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Jun 1, 2010 (Vol. 30, No. 11)

Surmounting siRNA Delivery Obstacles

Nanoparticle Carriers and Noninvasive Methods Are Among Recent Advances

  • Cocktail Therapeutics

    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.

  • Piggyback Therapeutics

    Like the fabled Trojan horse, siRNA entry into the cell’s interior requires some creative approaches. Paul White, Ph.D., senior lecturer at the Monash University Institute of Pharmaceutical Sciences in Melbourne, Australia, and his colleagues are utilizing one of the most abundant carrier proteins in the blood—albumin—to ferry siRNAs attached to nanoparticles across the vascular endothelium.

    “Our overall project focuses on the cardiovascular system,” he reported. “We have some targets that are involved in damaging reactive oxygen species production in cardiovascular disease and will be testing whether siRNA-albumin delivery can reduce the damage done to the heart and blood vessels in a model of high blood pressure. However, there are a number of other organs for which a delivery system capable of allowing siRNA extravasation would be valuable.”

    Dr. White described the technology as a piggyback approach that capitalizes on the property of albumin to penetrate cardiac and vascular interstitium. “We have utilized both covalent conjugation and nanoparticle construction approaches. For the covalent conjugation we employed a heterobifunctional linker to join amine-modified siRNA with albumin, via an exposed cysteine residue. We used fluorescently labeled siRNA and showed extravasation of these agents. We have also shown knockdown in mouse hearts using real-time RT-PCR. For the particle strategy, we used a cationic lipopeptide containing lysine residues to provide positive charge and histidine residues to aid endosomal escape.”

    Dr. White’s future studies will continue to refine and better understand the system. “We are on the way to a robust generic approach to delivery of siRNA across the vascular endothelium; we need to understand better the scope of the albumin-mediated delivery mechanism.

    “The issue of endosomal escape is another that we are working on at the moment. The hard part of siRNA delivery is not only addressing each individual barrier, but doing so in a way that does not bring other problems into play. Success here requires a thorough understanding of siRNA fate in plasma, route to the target cell, and activity inside the cell,” Dr. White concluded. “Gaining this understanding is a slow process, but we are getting there.”


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