The Future of Tissue-Targeted Lipid Nanoparticle-Mediated Nucleic Acid Delivery
The current state of the art for therapeutic nucleic acid delivery is lipid nanoparticles (LNP), which are composed of cholesterol, a helper lipid, a PEGylated lipid and an ionizable amine-containing lipid. The liver is the primary organ of LNP accumulation following intravenous administration and is also observed to varying degrees following intramuscular and subcutaneous routes. Delivery of nucleic acid to hepatocytes by LNP has therapeutic potential, but there are many disease indications that would benefit from non-hepatic LNP tissue and cell population targeting, such as cancer, and neurological, cardiovascular and infectious diseases.
One of the primary obstacles to tissue targeting is the natural physiological barrier to tissue accumulation presented by the vascular endothelium, as most tissues apart from the liver and spleen are not fenestrated, having a continuous endothelium. While tumor vasculature often contains openings in the endothelium, the passive accumulation of nanoparticles through these pores into the tumor tissue has been found to be highly variable and inefficient, largely due to inconsistent pore size and density and extracellular matrix and lymphatic blockage that creates back pressure that counters convective and diffusive movement into the pore. Additionally, animal cancer models, primarily mice, are often not representative of the clinical case and this has resulted in a poor correlation between preclinical and clinical efficacy of nanomedicine formulations.
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