Multivalent dendrimers at molecular printboards: influence of dendrimer structure on binding strength and stoichiometry and their electrochemically induced desorption

A fundamental understanding of multivalency can have a profound influence on bottom-up nanofabrication. For this purpose, three different types of ferrocenyl (Fc) functionalized dendrimers of generations 1-5 with various spacer groups were adsorbed at self-assembled monolayers (SAMs) of heptathioether-functionalized beta-cyclodextrin (betaCD) on gold. The dendrimers formed kinetically stable supramolecular assemblies at the betaCD host surface having up to eight multivalent supramolecular interactions, but could be efficiently removed from the host surface by electrochemical oxidation of the Fc end groups. Dendrimer desorption and re-adsorption could be repeated a number of times without significant decomposition of the system. The stoichiometries of the dendrimers at the surface were determined using cyclic voltammetry (CV). These were quantitatively confirmed for the lower generations by surface plasmon resonance (SPR) titrations of the dendrimers to the betaCD SAM. Measuring CV and SPR simultaneously gave crucial mechanistic information on the electrochemically induced desorption of the dendrimers from the host surface. The redox-active dendrimers effectively blocked the host surface for binding other molecules, e.g. adamantyl-functionalized dendrimers, but electrochemically induced release of the blocking layer revealed the host surface to which the adamantyl dendrimers could then bind.     

Binding control and stoichiometry of ferrocenyl dendrimers at a molecular printboard

Ferrocenyl-functionalized PPI dendrimers of generations 1-5 were adsorbed at self-assembled monolayers of heptathioether-functionalized beta-cyclodextrin (betaCD) on gold. The dendrimers form stable supramolecular assemblies at the betaCD host surface having multivalent supramolecular interactions and could be electrochemically desorbed from the surface. Using cyclic voltammetry, the stoichiometries of the dendrimers at the surface could be determined for all generations, which were quantitatively confirmed for generations 1 and 2 by surface plasmon resonance titrations.     

Electron capture dissociation,electron detachment dissociation,and collision-induced dissociation of polyamidoamine (PAMAM) dendrimer ions with amino,amidoethanol, and sodium carboxylate surface groups

Here, we investigate the effect of the structure (generation) and nature of the surface groups of different polyamidoamine (PAMAM) dendrimers on electron-mediated dissociation, either electron capture dissociation (ECD) or electron detachment dissociation (EDD), and compare the fragmentation with that observed in collision-induced dissociation (CID). ECD and EDD of the PAMAM dendrimers resulted in simple mass spectra, which are straightforward to interpret, whereas CID produced complex mass spectra. The results show that electron-mediated dissociation (ECD and EDD) of PAMAM dendrimers does not depend on the nature of the surface group but tends to occur within the innermost generations. CID of the PAMAM dendrimers showed a strong dependence on the nature of the surface group and occurred mostly in the outer generation. The results demonstrate the potential utility of ECD and EDD as a tool for the structural analysis of PAMAM dendrimers.     

Surface Properties of Low-Generation Polyphenylene Dendrimers

The surface properties were studied for the powders of the first- and second-generation polyphenylene dendrimers based on tetrakis(4-ethynylphen-1-yl)methane and the powders of the first- and third-generation dendrimers based on 1,3,5-triethylbenzene. The studied substances have low specific surface areas. The similarity in the surface properties of rigid-chain dendrimers whose branched macromolecules have an extended spatial structure is discussed.     

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

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

Dendrimer-based prodrugs: design, synthesis, screening and biological evaluation

Dendrimers are a new class of artificial macromolecules with well-defined hyperbranched structures which enable bio-active molecules such as drugs to be presented in a highly multi-valent fashion. Covalent conjugation of drugs to the surface of dendrimers can be easily achieved either by direct chemical reactions between dendrimers and drug molecules including esterification and amidation or through cleavable linkers, depending on the functional groups on the surface of dendrimers. The pharmacological properties of these dendrimer-based prodrugs such as biocompatibility, biodistribution, biostability, bioadhesion and biopermeability can be modulated by further modifying dendrimers with specific functional molecules to fit a specific medicinal purpose. In this mini-review, recent advances on the use of dendrimers as prodrug nano-scaffolds were briefly demonstrated. The design and synthesis of dendrimer-based prodrugs as well as screening their intrinsic properties in biological systems were fully discussed.     

New insights into the interactions between dendrimers and surfactants by two dimensional NOE NMR spectroscopy

The interactions between polyamidoamine dendrimers and different surfactants including sodium dodecyl sulfate (SDS) and dodecyltrimethyl ammonium bromide in aqueous solutions have been investigated by a NOESY NMR technique. Strong NOE cross-peaks between hydrophobic chain protons of SDS and methylene protons of cationic dendrimers were found, suggesting a strong tendency for the long hydrophobic tails of SDS to associate with the hydrophobic pockets of dendrimers. The hydrophilic head of SDS localizes near the core or the boundary of each generation of dendrimers, and the hydrophobic chain of SDS localizes in the relative nonpolar pockets of dendrimers. The encapsulation of surfactant monomers by dendrimers is dependent on the charge type of the surfactants, the surface functionality, and the generation of dendrimers. The NOESY analysis provides a new insight into interactions between dendrimers and surfactants in comparison with previous investigations.     

聚酰胺―胺的合成表征及对铝酸钠溶液物化性质的影响

用发散法合成以乙二胺为核的聚酰胺―胺(PAMAM 0.5～6.0代),采用元素分析、电位滴定等方法对合成产物进行表征分析,考察了不同分子代数、不同浓度的PAMAM对铝酸钠溶液表面张力和电导率等物理化学性质的影响。结果表明,该条件下合成的PAMAM具有较好的结构完整性。此外随着添加剂PAMAM的增加,铝酸钠溶液的表面张力急剧降低,半代数的PAMAM具有较好的表面活性,有望成为新一代的表面活性剂;整代数的PAMAM也有一定的表面活性。PAMAM属于非离子型表面活性剂,因此随着PAMAM的加入,铝酸钠溶液的电导率改变不大。     

A structural study of carbosilane dendrimers versus polyamidoamine

Several types of substituted carbosilane-based dendrimers are studied in comparison with polyamidoamine (PAMAM), using molecular mechanics approach, to evaluate the shape and steric interactions when the generation number (G) increases. A scaled van der Waals energy parameter: the scaled steric energy, is defined, and used, to compare the steric repulsion in these dendrimers. Our calculations indicate that the steric repulsions, between the end groups at the surface of dendrimers, do not increase for higher generations of such macromolecules. Density calculations show that this property decreases with the increase of G. The moment of inertia calculations show that the shape of the considered dendrimers is asymmetrical for lower generations and becomes spherical at higher generations. The shape of the carbosilane dendrimers is more spherical than PAMAM. The results show that higher generations can afford the increased number of terminal groups at the surface of the macromolecules, without increase of the density in this region, therefor these factors (steric repulsion between the end groups at the surface, or high density) would not impede the chemistry to build higher generations of completely branched dendrimers.     

Synthesis of Novel Amphiphilic Poly （ester-amine） Dendrimers and Their Recognition of Hg2＋ at the Air／Water Interface

Two novel amphiphilic poly(ester-amine)dendrimers were synthesized and characterized by 1H NMR,13C NMR and IR spectra.Their properties of Langmuir film were investigated at the air/water interface.The relationship between the surface pressure and area isotherms of the dendrimers was found to be dependent on the nature of subphases,Interaction between HgCl2 and the dendrimers was observed,indicating that the amphiphilic dendrimers could act as a sensor for Hg^2 .     

EPR and affinity studies of mannose-TEMPO functionalized PAMAM dendrimers

Mannose-TEMPO functionalized G4-PAMAM dendrimers with increasing mannose loadings have been synthesized and characterized by MALDI-TOF MS and EPR spectroscopy. Analysis of linebroadening effects in the EPR spectra of these dendrimers allowed us to determine the relative presentation of mannose and TEMPO on the dendrimer surface. Hemagglutination assays and affinity chromatography/EPR experiments to assess the activity of the mannose-TEMPO dendrimers with Concanavalin A are presented.     

Polyamidoamine dendrimers surface-engineered with biomimetic phosphorylcholine as potential drug delivery carriers

Biomimetic acryloyloxyethyl phosphorylcholine (APC) was used to react with generation 5 poly(amido amine) (PAMAM) dendrimers (G5) via the Michael addition reaction between primary amino group of PAMAM dendrimers and acrylic functional group of APC. FTIR and (1)H NMR confirmed the success of surface modification of G5. The primary amino and phosphorylcholine (PC) group numbers of the surface engineered PAMAM dendrimers (G5-PC) were calculated to be 56 and 50 via (1)H NMR and potentiometric titration. Cell viability and cell morphology studies indicated that biomimetic phosphorylcholine surface engineering successfully lowered the cytotoxicity of G5 PAMAM dendrimers. The hydrophobic interior of G5-PC was used to incorporate anti-cancer drug Adriamycin (ADR) and the G5-PC showed sustained releasing behavior for ADR. Cell morphology and viability tests indicated that the drug-loaded G5-PC conjugate could effectively enter the cancer cells and inhibit the growth of cancer cells. Biomimetic phosphorylcholine surface engineered PAMAM dendrimers with lowered cytotoxicity and high cellular penetrating ability showed great potential for the biomedical applications as nanocarrier system.     

Physicochemical properties of quaternized poly(amidoamine) dendrimers with alkyl groups and of their mixtures with sodium dodecyl sulfate

The physicochemical properties of quaternized poly(amidoamine) dendrimers (generation 4) with methyl or octyl groups and of their mixtures with sodium dodecyl sulfate (SDS) in aqueous solutions have been investigated using several techniques including surface tension, fluorescence of pyrene, and dynamic light scattering. In the single systems of the dendrimers, the dendrimer with octyl groups shows lower surface tension and lower micropolarity than the dendrimer with methyl groups. The hydrodynamic radii of two quaternized poly(amidoamine) dendrimers are considerably large, indicating the formation of aggregates. In the mixed systems of quaternized poly(amidoamine) dendrimers and SDS, the dendrimer with octyl groups-SDS mixed system shows very low surface tension and low micropolarity even in the presence of extremely low SDS concentration compared to those of the dendrimer with methyl groups-SDS mixed system. Maximum turbidity for both systems is observed at around the mixed molar ratio of dendrimer:SDS=1:1.5 where distinct changes have also been confirmed by surface tension, fluorescence of pyrene, and electrical conductivity measurements.     

Unraveling dendrimer translocation across cell membrane mimics

Poly(amidoamine) (PAMAM) dendrimers are promising candidates in several applications within the medical field. However, it is still to date not fully understood whether they are able to passively translocate across lipid bilayers. Recently, we used fluorescence microscopy to show that PAMAM dendrimers induced changes in the permeability of lipid membranes but the dendrimers themselves could not translocate to be released into the vesicle lumen. Because of the lack of resolution, these experiments could not assess whether the dendrimers were able to translocate but remained attached to the membrane. Using quartz crystal microbalance with dissipation monitoring and neutron reflectivity, a structural investigation was performed to determine how dendrimers interact with zwitterionic and negatively charged lipid bilayers. We hereby show that dendrimers adsorb on top of lipid bilayers without significant dendrimer translocation, regardless of the lipid membrane surface charge. Thus, most likely dendrimers are actively transported through cell membranes by protein-mediated endocytosis in agreement with previous cell studies. Finally, the higher activity of PAMAM dendrimers for phosphoglycerol-containing membranes is in line with their high antimicrobial activity against Gram-negative bacteria.     

PAMAM树状大分子对酮基布洛芬溶解度的影响

以酮洛芬为模型药物,研究聚酰胺-胺(PAMAM)树状大分子对酮洛芬的增溶作用,并探讨其作用机理.采用紫外光谱法测定了G1.0、G1.5、G2.0、G2.5、G3.0、G3.5PAMAM在不同浓度和不同pH时对酮洛芬的增溶量.并运用计算机模拟方法对PAMAM与酮洛芬相互作用的机理进行了探讨.实验结果表明,酮洛芬的溶解度随溶液pH值变化而变化,在pH4.0～6.0范围内,PAMAM树状大分子对酮洛芬的增溶量随着PAMAM的代数、浓度和溶液pH的增加而增大.整代和半代都具有增溶作用.然而,在同一pH条件下,对于具有相同官能团数目的整代和半代,整代增溶效果要高于半代.计算机模拟结果表明PAMAM与酮洛芬主要靠静电作用力结合.增溶机理可能是酮洛芬的羧基与PAMAM的伯胺和叔胺发生静电作用.     

Trimethylsilyl ethers of amphiphilic carbosilane dendrimers of the third–fifths generations. Specific features of hydrolysis at the water-air interface

Carbosilane dendrimers from the third to fifth generation with hydroxy groups in the surface layer of the dendrimer were synthesized, as well as their analogs with latent hydroxy groups. The dendrimers differ by the density of the carbosilane core and hydrophilic shell. The amphiphilic nature of the synthesized compounds was manifested already for more hydrophobic trimethylsilyl derivatives of dendrimers. This allowed one to observe the hydrolysis of these objects during compression of their monolayers at the water surface in the Langmuir bath. The parameters of the molecular structure of the dendrimers exert a determining effect on the rate and completeness of the hydrolysis. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2125–2133, November, 2007.     

Self-assembly of facially amphiphilic dendrimers on surfaces

Facially amphiphilic dendrimers have been shown to provide significant difference in surface behavior due to subtle changes in structure. The monodendrons are capable of providing hydrophobic surfaces, while the didendrons provide superhydrophobic surfaces. This provides an example of how a molecular level change could result in significant changes in surface behavior. This difference is attributed to the conformational differences exhibited by these dendrimers on surfaces.     

Synthesis of PAMAM Dendrimers Bearing BINOL Derivative

New functional dendrimers bearing 4,8 and 16 axial chiral units on their surface were synthesized from achiral PAMAM dendrimers and axial chiral (R)-BINOL derivative.     

Cytotoxicity, hemolysis, and acute in vivo toxicity of dendrimers based on melamine, candidate vehicles for drug delivery

A small library of dendrimers was prepared from a common precursor that is available in 5 g scale in five linear steps at 56% overall yield. The precursor is a generation three dendrimer that displays 48 peripheral sites by incorporating AB4 surface groups. Manipulation of these sites provided six dendrimers that vary in the chemistry of the surface group (amine, guanidine, carboxylate, sulfonate, phosphonate, and PEGylated) that were evaluated for hemolytic potential and cytotoxicity. Cationic dendrimers were found to be more cytotoxic and hemolytic than anionic or PEGylated dendrimers. The PEGylated dendrimer was evaluated for acute toxicity in vivo. No toxicity--neither mortality nor abnormal blood chemistry based on blood urea nitrogen levels or alanine transaminase activity--was observed in doses up to 2.56 g/kg i.p. and 1.28 g/kg i.v.     

Polyacrylamide gel electrophoresis separation and detection of polyamidoamine dendrimers possessing various cores and terminal groups

Detection and separation of polyamidoamine dendrimers possessing various cores and surface groups was studied by polyacrylamide gel electrophoresis. Although many dyes and staining techniques were able to detect dendrimers on polyacrylamide gels, Coomassie Blue was found to be the most sensitive and convenient. Amine and hydroxyl terminated dendrimers were best separated under acidic conditions, while dendrimers with carboxyl surfaces required alkaline buffers. Some dendrimers were very susceptible to diffusion that could occur during their separation, staining or destaining steps. In the absence of an appropriate fixation step, dendrimers could be resolved by using small pore size gels and low voltage or current. Increasing core lengths did not significantly affect migration of a given dendrimer generation but exhibited improved separation and staining characteristics. Polyacrylamide gel electrophoresis was found to be a rapid, inexpensive, and reliable procedure to characterize many different water-soluble dendritic macromolecules.