Peptides whose uptake by cells is controllable
View Patent ↗A generic structure for the peptides of the present invention includes A-X-B-C, where C is a cargo moiety, the B portion includes basic amino acids, X is a cleavable linker sequence, and the A portion includes acidic amino acids. The intact structure is not significantly taken up by cells; however, upon extracellular cleavage of X, the B-C portion is taken up, delivering the cargo to targeted cells. Cargo may be, for example, a contrast agent for diagnostic imaging, a chemotherapeutic drug, or a radiation-sensitizer for therapy. X may be cleaved extracellularly or intracellularly. The molecules of the present invention may be linear, cyclic, branched, or have a mixed structure.
1. A molecule comprising Formula (I):
A-X-B Formula (I)
wherein
A is a peptide with a sequence comprising 5 to 9 consecutive acidic amino acids,
wherein the amino acids are selected from: aspartates and glutamates; and
B is a peptide with a sequence comprising 5 to 20 consecutive basic amino acids; and
X is a linker.
2. The molecule of claim 1 , wherein A has a sequence comprising 8 consecutive glutamates.
3. The molecule of claim 1 , wherein B has a sequence comprising 9 to 16 consecutive arginines.
4. The molecule of claim 1 , wherein B has a sequence comprising 9 consecutive arginines.
5. The molecule of claim 1 , wherein (a) A has a sequence comprising 8 to 9 consecutive glutamates and (b) B has a sequence comprising 9 consecutive arginines.
6. The molecule of claim 1 , wherein A and B comprise D-amino acids.
7. The molecule of claim 1 , wherein the molecule further comprises a cargo moiety.
8. The molecule of claim 1 , wherein the molecule further comprises an imaging agent, a therapeutic agent, or any combination thereof.
9. The molecule of claim 1 , wherein the molecule further comprises a fluorescent moiety.
10. The molecule of claim 1 , wherein X is a cleavable linker.
11. The molecule of claim 1 , wherein X is a pH-sensitive linker.
12. The molecule of claim 1 , wherein X is cleaved in the extracellular space.
13. The molecule of claim 1 , wherein X is cleaved by a protease, a matrix metalloproteinase, or a combination thereof.
14. The molecule of claim 1 , wherein X comprises a peptide linkage.
15. The molecule of claim 1 , wherein X comprises aminocaproic acid.
16. The molecule of claim 1 , wherein X comprises a disulfide linkage.
17. The molecule of claim 1 , wherein X is about 6 to about 30 atoms in length.
18. The molecule of claim 1 , wherein the molecule further comprises an imaging agent selected from: a fluorescent moiety, a luminescent moiety, a phosphorescent moiety, a fluorescence-quenching moiety, a radioactive moiety, a radiopaque moiety, a paramagnetic moiety, a contrast agent, or a combination thereof.
19. The molecule of claim 1 , wherein the molecule further comprises a therapeutic agent selected from: a chemotherapeutic agent, a radiation sensitizer, or a combination thereof.
20. The molecule of claim 1 , wherein X is cleaved by a reducing agent.