Self‐Assembled Multivalent (SAMul) Polyanion Binding—Impact of Hydrophobic Modifications in the Micellar Core on DNA and Heparin Binding at the Peripheral Cationic Ligands

Abstract

This paper reports a small family of cationic surfactants designed to bind polyanions such as DNA and heparin. Each molecule has the same hydrophilic cationic ligand, and a hydrophobic aliphatic group with eighteen carbon atoms with either one, two or three alkene groups within the hydrophobic chain (C18-1, C18-2 and C18-3). Dynamic light scattering indicates that more alkenes lead to geometric distortion, giving rise to larger self-assembled multivalent (SAMul) nanostructures. Mallard Blue and Ethidium Bromide dye displacement assays demonstrate that heparin and DNA have markedly different binding preferences, with heparin binding most effectively to C18-1, and DNA to C18-3, even though the molecular structural differences of these SAMul systems are buried in the hydrophobic core. Multiscale modelling suggests that adaptive heparin maximises enthalpically-favourable interactions with C18-1, while shape-persistent DNA forms a similar number of interactions with each ligand display, but with slightly less entropic cost for binding to C18-3 -fundamental thermodynamic differences in SAMul binding of heparin or DNA. This study therefore provides unique insight into electrostatic molecular recognition between highly charged nanoscale surfaces in biologically-relevant systems.

Unchain My Blood: Lessons Learned from Self-Assembled Dendrimers as Nanoscale Heparin Binders

“…In the last decade, our group has been quite active in several international projects dealing with the development of amphiphilic dendrons that, upon self-assembling into micellar spherical pseudo-dendrimers, exhibited unique binding properties towards nucleic acids which entailed them to be exploited as nanocarriers for gene delivery in cancer therapeutics [18,19,20,22,23,25,27,28]. Notably, such systems are synthetically straightforward, with programmed self-assembly of simple building blocks being used as the key nanofabrication step.…”

“…In the panorama described above, during the last 5 years our laboratory, in collaboration with different international groups, has designed and produced a series of amphiphilic molecules bearing dendritic portions as polar heads and various hydrocarbon chains as hydrophobic moieties, able to self-organize into supramolecular nanostructures of different size and shape with the unique capability of selectively binding the two major polyanions, heparin and DNA [21,22,23,24,25,26,27,28,29]. This, with the goal of employing the resulting self-assembled dendrimers as protamine replacer and gene delivery nanovectors, respectively.…”

From fundamental supramolecular chemistry to self-assembled nanomaterials and medicines and back again – how Sam inspired SAMul

“…14). 71 The presence of more alkenes led to geometric distortion, yielding larger self-assembled multivalent (SAMul) nanostructures and hence modifying the ligand display. Polyanion binding was studied using dye displacement assays and ITC, with data in agreement that heparin bound most effectively to C 18 -1, and DNA to C 18 -3, even though the molecular-scale structural differences of the SAMul systems are buried in the hydrophobic core.…”

“…Fundamental differences between the binding of polyanionic heparin and DNA suggest the former is adaptive and the latter shape-persistent. 60,69,71 Selective electrostatic binding. Electrostatic binding does not only depend on charge density -selectivity can be achieved based on the precise details of ligand structure.…”

Self-Assembled Nanomicelles as Curcumin Drug Delivery Vehicles: Impact on Solitary Fibrous Tumor Cell Protein Expression and Viability

“…17,18 In the synthetic nanovector arena, we reported a variety of self-assembled multivalent (SAMul) nanostructures which achieved high affinity binding to biological polyanions (e.g., DNA and heparin). [19][20][21][22][23][24][25][26] We reasoned that the hydrophobic interiors of these SAMul nanomicelles (NMs) should be able to encapsulate CUR and deliver it to SFT cells, and this led to the design of this current study. In particular, we used a small family of SAMul entities (Figure 1 center) in which the ligand groups displayed on the surface of the relevant NMs were subtly varied, 23 in order to determine whether molecular-scale programming of the nanovector could have an impact on cellular uptake, release and subsequent anti-cancer activity of CUR.…”