Triton X-100-Modified Adenosine Triphosphate-Responsive siRNA Delivery Agent for Antitumor Therapy

Abstract

Modified polyethyleneimine (PEI) has been widely used as siRNA delivery agents. Here, a new Triton X-100-modified low-molecular-weight PEI siRNA delivery agent is developed together with the coupling of 4-carboxyphenylboronic acid (PBA) and dopamine grafted vitamin E (VEDA). Triton X-100, a nonionic detergent, greatly improves the cellular uptake of siRNA as well as the siRNA escape from endosome/lysosome because of its high transmembrane ability. In addition, the boronate bond between PBA and VEDA of the transfection agent can be triggered to release its entrapped siRNA because of the high level of adenosine triphosphate (ATP) in cancer cells. The transfection agent is successfully applied to deliver siRNAs targeting endogenous genes of epidermal growth factor receptor (EGFR) and kinesin-5 (Eg5) to cancer cells, showing good results on Eg5 and EGFR silencing ability and inhibition of cancer cell migration. Further in vivo study indicates that the Triton X-100-modified transfection agent is also efficient to deliver siRNA to cancer cells and shows significant tumor growth inhibition on mice tumor models. These results indicate that the Triton X-100-modified ATP-responsive transfection agent is a promising gene delivery vector for target gene silencing in vitro and in vivo.

Lipids and Lipid Derivatives for RNA Delivery

“…In 2020, Fan et al synthesized the Triton X-100-modified PEI (low molecular weight), which was then attached to dopamine grafted vitamin E (VEDA) and 4-carboxyphenylboronic acid (PBA) to obtain lipopolymer 388 (Figure ). 388-siEGFR complexes suppressed the protein expression of EGFR in A375 cells to 43.1% and reduced its EGFR mRNA level to 34.9% (Figure ).…”

Charge reversal nano-systems for tumor therapy

“…As the “energy currency” of cells, adenosine triphosphate (ATP) plays fundamental roles in cell metabolism. Meanwhile, ATP also shows great potential for nucleic acid or protein delivery as one of the stimuli-responsive triggers for cancer therapy [ 94 , 95 ]. Intracellular ATP concentration in the TME (1–10 mM) is more than 1,000-fold higher than in normal tissues, which difference is much higher than that of pH, thus ATP can be used to distinguish the environment between solid tumors and normal tissues [ 96 ].…”

Stimuli‐Responsive Nanotechnology for RNA Delivery

“…siRNA [93] ATP responsive Phenylboric acid siRNA, [94][95] mRNA [96] GSH: glutathione; MMP: Matrix metalloproteinase; ROS: Reactive oxygen species; ATP: Adenosine triphosphate each other. Peptide CNGQ, on the other hand, interacted with highly expressed 𝛼3𝛽1 integrin on the surface of lung cancer cells to improve tumor cell targeting and siRNA uptake.…”