Host–Guest‐Mediated DNA Templation of Polycationic Supramolecules for Hierarchical Nanocondensation and the Delivery of Gene Material

Abstract

Only a few examples of monodisperse molecular entities that can compact exogenous nucleic acids into nanocomplexes, protect the cargo from the biological environment, facilitate cell internalization, and promote safe transfection have been reported up to date. Although these species open new venues for fundamental studies on the structural requirements that govern the intervening processes and their application in nonviral gene-vector design, the synthesis of these moieties generally requires a relatively sophisticated chemistry, which hampers further development in gene therapy. Herein, we report an original strategy for the reversible complexation and delivery of DNA based on the supramolecular preorganization of a β-cyclodextrin-scaffolded polycationic cluster facilitated by bisadamantane guests. The resulting gemini-type, dual-cluster supramolecules can then undergo DNA-templated self-assembly at neutral pH value by bridging parallel DNA oligonucleotide fragments. This hierarchical DNA condensation mechanism affords transfectious nanoparticles with buffering capabilities, thus facilitating endosomal escape following cell internalization. Protonation also destabilizes the supramolecular dimers and consequently the whole supramolecular edifice, thus assisting DNA release. Our advanced hypotheses are supported by isothermal titration calorimetry, NMR and circular dichroism spectroscopic analysis, gel electrophoresis, dynamic light scattering, TEM, molecular mechanics, molecular dynamics, and transfection studies conducted in vitro and in vivo.

Plasmid‐Templated Control of DNA–Cyclodextrin Nanoparticle Morphology through Molecular Vector Design for Effective Gene Delivery

“…We recently demonstrated that the propensity of non‐amphiphilic CD‐based molecular nanoparticle entities to integrate pDNA‐templated bilayer arrangements could be programmed by supramolecular preorganization into dimers (Figure B), thereby dramatically enhancing the transfection efficiency in vitro compared to the monomer by more than three orders of magnitude . High transgene expression levels, comparable to those obtained with paCDs, were achieved in the lung and the liver in vivo in mice.…”

Access to Versatile β‐Cyclodextrin Scaffolds through Guest‐Mediated Monoacylation

“…Amine-functionalized CD 1 is av ersatile scaffold, which has been used for the design of fluorescent sensors, [10,45] synthetic receptors, [46] investigated as ap recursor to forming glycoclusters, [47] controlling protein self-assembly, [48] DNA transfection, [49] and as an inhibitor of anthraxl ethal toxin. [50][51][52][53] In these examples, the amine groups of 1 were either per-functionalized, or monofunctionalized nonselectively with desired reagents.…”

Docetaxel-Loaded Nanoparticles Assembled from β-Cyclodextrin/Calixarene Giant Surfactants: Physicochemical Properties and Cytotoxic Effect in Prostate Cancer and Glioblastoma Cells

“…Of particular interest for our goals is the fact that βCD can form inclusion complexes with docetaxel and that the incorporation of βCD in nanomaterials can be used to impart high DTX loading capabilities (Zhao and Astruc, 2012; Wang et al, 2016). Although canonic βCD exhibit some renal toxicity after parenteral administration, related to its greater ability to interact with cellular lipids leading to cell-membrane damage, toxicity is greatly reduced after chemical modification (Stella and He, 2008; Gallego-Yerga et al, 2015a). Indeed, amphiphilic βCD derivatives showed no apparent toxicity in animal models (Mendez-Ardoy et al, 2011; Aranda et al, 2013; Gallego-Yerga et al, 2015a).…”

“…Although canonic βCD exhibit some renal toxicity after parenteral administration, related to its greater ability to interact with cellular lipids leading to cell-membrane damage, toxicity is greatly reduced after chemical modification (Stella and He, 2008; Gallego-Yerga et al, 2015a). Indeed, amphiphilic βCD derivatives showed no apparent toxicity in animal models (Mendez-Ardoy et al, 2011; Aranda et al, 2013; Gallego-Yerga et al, 2015a). …”