Biomimetics: From Bioinformatics to Rational Design of Dendrimers as Gene Carriers

Abstract

Biomimetics, or the use of principles of Nature for developing new materials, is a paradigm that could help Nanomedicine tremendously. One of the current challenges in Nanomedicine is the rational design of new efficient and safer gene carriers. Poly(amidoamine) (PAMAM) dendrimers are a well-known class of nanoparticles, extensively used as non-viral nucleic acid carriers, due to their positively charged end-groups. Yet, there are still several aspects that can be improved for their successful application in in vitro and in vivo systems, including their affinity for nucleic acids as well as lowering their cytotoxicity. In the search of new functional groups that could be used as new dendrimer-reactive groups, we followed a biomimetic approach to determine the amino acids with highest prevalence in protein-DNA interactions. Then we introduced them individually as terminal groups of dendrimers, generating a new class of nanoparticles. Molecular dynamics studies of two systems: PAMAM-Arg and PAMAM-Lys were also performed in order to describe the formation of complexes with DNA. Results confirmed that the introduction of amino acids as terminal groups in a dendrimer increases their affinity for DNA and the interactions in the complexes were characterized at atomic level. We end up by briefly discussing additional modifications that can be made to PAMAM dendrimers to turned them into promising new gene carriers.

Effect of Terminal Groups of Dendrimers in the Complexation with Antisense Oligonucleotides and Cell Uptake

“…In this regard, previous studies have suggested that dendrimers can display a propensity to bind some nucleotide bases with better affinity. Maiti and coworkers [ 41 ] have performed theoretical studies with homopolymers—i.e., poly G, poly T, poly A, and poly C—and revealed that the interaction energy between PAMAM-NH 2 and poly G/poly C are the most favorable, in comparison with poly A and poly T. In fact, a recent article of our group [ 42 ] has shown that lysine-terminated dendrimers, bearing amine moieties like native PAMAM-NH 2 , can bind guanine bases in a double-strand DNA with the highest propensity, which was correlated with the information given by protein–DNA interaction obtained from a total of 2013 crystal structures. To determine here if PAMAM-NH 2 shows any propensity to bind better some bases, we calculated the interaction energy over the last 10 ns of MD trajectory, between amine terminal groups and a single base (A, C, G, T) of the asODN (Fig.…”

The complex of PAMAM-OH dendrimer with Angiotensin (1–7) prevented the disuse-induced skeletal muscle atrophy in mice

“…Related to this, a new bioinformatics-based strategy for the rational design of new dendrimers as DNA carriers that employs the knowledge of protein-DNA interactions was recently reported. 3 Among the dendrimers with potential applications, hydroxyl-terminated PAMAM (PAMAM-OH) dendrimers are suggested safe drug carriers due to non-toxic effects observed during in vitro and in vivo applications. 4 Furthermore, the PAMAM-OH dendrimer can preferentially distribute in the brain, enabling targeted therapeutic delivery in disorders such as cerebral palsy, Alzheimer's disease, and multiple sclerosis.…”

Self-Assembly of Amphiphilic Dendrimers: The Role of Generation and Alkyl Chain Length in siRNA Interaction

“…Due to a positive charge at physiological pH, PAMAM-NH 2 dendrimers are efficient nucleic carriers 11 12 . Terminal groups theorised to increase the gene carrying abilities of dendrimers include amino acids 13 14 , cell-penetrating peptides such as GALA 11 , and polyethylene glycol groups on dendrimer surfaces 15 , among others.…”