Liposome comprising elastin-like polypeptide and tumor cell targeting material and use thereof
A liposome including an elastin-like polypeptide (ELP) and a tumor cell targeting material, a pharmaceutical composition including the liposome, and a method of delivering an active agent to a target site using the liposome.
1. A liposome comprising:
a lipid bilayer;
an elastin-like polypeptide (ELP) conjugated to a hydrophobic moiety, wherein the hydrophobic moiety is in the lipid bilayer; and
a lipid bilayer stabilizing agent comprising cholesterol, a fatty acid ester of cholesterol, sitosterol, ergosterol, stigmasterol, 4,22-stigmastadien-3-one, stigmasterol acetate, lanosterol, or a combination thereof;
wherein the lipid bilayer comprises a DSPE-cRGDyK molecule having Formula 5 below, salts thereof, stereoisomer thereof, or a combination thereof:
wherein R 1 is —C(O)—(R 2 )—C(O)— and R 2 is C1-C50 alkylene, or R 2 is a PEG moiety comprising —[OCH 2 CH 2 ]n-, wherein n is an integer of 1 to 1,000.
2. The liposome of claim 1 , wherein the ELP comprises repeating units of VPGXG (SEQ ID NO: 1), PGXGV (SEQ ID NO: 2), GXGVP (SEQ ID NO: 3), XGVPG (SEQ ID NO: 4), GVPGX (SEQ ID NO: 5) or a combination thereof, wherein V is valine, P is proline, G is glycine, and X is any amino acid except proline.
3. The liposome of claim 1 , wherein the hydrophobic moiety conjugated to the ELP is a saturated or unsaturated hydrocarbon group, a saturated or unsaturated acyl group, or a saturated or unsaturated alkoxy group.
4. The liposome of claim 1 , wherein the lipid bilayer further comprises a phospholipid derivatized with a hydrophilic polymer, wherein the hydrophilic polymer is polyethylene glycol (PEG), polylactic acid, polyglycolic acid, a copolymer of polylactic acid and polyglycolic acid, polyvinyl alcohol, polyvinyl pyrrolidone, oligosaccharide, or a combination thereof.
5. The liposome of claim 1 , wherein the liposome has a phase transition temperature of about 39° C. to about 45° C.
6. The liposome of claim 1 , wherein the liposome has a diameter in a range of about 50 nm to about 500 nm.
7. The liposome of claim 1 , wherein the liposome further comprises at least one active agent.
8. The liposome of claim 7 , wherein the active-agent is an anti-tumor agent.
9. A liposome comprising a lipid bilayer;
an elastin-like polypeptide (ELP) conjugated to a hydrophobic moiety, wherein the hydrophobic moiety is in the lipid bilayer; and
a lipid bilayer stabilizing agent comprising cholesterol, a fatty acid ester of cholesterol, sitosterol, ergosterol, stigmasterol, 4,22-stigmastadien-3-one, stigmasterol acetate, lanosterol, or a combination thereof;
wherein the lipid bilayer comprises a DSPE-cRGDyK molecule having Formula 5 below, salts thereof, stereoisomer thereof, or a combination thereof:
wherein R 1 is —C(O)—(R 2 )—C(O)— and R 2 is C1-C50 alkylene, or R 2 is a PEG moiety comprising —[OCH 2 CH 2 ]n-, wherein n is an integer of 1 to 1,000,
wherein the liposome comprises SA-V3-NH 2 , DSPC+DPPC, DSPE-PEG and cholesterol;
SA-V3-NH 2 , DSPC+DPPC, DSPE-PEG-cRGDyK (SEQ ID NO:21), and cholesterol;
SA-V3-NH 2 , DSPC+DPPC, DSPE-PEG-cRGDyK (SEQ ID NO:21), DSPE-PEG and cholesterol;
SA-V3-NH 2 , DSPC+DPPC, DSPE-DTPA(Gd), DSPE-PEG and cholesterol;
SA-V3-NH 2 , DSPC+DPPC, DSPE-PEG-cRGDyK (SEQ ID NO:21), DSPE-DTPA(Gd), DSPE-PEG and cholesterol;
SA-V3-NH 2 , DPPC, DSPE-PEG and cholesterol;
SA-V3-NH 2 , DPPC, DSPE-PEG-cRGDyK (SEQ ID NO:21), and cholesterol;
SA-V3-NH 2 , DPPC, DSPE-PEG-cRGDyK (SEQ ID NO:21), DSPE-PEG and cholesterol;
SA-V3-NH 2 , DPPC, DSPE-DTPA(Gd), DSPE-PEG and cholesterol; or
SA-V3-NH 2 , DPPC, DSPE-PEG-cRGDyK (SEQ ID NO:21), DSPE-DTPA(Gd), DSPE-PEG and cholesterol, wherein DSPE-PEG-cRGDyK is the DSPE-cRGDyK molecule wherein R 2 is the PEG moiety comprising —[OCH 2 CH 2 ] n —.
10. A pharmaceutical composition for delivering an active agent to a subject comprising:
the liposome of claim 7 ; and
a pharmaceutically acceptable carrier or diluent.
11. The composition of claim 10 , wherein the ELP comprises repeating units of VPGXG (SEQ ID NO: 1), PGXGV (SEQ ID NO: 2), GXGVP (SEQ ID NO: 3), XGVPG (SEQ ID NO: 4), GVPGX (SEQ ID NO: 5) or a combination thereof, wherein V is valine, P is proline, G is glycine, and X is any amino acid except proline.
12. The composition of claim 10 , wherein the liposome has a phase transition temperature of about 39° C. to about 45° C.
13. The composition of claim 10 , wherein the liposome has a diameter of about 50 nm to about 500 nm.
14. The composition of claim 10 , wherein the hydrophobic moiety conjugated to the ELP is a saturated or unsaturated hydrocarbon group, a saturated or unsaturated acyl group, or a saturated or unsaturated alkoxy group.
15. A pharmaceutical composition for delivering an active agent to a subject comprising:
the liposome of claim 7 ; and
a pharmaceutically acceptable carrier or diluent, wherein the liposome comprises
SA-V3-NH 2 , DSPC+DPPC, DSPE-PEG and cholesterol;
SA-V3-NH 2 , DSPC+DPPC, DSPE-PEG-cRGDyK (SEQ ID NO:21), and cholesterol;
SA-V3-NH 2 , DSPC+DPPC, DSPE-PEG-cRGDyK (SEQ ID NO:21), DSPE-PEG and cholesterol;
SA-V3-NH 2 , DSPC+DPPC, DSPE-DTPA(Gd), DSPE-PEG and cholesterol;
SA-V3-NH 2 , DSPC+DPPC, DSPE-PEG-cRGDyK (SEQ ID NO:21), DSPE-DTPA(Gd), DSPE-PEG and cholesterol;
SA-V3-NH 2 , DPPC, DSPE-PEG and cholesterol;
SA-V3-NH 2 , DPPC, DSPE-PEG-cRGDyK (SEQ ID NO:21), and cholesterol;
SA-V3-NH 2 , DPPC, DSPE-PEG-cRGDyK (SEQ ID NO:21), DSPE-PEG and cholesterol;
SA-V3-NH 2 , DPPC, DSPE-DTPA(Gd), DSPE-PEG and cholesterol; or
SA-V3-NH 2 , DPPC, DSPE-PEG-cRGDyK (SEQ ID NO:21), DSPE-DTPA(Gd), DSPE-PEG and cholesterol, wherein DSPE-PEG-cRGDyK is the DSPE-cRGDyK molecule wherein R 2 is the PEG moiety comprising —[OCH 2 CH 2 ] n —.
16. A method of delivering an active agent to a target site in a subject, the method comprising:
administering the pharmaceutical composition of claim 10 to the subject, wherein the active agent is an anti-tumor agent; and
heating the target site of the subject to release the active agent from the liposome at the target site.
17. The method of claim 16 , wherein the ELP comprises repeating units of VPGXG (SEQ ID NO: 1), PGXGV (SEQ ID NO: 2), GXGVP (SEQ ID NO: 3), XGVPG (SEQ ID NO: 4), GVPGX (SEQ ID NO: 5) or a combination thereof, wherein V is valine, P is proline, G is glycine, and X is any amino acid except proline.
18. The method of claim 16 , wherein the liposome has a phase transition temperature of about 39° C. to about 45° C.
19. The method of claim 16 , wherein the heating is heating to a temperature of about 39° C. to about 45° C.