RNA nanoparticle for liver cancer treatment
Disclosed herein are compositions and methods for targeted treatment of liver cancers with Paclitaxel and miR-122. The disclosed composition comprises RNA nanostructure conjugated to a hepatocyte targeting ligand, paclitaxel, and miR-122 for use in intracellular drug delivery to liver cancer cells. The RNA nanoparticle can involve three or more self-assembled synthetic RNA oligonucleotides that form a central core domain and at least three double-stranded arms arranged around the core domain and extending away from the central core domain.
1 . A composition for treating hepatocellular carcinoma (HCC), comprising an RNA nanostructure conjugated to
a) one to three hepatocyte targeting ligands,
b) a plurality of paclitaxel prodrugs, and
c) a therapeutic miR122 oligonucleotide that suppresses or silences a drug efflux transporter,
wherein at least one of the one to three hepatocyte targeting ligands comprises a 4-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-N-(6-(4,4-bis(hydroxymethyl)piperidin-1-yl)-6-oxohexyl)butanamide molecule.
2 . The composition of claim 1 , wherein the composition three parallel 4-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-N-(6-(4,4-bis(hydroxymethyl)piperidin-1-yl)-6-oxohexyl)butanamide molecules.
3 . The composition of claim 1 , comprising about 24 paclitaxel prodrug molecules.
4 . The composition of claim 1 , wherein the RNA nanoparticle comprises three to six self-assembled synthetic RNA oligonucleotides.
5 . The composition of claim 4 , wherein the three to six synthetic RNA oligonucleotides form a central core domain and at three to six double-stranded arms arranged around the core domain and extending away from the central core domain.
6 . The composition of claim 5 , wherein the one to three hepatocyte targeting ligands are conjugated to a first double-stranded arm.
7 . The composition of claim 3 , wherein the at least three hepatocyte targeting ligands are all conjugated to the first double-stranded arm.
8 . The composition of claim 4 , wherein a second double stranded arm comprises a sequence portion that is bound to the therapeutic miR122 oligonucleotide by complementary or partial complementary binding.
9 . The composition of claim 4 , wherein the paclitaxel prodrugs are conjugated to one or more of the double-stranded arms by click chemistry.
10 . A method of treating a liver cancer in a subject, comprising administering to the subject a therapeutically effective amount of the composition of claim 1 .
11 . The composition of claim 1 , wherein the one to three hepatocyte targeting ligands are connected to one another via a phosphate backbone.