Structure of DNA-Functionalized Dendrimer Nanoparticles

Atomistic molecular dynamics simulations have been carried out to reveal the characteristic features of ethylenediamine (EDA) cored protonated poly amido amine (PAMAM) dendrimers of generation 3 (G3) and 4 (G4) that are functionalized with single stranded DNAs (ssDNAs). The four ssDNA strands that are attached via alkythiolate [-S (CH2)6-] linker molecule to the free amine groups on the surface of the PAMAM dendrimers observed to undergo a rapid conformational change during the 25 ns long simulation period. From the RMSD values of ssDNAs, we find relative stability in the case of purine rich ssDNA strands than pyrimidine rich ssDNA strands. The degree of wrapping of ssDNA strands on the dendrimer molecule was found to be influenced by the charge ratio of DNA and the dendrimer. As G4 dendrimer contains relatively more positive charge than G3 dendrimer, we observe extensive wrapping of ssDNAs on the G4 dendrimer. The ssDNA strands along with the linkers are seen to penetrate the surface of the dendrimer molecule and approach closer to the center of the dendrimer indicating the soft sphere nature of the dendrimer molecule. The effective radius of DNA-functionalized dendrimer nanoparticle was found to be independent of base composition of ssDNAs and was observed to be around 19.5 {\AA} and 22.4 {\AA} when we used G3 and G4 PAMAM dendrimer as the core of the nanoparticle respectively. The observed effective radius of DNA-functionalized dendrimer molecule apparently indicates the significant shrinkage in the structure that has taken place in dendrimer, linker and DNA strands. As a whole our results describe the characteristic features of DNA-functionalized dendrimer nanoparticle and can be used as strong inputs to design effectively the DNA-dendrimer nanoparticle self-assembly for their active biological applications.Comment: 13 pages, 10 figures, 3 Table

Molecular modeling to study dendrimers for biomedical applications

© 2014 by the authors; licensee MDPI; Basel; Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/). Date of Acceptance: 17/11/2014Molecular modeling techniques provide a powerful tool to study the properties of molecules and their interactions at the molecular level. The use of computational techniques to predict interaction patterns and molecular properties can inform the design of drug delivery systems and therapeutic agents. Dendrimers are hyperbranched macromolecular structures that comprise repetitive building blocks and have defined architecture and functionality. Their unique structural features can be exploited to design novel carriers for both therapeutic and diagnostic agents. Many studies have been performed to iteratively optimise the properties of dendrimers in solution as well as their interaction with drugs, nucleic acids, proteins and lipid membranes. Key features including dendrimer size and surface have been revealed that can be modified to increase their performance as drug carriers. Computational studies have supported experimental work by providing valuable insights about dendrimer structure and possible molecular interactions at the molecular level. The progress in computational simulation techniques and models provides a basis to improve our ability to better predict and understand the biological activities and interactions of dendrimers. This review will focus on the use of molecular modeling tools for the study and design of dendrimers, with particular emphasis on the efforts that have been made to improve the efficacy of this class of molecules in biomedical applications.Peer reviewedFinal Published versio

Electrophoretic mobility and molecular distribution studies of poly(amidoamine) dendrimers of defined charges

Generation 5 ethylenediamine (EDA)-cored poly(amidoamine) (PAMAM) dendrimers (E5, E denotes the EDA core and 5 the generation number) with different degrees of acetylation and carboxylation were synthesized and used as a model system to investigate the effect of charge and the influence of dendrimer surface modifications on electrophoretic mobility (EM) and molecular distribution. The surface-modified dendrimers were characterized by size-exclusion chromatography, 1 H NMR, MALDI-TOF-MS, PAGE, and CE. The focus of our study was to determine how EM changes as a function of particle charge and molecular mass, and how the molecular distribution changes due to surface modifications. We demonstrate that partially modified dendrimers have much broader migration peaks than those of fully surface functionalized or unmodified E5 dendrimers due to variations in the substitution of individual dendrimer surfaces. EM decreased nonlinearly with increases in surface acetylation for both PAMAM acetamides and PAMAM succinamic acids, indicating a complex migration activity in CE separations that is not solely due to charge/mass ratio changes. These studies provide new insights into dendrimer properties under an electric field, as well as into the characterization of dendrimer-based materials being developed for medical applications.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50647/1/1758_ftp.pd

Tuning the Size of Nanoassembles: A Hierarchical Transfer of Information from Dendrimers to Polyion Complexes

This is the peer reviewed version of the following article: Amaral, S., Tawara, M., Fernandez-Villamarin, M., Borrajo, E., Martínez-Costas, J., & Vidal, A. et al. (2018). Tuning the Size of Nanoassembles: A Hierarchical Transfer of Information from Dendrimers to Polyion Complexes. Angew. Chem. Int. Ed., 57(19), 5273-5277, which has been published in final form at https://doi.org/10.1002/anie.201712244. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived VersionsThe generation of dendrimers is a powerful tool in the control of the size and biodistribution of polyion complexes (PIC). Using a combinatorial screening of six dendrimers (18–243 terminal groups) and five oppositely charged PEGylated copolymers, a dendrimer‐to‐PIC hierarchical transfer of structural information was revealed with PIC diameters that increased from 80 to 500 nm on decreasing the dendrimer generation. This rise in size, which was also accompanied by a micelle‐to‐vesicle transition, is interpreted according to a cone‐ to rod‐shaped progression in the architecture of the unit PIC (uPIC). This precise size tuning enabled dendritic PICs to act as nanorulers for controlled biodistribution. Overall, a domino‐like control of the size and biological properties of PIC that is not attainable with linear polymers is feasible through dendrimer generationMinisterio de Economía y Competitividad. Grant Numbers: CTQ2015-69021-R, CTQ2014-61470-EXP, BFU2013-43513-R Consellería de Cultura, Educación e Ordenación Universitaria, Xunta de Galicia. Grant Numbers: GRC2014/040, Centro Singular de Investigación de Galicia Accreditation 2016-2019, ED431G/09 European Regional Development FundS

Dibutyl 5-[(4-ethoxycarbonylphenyl)diazenyl]benzene-1,3-dicarboxylate

In the title compound, C25H30N2O6, the dihedral angle between the aromatic rings is 3.79 (1) Å and the N=N bond shows a trans conformation. Both butyl side chains show evidence of disorder

Ultrafast time-resolved photoluminescence from novel metal–dendrimer nanocomposites

We report the first results of ultra-fast enhanced light emission from gold– and silver–dendrimer nanocomposites. There is a fast (70 fs) fluorescence decay component associated with the metal nanocomposites. Anisotropy measurements show that this fast component is depolarized. The enhanced emission is suggestively due to local field enhancement in the elongated metal–dendrimer nanoparticles. © 2001 American Institute of Physics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71043/2/JCPSA6-114-5-1962-1.pd

Exploring the loading capacity of generation six to eight dendronized polymers in aqueous solution

Aspects of size, structural (im)perfection, inner density, and guest loading capacity of dendronized polymers (DPs) of high generation g (6≤g≤8) in aqueous solution were studied using electron paramagnetic resonance (EPR) spectroscopy on amphiphilic, spin- labeled guest molecules. The presented results show that the interior of the charged DPs is strongly polar, especially in comparison to their lower generation analogues 1-4. This is a direct sign of large amounts of water penetrating the DP surface, which in return mirrors structural imperfections and much lower than theoretically achievable segmental densities of these high generation DPs. Images obtained with atomic force microscopy (AFM) reveal that the high g DPs show no aggregation and give further insights into structural (im)perfections. EPR- spectroscopic data further show that despite their structural imperfections, these DPs can bind and release large numbers of amphiphilic molecules. It can be concluded that attention should be paid to synthesis which needs to develop a protocol that avoids the relatively large amount of defects generated in the direct conversion of PG4 to PG6 which had to be employed here

Synthesis, internalization and visualization of n-(4-carbomethoxy) pyrrolidone terminated PAMAM [G5:G3-TREN] Tecto(dendrimers) in mammalian cells

Tecto(dendrimers) are well-defined, dendrimer cluster type covalent structures. In this article, we present the synthesis of such a PAMAM [G5:G3-(TREN)]-N-(4-carbomethoxy) pyrrolidone terminated tecto(dendrimer). This tecto(dendrimer) exhibits nontraditional intrinsic luminescence (NTIL; excitation 376 nm; emission 455 nm) that has been attributed to three fluorescent components characterized by different fluorescence lifetimes. Furthermore, it has been shown that this PAMAM [G5:G3-(TREN)]-N-(4-carbomethoxy) pyrrolidone terminated tecto(dendrimer) is able to form a polyplex with double stranded DNA, and is nontoxic for HeLa and HMEC-1 cells up to a concentration of 10 mg/mL, even though it accumulates in endosomal compartments as demonstrated by its unique NTIL emission properties. Many of the above features would portend the proposed use of this tecto(dendrimer) as an efficient transfection agent. Quite surprisingly, transfection activity could not be demonstrated in HeLa cells, and the possible reasons are discussed in the article. © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)

CE of poly(amidoamine) succinamic acid dendrimers using a poly(vinyl alcohol)-coated capillary

Various generations (G1–G8) of negatively charged poly(amidoamine) (PAMAM) succinamic acid dendrimers (PAMAM-SAH) were analyzed by CE using a poly(vinyl alcohol)-coated capillary. Due to its excellent stability and osmotic flow-shielding effect, highly reproducible migration times were achieved for all generations of dendrimer ( e.g ., RSD for the migration times of G5 dendrimer was 0.6%). We also observed a reverse trend in migration times for the PAMAM-SAH dendrimers ( i.e ., higher generations migrated faster than lower generation dendrimers) compared to amine-terminated PAMAM dendrimers reported in the literature. This reversal in migration times was attributed to the difference in counterion binding around these negatively charged dendrimers. This reverse trend allowed a generational separation for lower generation (G1–G3) dendrimers. However, a sufficient resolution for the migration peaks of higher generations (G4–G5) in a mixture could not be achieved. This could be due to their nearly identical charge/mass ratio and dense molecular conformations. In addition, we show that dye-functionalized PAMAM-SAH dendrimers can also be analyzed with high reproducibility using this method.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/57911/1/510_ftp.pd