Polyamidoamide Dendrimers Research Articles

β‐Cyclodextrin PAMAM Dendrimer: How to Overcome the Tumbling Process for Getting Fully Available Host Cavities

The synthesis of a G0 polyamidoamide (PAMAM) dendrimer end‐capped with four β‐cyclodextrin (β‐CD) units, named as Tetra‐CD was performed by using copper(I)‐catalyzed alkyne‐azide cycloaddition (CuAAC). This new platform presents a considerable high water‐solubility in comparison to native β‐CD. Tumbling process involving half of the CD cavities in D2O was evidenced by 1H NMR spectroscopy. Interaction of adamantane with Tetra‐CD has been fully investigated by 1D/2D NMR techniques and mass spectrometry besides a joint study on new β‐CD monomers (named as A and B) and on a dimer (Di‐CD) and a trimer (Tri‐CD). The obtained results demonstrate that the tumbling effect can be shifted in the presence of an appropriate hydrophobic guest resulting in the full host‐ability of the CD units in water for that guest.

Poly-L-histidine inhibits prion propagation in a prion-infected cell line

ABSTRACTTransmissible spongiform encephalopathies (TSEs) are a group of lethal neurodegenerative diseases involving the structural conversion of cellular prion protein (PrPC) into the pathogenic isoform (PrPSc) for which no effective treatment is currently available. Previous studies have implicated that a polymeric molecule with a repeating unit, such as pentosane polysulfate and polyamidoamide dendrimers, exhibits a potent anti-prion activity, suggesting that poly-(amino acid)s could be a candidate molecule for inhibiting prion propagation. Here, by screening a series of poly-(amino acid)s in a prion-infected neuroblastoma cell line (GTFK), we identified poly-L-His as a novel anti-prion compound with an IC50 value of 1.8 µg/mL (0.18 µM). This potent anti-prion activity was specific to a high-molecular-weight poly-L-His and absent in monomeric histidine or low-molecular-weight poly-L-His. Solution NMR data indicated that poly-L-His directly binds to the loop region connecting Helix 2 and Helix 3 of PrPC and sterically blocks the structural conversion toward PrPSc. Poly-L-His, however, did not inhibit prion propagation in a prion-infected mouse when administered intraperitoneally, suggesting that the penetration of blood-brain barrier and/or the chemical stability of this polypeptide must be addressed before its application in vivo. Taken together, this study revealed the potential use of poly-L-His as a novel treatment against TSEs. (203 words)

Role of PAMAM-OH dendrimers against the fibrillation pathway of biomolecules

The binding behavior of nanoparticle with proteins determines its biocompatibility. This study reports the interaction of ten different biomolecules (proteins-BSA, HSA, haemoglobin, gamma globulin, transferrin and enzymes-hog and bacillus amylase, lysozyme from chicken and human and laccases from Tramates versicolor) with a surface group hydroxylated Poly AMido AMide dendrimer (PAMAM) of generation 5. The study has utilized various spectroscopic methods like UV–vis spectroscopy, Fluorescence emission, Synchronous, 3-D spectroscopy and Circular Dichroism to detect the binding induced structural changes in biomolecules that occur upon interaction with mounting concentration of the dendrimers. Aggregation of proteins results in the formation of amyloid fibrils causing several human diseases. In this study, fibrillar samples of all ten biomolecules formed in the absence and the presence of dendrimers were investigated with Congo Red absorbance and ThT Assay to detect fibril formation, Trp Emission and 3-D scan to evaluate the effect of fibrillation on aromatic environment of biomolecules, and CD spectroscopy to measure the conformational changes in a quantitative manner. These assays have generated useful information on the role of dendrimers in amyloid fibril formation of biomolecules. The outcomes of the study remain valuable in evaluating the biological safety of PAMAM-OH dendrimers for their biomedical application in vivo.

Stability of Amphiphilic Dendrimers at the Water/Air Interface

By means of atomistic molecular dynamics simulations, we investigate the structure and stability of alkyl-modified polyamido-amide (PAMAM) dendrimers at the air/water interface as a function of the number and the relative position of the modified end groups. We find that the PAMAM dendrimer with all terminal groups functionalized is more stable at the interface than the Janus dendrimer where only half the amine groups are modified. This result is explained in terms of softness of the dendrimer molecule which adapts its conformation to maximize the favorable amide-water contacts segregating the alkyl chains and increasing the structural order of the "hydrophilic core". We interpret the stability of the molecule at the interface also in terms of particle wettability and energy components. We verify that the atomistic model follows the prediction of the thermodynamic analytical theory adopting an oblate or prolate shape and orientating its longest axis parallel to the normal to the interface. These results indicate that monolayers of fully functionalized molecules could be as stable as (or more stable than) those self-assembled from proper Janus molecules.

Structure of polyamidoamide dendrimers up to limiting generations: A mesoscale description

The polyamidoamide (PAMAM) class of dendrimers was one of the first dendrimers synthesized by Tomalia and co-workers at Dow. Since its discovery the PAMAMs have stimulated many discussions on the structure and dynamics of such hyperbranched polymers. Many questions remain open because the huge conformation disorder combined with very similar local symmetries have made it difficult to characterize experimentally at the atomistic level the structure and dynamics of PAMAM dendrimers. The higher generation dendrimers have also been difficult to characterize computationally because of the large size (294,852 atoms for generation 11) and the huge number of conformations. To help provide a practical means of atomistic computational studies, we have developed an atomistically informed coarse-grained description for the PAMAM dendrimer. We find that a two-bead per monomer representation retains the accuracy of atomistic simulations for predicting size and conformational complexity, while reducing the degrees of freedom by tenfold. This mesoscale description has allowed us to study the structural properties of PAMAM dendrimer up to generation 11 for time scale of up to several nanoseconds. The gross properties such as the radius of gyration compare very well with those from full atomistic simulation and with available small angle x-ray experiment and small angle neutron scattering data. The radial monomer density shows very similar behavior with those obtained from the fully atomistic simulation. Our approach to deriving the coarse-grain model is general and straightforward to apply to other classes of dendrimers.

Counterion Distribution and ζ-Potential in PAMAM Dendrimer

Using several hundred nanosecond long fully atomistic molecular dynamics simulations, we investigate the monomer and counterion local concentrations in poly amido amide (PAMAM) dendrimer systems for various generations at neutral pH. We also calculate the ζ potential as a function of dendrimer generation. It is found that the ζ potential increases with dendrimer generation, but slowly at high generation. The ζ potential behavior is remarkably well reproduced when employing Monte Carlo simulations and the Poisson−Boltzmann theory for colloidal particles with size and effective charge of the dendrimer as relevant input parameters from the fully atomistic simulations.