Bolaamphiphiles as carriers for siRNA delivery: From chemical syntheses to practical applications

Abstract

In this study we have investigated a new class of cationic lipids – “bolaamphiphiles” or “bolas” for their ability to efficiently deliver small interfering RNAs (siRNAs) to cancer cells. The bolas of this study consist of a hydrophobic chain with one or more positively charged head groups at each end. Recently, we reported that micelles of the bolas GLH-19 and GLH-20 (derived from vernonia oil) efficiently deliver siRNAs, while having relatively low toxicities in vitro and in vivo. Our previous studies validated that; bolaamphiphiles can be designed to vary the magnitude of siRNA shielding, its delivery, and its subsequent release. To further understand the structural features of bolas critical for siRNAs delivery, new structurally related bolas (GLH-58 and GLH-60) were designed and synthesized from jojoba oil. Both bolas have similar hydrophobic domains and contain either one, in GLH-58, or two, in GLH-60 positively charged head groups at each end of the hydrophobic core. We have computationally predicted and experimentally validated that GLH-58 formed more stable nano sized micelles than GLH-60 and performed significantly better in comparison to GLH-60 for siRNA delivery. GLH-58/siRNA complexes demonstrated better efficiency in silencing the expression of the GFP gene in human breast cancer cells at concentrations of 5 μg/mL, well below the toxic dose. Moreover, delivery of multiple different siRNAs targeting the HIV genome and further inhibition of virus production was demonstrated.

Programmable Nucleic Acid Based Polygons with Controlled Neuroimmunomodulatory Properties for Predictive QSAR Modeling

“…Nano‐TNAs have the potential to overcome both of these barriers. Their delivery to the brain can be achieved by previously characterized carriers, such as bolaamphiphiles, and rational design of nano‐TNAs can help avoid the undesirable neuroinflammation. Therefore, it is necessary to characterize the immunomodulatory effects of nano‐TNAs on resident CNS cells such as microglia and astrocytes that are essential for the initiation and progression of immune responses in the CNS through the production of various inflammatory cytokines .…”

Cellular Delivery of RNA Nanoparticles

“…Similar effects were observed in a more recent study in which two other bola micelle variants GLH-58 and GLH-60 were characterized both computationally and experimentally (in vitro). 243 GLH-58 and GLH-60 have hydrophobic cores derived from jojoba oil, and two (GLH-58) or four (GLH-60) GLH-20-like ACh head groups. 3D structure modeling and MD simulations (Figure 4), combined with experimental results indicated that the design differences between GLH-58 and GLH-60 influence the balance between the RNA protection against degradation, efficiency of delivery, and ease of RNA release.…”

Nucleic Acid Nanoparticles at a Crossroads of Vaccines and Immunotherapies

“…NANPs' molecular weight and structure are different from those of the traditional TNA. While NANPs versatility and strategies for design of functional NANPs have been studied extensively [46][47][48][49][50][51][52][53]55,57,[65][66][67][68][70][71][72][73][74][76][77][78][79][80][81]83,86,91,92,[95][96][97][98]100,102,103,121,[129][130][131][132][133][134][135][136][137][138][139][140][141]…”