Specific delivery of delta-5-desaturase siRNA via RNA nanoparticles supplemented with dihomo-γ-linolenic acid for colon cancer suppression

Abstract

We have previously demonstrated that DGLA treatment along with Delta-5-Desaturase (D5D) siRNA in various types of cancer cells enhances the formation of 8-HOA from COX-2-catalyzed DGLA peroxidation, which in turn inhibits cancer cell growth and migration. However, delivery of naked siRNA remains a formidable challenge due to its “off-target” effect. In this study, we employed RNA nanotechnology for specific delivery of D5D-siRNA to xenograft colon tumors using 3WJ RNA nanoparticles. When a targeting module, i.e. , the EpCAM aptamer, was incorporated, the 3WJ pRNA nanoparticles were able specifically deliver D5D siRNA to human colon cancer HCA-7 cells both in vitro and in vivo , resulting in significant downregulation of D5D expression. Co-treatment with DGLA in combination with 3WJ-EpCAM-siRNA induced a higher DGLA/AA ratio and enhanced formation of 8-HOA at a threshold level, and in HCA-7 tumor-bearing mice, induced significant tumor suppression. We further confirmed that 8-HOA formation, promoted by COX-2-catalyzed DGLA peroxidation, inhibited HDAC and consequently induced apoptosis in tumor cells. Therefore, the 3WJ RNA nanoparticle system holds great promise as a suitable therapeutic delivery platform for colon cancer therapy.

A prospective study of erythrocyte polyunsaturated fatty acids and risk of colorectal serrated polyps and conventional adenomas

“…44,45 Thus, the anti-inflammatory property of DGLA and its ability to compete with AA in the synthesis of pro-inflammatory products may reduce risk of colorectal cancer. 45,46 As for EDA, a previous study found that EDA was inversely associated with colorectal cancer. The anti-inflammatory effect of EDA has been reported.…”

“…DGLA is a substrate of prostaglandin‐endoperoxide synthase 2, giving rise to prostaglandin E1 (PGE 1 ), an inflammation‐suppressing eicosanoids 44,45 . Thus, the anti‐inflammatory property of DGLA and its ability to compete with AA in the synthesis of pro‐inflammatory products may reduce risk of colorectal cancer 45,46 . As for EDA, a previous study found that EDA was inversely associated with colorectal cancer.…”

Therapeutic siRNA: state of the art

“…6); (iii) extracellular vesicles or exosomes derived from various cell types (Fig. 5f, m); 16,238,239 (iv) peptides; [240][241][242][243] (v) dendrimers; [244][245][246] (vi) RNA nanoparticles (e.g., three way-junction, 3WJ); [247][248][249][250][251][252][253][254] and (vii) inorganic nanoparticles 229,255 (Fig. 6).…”

Tuning the size, shape and structure of RNA nanoparticles for favorable cancer targeting and immunostimulation

“…This non‐specificity not only distracts nanoparticles from transporting to tumors, but also causes toxicity and unwanted side effects. To address this challenge, Guo Lab has developed a series of pRNA‐3WJ based RNA nanoparticles incorporated with targeting ligands (Binzel et al, ; Cui et al, ; Lee et al, ; Pi et al, ; Rychahou et al, ; Shu et al, ; Shu et al, ; Shu, Haque, et al, ; Xu et al, ). Upon systemic administration in tumor‐bearing mice, these RNA nanoparticles specifically transport to tumors within about 4 hours (h), and successfully remain at the tumor site for over 24 h. No or minimal organ accumulation was detected several hours post‐injection.…”