Synthetically controlling dendrimer flexibility improves delivery of large plasmid DNA

Abstract

Tools for editing the genome and epigenome have revolutionised the field of molecular biology and represent a new frontier in targeted therapeutic intervention.

A facile methodology using quantum dot multiplex labels for tracking co-transfection

“…A new dendronised polymer system that is capable of delivering large pDNA constructs with high efficiency was prepared and utilised for the study. 15 The dendronised polymer was prepared by a copper-catalysed 'click' reaction of 4.5-generation poly(amidoamine) (G4.5 PAMAM) dendrons onto a random poly[(2hydroxyethyl methacrylate)-ran-(glycidyl methacrylate)] copolymer backbone (Scheme 1). The dendronised polymer design and composition was selected over sterically-hindered traditional G5 PAMAM dendrimers to allow for optimal exibility and charge density for plasmid binding and efficient delivery.…”

“…The dendronised polymer design and composition was selected over sterically-hindered traditional G5 PAMAM dendrimers to allow for optimal exibility and charge density for plasmid binding and efficient delivery. 15 Incorporation of the HEMA monomer as a spacer unit increases polymer biocompatibility, avoiding the high toxicity levels observed with G5 PAMAM dendrimers. [15][16][17] Forming polyplexes from premixed pDNAs improves rates of co-transfection compared to the formation and addition of two distinct polyplexes.…”

“…15 Incorporation of the HEMA monomer as a spacer unit increases polymer biocompatibility, avoiding the high toxicity levels observed with G5 PAMAM dendrimers. [15][16][17] Forming polyplexes from premixed pDNAs improves rates of co-transfection compared to the formation and addition of two distinct polyplexes. Presumably this is because pre-mixing pDNAs increases the chance that a given polyplex, which is usually composed of several pDNA macromolecules, 18 will contain both pDNAs.…”

Advances in CRISPR/Cas9 Technology for <i>in Vivo</i> Translation

“…72) There are limitations to lipid-based systems in a therapeutic context, low stability in physiological conditions, high toxicity and inability to efficiently entrap larger molecular weight therapeutics such as larger pDNA. 73,74) Kreiss et al reported that while the physicochemical properties of liposomes are not affected by pDNA size, the transfer efficiency of the complex significantly decreases with large pDNA size. Notably, the study demonstrated that the number of pDNA molecules incorporated into each liposome was inversely proportional to the size of the plasmid.…”

Recent trends in click chemistry as a promising technology for virus-related research

“…Viral vectors, including those of the lentivirus and adeno-associated virus, as well as some nonviral strategies, such as cationic polymer and liposome, are limited by their packaging capacity, poor delivery, toxicity, and immunogenicity (Kretzmann et al, 2017). Therefore, improving the delivery of viral vectors remains a challenge for medical chemistry.…”