Abstract:
Diseases and molecular targets considered undruggable, particularly those hidden within the tumor microenvironment (TME), remain challenging for existing therapeutic approaches. In such cases RNA interference (RNAi) therapeutics, such as small interfering RNA (siRNA) present a potential therapeutic approach. siRNAs are engineered to degrade mRNAs or inhibit/decrease translation to decrease target protein expression to counteract the transcriptional and translational alterations seen in cancer cells. However, their clinical application is hindered due to their large size and negative charge. Nucleic acids like mRNA and siRNA need delivery systems to bypass the liver's reticuloendothelial system (RES), enhance targeted uptake, minimize off-target effects, and protect against RNAse degradation. Several delivery strategies, including GalNAc conjugation and lipid nanoparticles (LNPs) mediated delivery systems have been explored. In this study our aim was to develop a formulation which could be resistant in stomach acid and release its content only in large intestine. Here in this study a novel double layer coated solid lipid nanoparticle (SLNs) formulation was developed featuring an outer eudragit S100 layer to bypass gastric environment and inner hyaluronic acid layer with a PEGylated lipid core. CT-DNA encapsulated in SLNs showed a good encapsulation and minimal to low cytotoxicity even at 100μM in HCT-116 human colorectal cancer cells and CT-26 rat colon cancer cells. This formulation uses neutral lipid compare to usual cationic and ionizable lipids. Further studies are planned to assess its ability to deliver siRNA through the oral route and downregulate specific targets in DMH-induced colorectal cancer in rats.
Audience Take Away Notes:
- RNAi Delivery Challenges: Understand the obstacles in delivering siRNA, including its size, charge, and degradation risk.
- Novel SLN Formulation: Learn about a new double-layer SLN designed to resist stomach acid and release in the large intestine.
- Neutral Lipid Benefits: Discover the advantages of using neutral lipids over cationic/ionizable lipids for reduced toxicity.
- In Vitro Results: Review the formulation's effectiveness and low cytotoxicity in colorectal cancer cells.
- Future Potential: Explore the formulation's potential for oral siRNA delivery in cancer treatment.
