NEW YORK (GenomeWeb) – A team led by researchers from the Massachusetts Institute of Technology this week published a study describing a new type of nanoparticle capable of delivering siRNAs to endothelial cells, while dodging hepatocytes and immune cells, at doses far lower than previously required.
The siRNA-loaded nanoparticles were also able to mediate highly durable non-liver gene silencing, further opening the door for RNAi as a therapeutic modality in diseases such as cancer and emphysema.
Given the role of the endothelial cells in the vascular system, endocytosis, metabolism, and other areas of human biology, dysfunctional endothelium is associated with more disease than any other tissue in the body, the investigators wrote in their report. "Yet, modulating the behavior of endothelial cells in vivo remains challenging, particularly in cases that require the inhibition of multiple endothelial genes."
When it comes to RNAi, this is particularly true. While cationic lipids have been shown to carry siRNAs to endothelial cells, these delivery systems require cumulative doses of up to 7.5 mg/kg to achieve robust target gene silencing. Other delivery approaches, meantime, have been associated with off-target effects.
To address this, the researchers developed a polymeric nanoparticle formulation — dubbed 7C1 — composed of low-molecular-weight polyamines and lipids that can deliver siRNAs to endothelial cells with high efficiency, allowing for the simultaneous knock down to multiple endothelial genes in vivo.
As described in Nature Nanotechnology, 7C1/siRNA nanoparticles were able to transfect endothelial cells in various animal models — including ones of vascular permeability, emphysema, lung tumor growth, and lung metastasis — at low doses, without significantly reducing gene expression in hepatocytes, peritoneal immune cells, pulmonary epithelial cells, or pulmonary immune cells.
"The exact molecular mechanism governing this effect remains to be determined, but it seems to involve the interaction of 7C1 with serum proteins, which can promote delivery to certain cell types," the study's authors, which included scientists from Alnylam Pharmaceuticals, wrote. "As a result, 7C1 may be an interesting system to study how physiochemical interactions between nanomaterials and serum proteins direct nanoparticles to endothelial cells in vivo."
Meanwhile, because 7C1 enables multi-gene knockdown — the researchers used it to silence up to five genes at once — it may also prove useful for studying gene combinations in complex biological pathways in vivo, they noted.
In addition to its utility for research applications, the MIT-led group also sees therapeutic potential for 7C1, demonstrating that siRNAs delivered with the technology were able to reduce primary tumor growth and lung metastases in an animal model of lung cancer.
7C1 also proved well tolerated at doses "far higher" than those required for gene silencing, according to the Nature Nanotechnology paper. Target gene expression could be cut by 90 percent at an siRNA/7C1 dose of 0.1 mg/kg and by 50 at doses as low as 0.02 mg/kg, but treatment appeared well tolerated at dosages of up to 2 mg/kg.
The rights to the technology are held by MIT.