Human diseases often represent complex pathological processes associated with abnormal gene expression. Although single-drug treatments may provide significant therapeutic benefits, disease progression or development of drug resistance can circumvent the effect of a single drug. Sirnaomics is pursuing a strategy to overcome such hurdles utilizing a combination of multiple drugs to gain a stronger therapeutic efficacy.
“siRNAs are ideal components of therapeutic cocktails because of their chemical homogeneity. They have the same four nucleotides, the same charge/hydrophobicity for each sequence irrespective of the target gene, the same source of origin, and a common, reproducible manufacturing process,” Patrick Lu, Ph.D., president and CEO, said.
“Our approach is to use multitargeted siRNA cocktails with nanoparticle-mediated delivery to enhance therapeutic efficacy. But, the multitargeted siRNA cocktail needs to be logically designed and able to work in vivo. We use a proprietary algorithm to develop a Tri-blocker design for siRNA duplexes that targets up to three disease-causing genes in one cocktail.”
For delivering the cocktail, the company continues to develop three generations of nanoparticle systems. “The first generation nanoparticle is based on a self-assembling property in which cationic liposomal or polymeric materials are mixed with siRNA molecules,” Dr. Lu said. “The second-generation nanoparticle is chemically modified with specific ligands to target desired tissues or cells. The third generation of nanoparticles, developed in house, is a silica-based nanoparticle system comprising an up-conversion core coated by a photosensitizer drug and siRNA. It can be temporally and spatially controlled with near infrared activation.”
According to Dr. Lu, third-generation nanoparticles are especially valuable for the treatment of cancers. “An infrared light is used to excite up-conversion nanoparticles to produce visible light, which activates the photosensitizer on the nanoparticles to produce singlet oxygen. This then destroys and weakens the cell membrane, promoting the delivery and release of siRNA molecules into the cytoplasm. This strategy provides an effective treatment of cancers, especially those located deep within the human body.”
Dr. Lu noted that the technology can be used in cancer applications including hepatocellular carcinoma, renal carcinoma, non-small-cell lung carcinoma, breast carcinoma, and pancreatic carcinomas. Preclinical studies are ongoing for each of the nanoparticle systems.