimers were characterized by 1H-NMR, DLS, DSC and HPLC. The hydrophobic modification caused aggregation and molecular interactions between dendrimers that is absent in unmodified dendrimers. In vitro tissue culture showed that increasing the amount of dodecyl modification gave a proportional increase in toxicity of the dendrimers, while with increasing cholesteryl modification there was no corresponding increase in toxicity. Storage and loss modulus were measured for selected formulations. The hydrophobic modification caused an increase in loss modulus, while the effect on storage modulus was more complex. Rheological properties of the dendrimer solutions were comparable to those of porcine lens crystallins.

Cooperative and Noncooperative Binding of *Ru(bpy)32+ to DNA and SB4.5G Dendrimers

The process *Ru(bpy)(3)(2+) + S(2)O(8)(2-) in two different reaction media, the SB4.5G dendrimer and DNA solutions, was studied. In both media, the receptors have anionic characteristics. This fact will produce a binding of the ruthenium complex to the two receptors by attractive electrostatic interactions. On the contrary, the peroxodisulfate ions will be preferentially located in the aqueous solution due to electrostatic repulsions with the receptors. Despite the similarities of the receptors, some differences are observed in these two reaction media. These differences arise from the fact that the binding of the *Ru(bpy)(3)(2+) complex to DNA shows a negative cooperativity, whereas the binding to the dendrimer is noncooperative in character. The anticooperative character of the binding that happens in DNA solutions becomes noncooperative when an electrolyte, NaNO(3), is added to the medium. This is related to a condensation of the salt's counterions on the surface of the DNA which produces a decrease of the equilibrium constant corresponding to the binding of the complex to the receptor. Therefore, it is shown that the ionic strength of the reaction medium exerts a great influence on the cooperative nature of the ligand/receptor binding. This also explains the different behavior observed in DNA and dendrimer solutions.

Liquid-crystalline dispersions formed by the complexes of linear double-stranded DNA molecules with dendrimers

The formation of liquid-crystalline dispersions as a result of interaction of linear, double-stranded DNA molecules with poly(propyleneimine) dendrimers in water-salt solutions was studied. It was shown, that this process does not depend on the ionic strength of solution and molecular structure of dendrimer. By means of the atomic force microscopy, it was established, that in the case of the dendrimer molecules of the 4th generation (G4), the mean size of particles of (DNA-dendrimer G4) liquid-crystalline dispersion is equal to 300-400 nm. The "boundary" conditions (ionic strength of solutionand molecular mass of dendrimer) of formation of optically active (cholesteric) and optically inactive of the (DNA-dendrimer) dispersions were determined using circular dichroism spectroscopy. The interaction of dendrimers of 1st, 2nd, 3rd and 5th generations with DNA molecules results in the obtaining of the optically inactive dispersions. Dendrimer molecules of 4th generation induce the formation of two types dispersions: in solutions of high ionic strength (micro > 0.4) they induce the formation of cholesteric liquid-crystalline dispersions, and in solutions of low or intermediate ionic strength (micro < 0.4) they can form the optically inactive one. The "molecular crowding" affects both the efficiency of binding of dendrimer molecules of 4th generation to DNA, and the mode of spatial packing of (DNA-dendrimer G4) complexes in particles of liquid-crystalline dispersion. The possible reasons capable of explaining the structural polymorphism of (DNA-dendrimer) liquid-crystalline dispersions are discussed.

Photochemical and photophysical reactions of poly(propylene imine) dendrimers tethering cinnamamide groups

Here we report on photochemical and photophysical properties of poly(propylene imine) dendrimers tethering cinnamamide groups at the peripheral positions. Photoexcitation of the dendrimer solutions with 313 nm brought about monotonous decrease of absorption band of trans-cinnamamide around 270 nm as a result of trans-to- cis photoisomerization and [2+2] photocycloaddition. The first-generation dendrimer showed preferential formation of cis-isomer, whereas photocycloaddition was more favorable for the third- and fifth-generation dendrimers. Interestingly, the third- and fifth-generation dendrimers could encapsulate phosphorescent donors into the dendrimer nanocavities. When the dendrimers capturing the donors were excited at 365 nm, photocycloaddition proceeded efficiently through triplet–triplet energy transfer. By analyzing phosphorescence spectra with theoretical Perrin’s formula, we found that this triplet–triplet energy transfer is quenched within a radius of ∼0.5 nm. Such triplet–triplet energy transfer within dendrimer nanocavities would provide promising strategy to design and fabricate novel molecular devices by utilizing the dendrimers.

Transfer-Printing and Host−Guest Properties of 3D Supramolecular Particle Structures

Mechanically robust and crystalline supramolecular particle structures have been constructed by decoupling nanoparticle assembly and supramolecular glue infiltration into a sequential process. First, beta-cyclodextrin (CD)-functionalized polystyrene particles (d approximately 500 nm) were assembled on a CD-functionalized surface via convective assembly to form highly ordered, but mechanically unstable, particle crystals. Subsequently, the crystals were infiltrated by a solution of adamantyl-functionalized dendrimers, functioning as a supramolecular glue to bind neighboring particles together and to couple the entire particle crystal to the CD surface, both in a noncovalent manner. The supramolecular particle crystals are highly robust, as witnessed by their ability to withstand agitation by ultrasonication. When assembled on a poly(dimethylsiloxane) (PDMS) stamp, the dendrimer-infiltrated particle crystals could be transfer-printed onto a CD-functionalized target surface. By variation of the geometry and size of the PDMS stamps, single particle lines, interconnected particle rings, and V-shaped particle assemblies were obtained. The particle structures served as 3D receptors for the binding of (multiple) complementary guest molecules, indicating that the supramolecular host functionalities of the particle crystals were retained throughout the fabrication process.

Dynamics of counterions in dendrimer polyelectrolyte solutions

Molecular dynamics simulations were employed in models of peripherally charged dendrimers in solutions of explicit solvent and monovalent counterions in order to explore aspects of the dynamic behavior of counterions. The present study explores the effects of varying strength of electrostatic interactions for models of two dendrimer generations, in explicit solvent solutions below the dendrimer overlap concentration. Counterion diffusional motion as well as residence lifetimes of pairs formed by charged dendrimer beads and condensed counterions is monitored in the different electrostatic regimes. Spatiotemporal characteristics of self- and collective counterion motion are explored by means of space-time Van Hove correlation functions. A characteristic scaling law is found to describe the counterion diffusion coefficient as a function of Bjerrum length in the strong electrostatic regime, independent of the size of the dendrimer molecules at the examined volume fractions. The change noted in the diffusional motion of counterions in the range of strong Coulombic interactions is also reflected to their relevant residence times. Development of dynamic heterogeneities in counterion self-motion is observed during the gradual increase in the strength of electrostatic interactions, characterized by the emergence of distinct counterion populations in terms of their mobility. The time scale for the development of such a mobility contrast in the self-motion of the counterions can be correlated with that describing their collective motion as well. The latter increases with Bjerrum length but remains shorter compared to the time scale at which free diffusional motion sets in. Findings from the present study provide further insight on the mechanisms pertinent to ion migration in macroion dispersions and may serve as a basis for the interpretation of ionic motion in a broader range of polyelectrolyte systems.