Abstract
The studies of bolaamphiphile-based nanoparticles as delivery vectors are still rudimentary and under development. In this study, several asymmetric bolaamphiphiles containing lysine and another moiety with special functions, such as pH-sensitive or cell-targeting property, were designed and synthesized. The potentials of these bolaamphiphile-based nanoparticles as versatile vectors for both nucleic acids and chemical drugs were studied. With the presence of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), these amphiphiles could be prepared into bolasomes, which showed good DNA binding ability and could condense plasmid DNA into nanoparticles with appropriate size and surface potential. Lys-His, which has a pH-sensitive histidine on one head, exhibited higher transfection efficiency than the symmetric counterpart and comparable efficiency to commercially available transfection reagent. Mechanism studies confirmed that the bolaplexes formed from Lys-His might induce the highest cellular uptake and the best endosomal escape ability. On the other hand, these bolaamphiphiles also exhibited good drug loading ability. The self-assembly vesicles could efficiently encapsulate the hydrophobic anti-cancer drug doxorubicin (DOX) in aqueous solution with high drug loading content and encapsulation efficiency. Confocal laser scanning microscopy (CLSM) experiment and cell viability assay exhibited a controlled release of the drug with the assistance of bolasomes. It was shown that such bolaamphiphiles have great potential as nano-vectors for both drug and gene or their co-delivery.
Highlights
Development of effective and safe delivery vectors is a critical challenge for the application of gene therapy, which provides a promising method for many acquired or inherited diseases by transporting a specific gene to the target cells combating the disease at the level of its origin [1,2,3,4]
We recently found that lysine or cyclen headgroups-based symmetric cationic bolalipids showed a certain potential for gene delivery [26]
Lysine has excellent DNA binding ability due to its two primary amines, it has been widely used as a hydrophilic head in various biomaterials
Summary
Development of effective and safe delivery vectors is a critical challenge for the application of gene therapy, which provides a promising method for many acquired (such as AIDS or cancer) or inherited (cystic fibrosis etc.) diseases by transporting a specific gene to the target cells combating the disease at the level of its origin [1,2,3,4]. Unlike regular lipid-like amphiphiles (termed “mono-amphiphile”) consisting of one or more hydrophobic tails and a single hydrophilic headgroup, bola-type amphiphiles (termed “bolaamphiphile”), which are composed of one or two hydrophobic chains that are covalently linked at both ends to hydrophilic head groups, have not had extensive attention [20]. In nature, this type of dumbbell-shaped architecture has been mainly found in membranes of some certain kinds of extremophile archaebacteria [21]. Bola-type vectors are increasingly attractive for biomaterial applications ranging from nanomaterial synthesis to gene or drug delivery due to their unique molecular architecture
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