Dynamic constitutional frameworks (DCFs) as nanovectors for cellular delivery of DNA

Abstract

We introduce Dynamic Constitutional Frameworks (DCFs), macromolecular structures that efficiently bind and transfect double stranded DNA. DCFs are easily synthesizable adaptive 3D networks consisting of core connection centres reversibly linked via labile imine bonds both to linear polyethyleneglycol (PEG, ∼1500 Da) and to branched polyethyleneimine (bPEI, ∼800 Da). DCFs bind linear and plasmid DNA, forming particulate polyplexes of 40-200 nm in diameter. The polyplexes are stable during gel electrophoresis, well tolerated by cells in culture, and exhibit significant transfection activity. We show that an optimal balance of PEG and bPEI components is important for building DCFs that are non-toxic and exhibit good cellular transfection activity. Our study demonstrates the versatility and effectiveness of DCFs as promising new vectors for DNA delivery.

Dynamic covalent polymers for biomedical applications

“…Barboiu and coworkers used imines as reversible covalent linkage for generating cross-linked dynamic covalent polymers, coined Dynamic Constitutional Frameworks (DCFs). [117][118][119][120] The design uses commercially-available 1,3,5-benzenetrialdehyde, a building block which can be connected to mono-, di-and polyamines through imine-bond formations (Figure 8). Varying the ratio of the latter enables tuning the density of functional positive groups brought by the monoamine (PEG-ylated squalene-PEI, Girard's reagent T, N,N-dimethylethylene amine, amino-guanidine), the length of the linear chains imposed by the diamine (poly-(ethylene-glycol)-bis(3-amino-propyl)terminated, Mn ≈ 1500 g.mol -1 ; Jeffamine-400, Jeffamine-2000), and the degree of cross-links given by the polyamine (branched polyethyleneimine 800 and 2000), within the dynamic frameworks, thereby allowing screening effectively, by selfassembly, subtle changes in dendrimer structures that may Please do not adjust margins Please do not adjust margins have a profound effect on nucleic acid complexation and delivery.…”

Growing Prospects of Dynamic Covalent Chemistry in Delivery Applications

“…The group of Barboiu has also proposed such approach using imine-based dynamic covalent frameworks ( Figure 6B). [69][70][71][72] Also in 2015, while working on guanidinium-based molecular glues for multivalent biomolecular recognition, 73 the group of Aida came across a small water-soluble tetraguanydilated dithiol which undergo a template-assisted oxidative polymerization in presence of siRNA, leading to polydisulfide nanocaplets of small and uniform size. 74 Depolymerization in the reductive cytosolic environment was shown to liberate the packaged siRNA (Figure 7).…”

Synergistic Effect of Low Molecular Weight Polyethylenimine and Polyethylene Glycol Components in Dynamic Nonviral Vector Structure, Toxicity, and Transfection Efficiency

“…In the present study, we have addressed and investigated the above mentioned issues by applying a dynamic combinatorial chemistry approach developed by our group [34,35,36] to produce a series of new systems (dynamic combinatorial frameworks (DCFs)) containing PEGylated squalene (SQ-PEG-NH 2 ) [34,37], poly-(ethyleneglycol)-bis(3-aminopropyl) (Mn~1500 g/mol) (NH 2 -PEG-HN 2 ), and branched polyethylenimine of 2000 Da (PEI2000) components, reversibly connected in a hyperbranched structure. The obtained frameworks were capable to self-assemble in supramolecular amphiphilic architectures, driven by self-assembly properties of squalene derivatives, thus cumulating the number of PEI units per carrier.…”