Programmed cargo release using nucleic acid-stabilized micelles
Methods and compositions for serum-stabilizing micelles for drug delivery or imaging agent delivery are provided, as well as methods and compositions to enhance micelle-mediated drug delivery. This invention provides a process for synthesizing a lipid micelle comprising one or more lipid-oligonucleotide conjugate molecules, the process comprising contacting an amount of lipid molecules with an amount of lipid-oligonucleotide conjugate molecules sufficient to create a lipid micelle comprising lipid-oligonucleotide conjugate molecules.
1. A process for synthesizing a stabilized lipid micelle comprising lipid-oligonucleotide conjugate molecules, the process comprising contacting at least one lipid-oligonucleotide conjugate molecule with at least one other lipid-oligonucleotide conjugate molecule,
wherein the at least one lipid-oligonucleotide conjugate molecule serves as a lipid head-group and associates with the at least one other lipid-oligonucleotide conjugate molecule forming a G-quadruplex through intermolecular bonds that are disrupted by the addition of an antisense molecule complementary to the G-quadruplex,
wherein the lipid of the lipid-oligonucleotide conjugate molecule comprises 1,2-dioctadecyl-sn-glycerol, cholesterol, orcholic acid,
wherein the oligonucleotide is 2 to 60 nucleotides in length,
wherein disruption of the intermolecular bonds disrupts the micelle, and
wherein the lipid micelle is stable in serum for at least 12 hours.
2. The process of claim 1 , wherein the oligonucleotide of the lipid-oligonucleotide conjugate is an oligoribonucleotide.
3. The process of claim 1 , wherein the oligonucleotide comprises one or more 2′OMe-, 2′F-, 2′NH3-, or 2′H-modified residue and/or phosphosphorothioate.
4. The process of claim 1 , wherein all the residues of the oligonucleotide are 2′ OMe-, 2′F-, 2′NH 3 -, or 2′H-modified residues or comprise phosphosphorothioate.
5. The process of claim 1 , wherein the oligonucleotide is attached at its 5′ end to a lipid molecule of the lipid-oligonucleotide conjugate molecule.
6. The process of claim 1 , wherein the micelle further comprises an additional oligonucleotide, at least a portion of which is on an external surface of the micelle, and which portion binds to a receptor protein.
7. The process of claim 6 , wherein the receptor protein is present on a cell of a subject.
8. The process of claim 7 , wherein the receptor protein is present on a tumor cell of a subject.
9. The process of claim 8 , wherein the receptor protein is preferentially expressed on tumor cells over non-tumorous cells of a subject.
10. The process of claim 1 , wherein the sequence of a first portion of the oligonucleotide is UGGGU.
11. The process of claim 1 , wherein the lipid-oligonucleotide conjugate molecule comprises 1,2-dioctadecyl-sn-glycerol phosphoramidite.
12. The process of claim 1 , wherein the diameter of the lipid micelle is 5 to 60 nm.
13. The process of claim 1 , wherein the process further comprises contacting the lipid micelle with an amount of a predetermined drug molecule, or of a predetermined imaging molecule, sufficient for uptake of at least a portion of the predetermined drug molecule or imaging molecule into the lipid micelle.
14. The process of claim 13 , wherein the predetermined drug molecule is an anti-tumor drug.
15. The process of claim 1 , wherein the lipid micelle is stable in serum for at least 24 hours.
16. The process of claim 1 , wherein the oligonucleotide is attached at its 3′ end to a lipid molecule of the lipid-oligonucleotide conjugate molecule.