Texaphyrin-phospholipid conjugates and methods of preparing same

Patent metadata

Field	Value
Publication number	US-10729792-B2
Application number	US-201615567294-A
Country	US
Kind code	B2
Filing date	Apr 14, 2016
Priority date	Apr 17, 2015
Publication date	Aug 4, 2020
Grant date	Aug 4, 2020

Abstract

There is provided herein, a texaphyrin-phospholipid conjugate, wherein the texaphyrin-phospholipid conjugate comprises a texaphyrin, texaphyrin derivative or texaphyrin analog covalently attached to a lipid side chain of a phospholipid.

First claim

The invention claimed is:

1. A method of preparing a texaphyrin-phospholipid conjugate, wherein the texaphyrin-phospholipid conjugate comprises a texaphyrin, texaphyrin derivative or texaphyrin analog covalently attached to a lipid side chain of a phospholipid, the texaphyrin derivative or texaphyrin analog having a core moiety represented by Formula I:

the method comprising reacting

with

to yield

under hydrogen chloride and a temperature of between 50 to 52° C.;
where R 1 -R 6 are each independently selected from the group consisting of H, an alkyl group, or an alkyl group substituted with an OH, SH, heteroalkyl, aryl, heteroaryl, or heterocyclic group;
one of R 7 , R 8 , R 9 , and R 10 is a phospholipid moiety and the remainder of R 7 -R 10 are each independently selected from H, an alkyl group, a heteroalkyl group, a cycloalkyl group, an alkenyl group, a heteroalkenyl group, an alkynyl group, a heteroalkynyl group, an aryl group, a heteroaryl group, a heterocyclic group, and an acyl group;
wherein the phospholipid comprises phosphatidylcholine, phosphatidylethanoloamine, phosphatidylserine or phosphatidylinositol.

2. The method of claim 1 , wherein

is prepared by reducing:

under hydrogen, Pd/C, and HCl;
wherein one of R 7 , R 8 , R 9 , and R 10 is the phospholipid moiety, and the remainder of R 7 -R 10 are each independently selected from H, an alkyl group, a heteroalkyl group, a cycloalkyl group, an alkenyl group, a heteroalkenyl group, an alkynyl group, a heteroalkynyl group, an aryl group, a heteroaryl group, a heterocyclic group, and an acyl group.

3. The method of claim 2 , wherein

where one of R 7 -R 10 is the phospholipid moiety and the remainder of R 7 -R 10 are each independently selected from H, an alkyl group, a heteroalkyl group, a cycloalkyl group, an alkenyl group, a heteroalkenyl group, an alkynyl group, a heteroalkynyl group, an aryl group, a heteroaryl group, a heterocyclic group, and an acyl group is prepared by reacting

where one of R′ 7 -R′ 10 is a carbon chain linker represented by Formula A

with n=1 to 20, and the remainder of R′ 7 -R′ 10 are each independently selected from H, an alkyl group, a heteroalkyl group, a cycloalkyl group, an alkenyl group, a heteroalkenyl group, an alkynyl group, a heteroalkynyl group, an aryl group, a heteroaryl group, a heterocyclic group, and an acyl group;
with
b) the phospholipid in the presence of EDC, DIPEA, and DMAP.

4. The method of claim 1 , further comprising synthesizing the texaphyrin, texaphyrin derivative or texaphyrin analog, comprising cleaving the texaphyrin, texaphyrin derivative or texaphyrin analog from the conjugate.

5. The method of claim 4 , wherein the cleaving is performed using an enzyme.

6. The method of claim 1 , wherein the phospholipid is branched or unsaturated.

7. The method of claim 1 , wherein the phospholipid moiety is

where n is 0 to 20.

8. The method of claim 3 , wherein:
compound (4) is

the phospholipid is

compound (5) is

compound (6) is

compound (7) is

and
compound (8) is

9. The method of claim 1 , wherein the texaphyrin, texaphyrin derivative or texaphyrin analog is attached to the lipid side chain at the sn-1 or the sn-2 position.

10. The method of claim 1 , wherein the texaphyrin, texaphyrin derivative or texaphyrin analog is texaphyrin.

11. The method of claim 1 , wherein the phospholipid comprises an acyl side chain of 12 to 22 carbons.

12. The method of claim 1 , wherein the texaphyrin, texaphyrin derivative or texaphyrin analog is conjugated to the glycerol group on the phospholipid by a carbon chain linker of 0 to 20 carbons.

13. The method of claim 1 , further comprising complexing the texaphyrin-phospholipid conjugate with a metal selected from Mn, Fe, Co, Zn, Y, Cd, In, La, Hg, Pb, Bi, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu.

14. The method of claim 1 , further comprising forming a nanoparticle comprising the texaphyrin-phospholipid conjugate defined in claim 1 , wherein the nanoparticle comprises at least 15, 25, 35, 45, 55, 65, 75, 85, 95 or 100 molar % texaphyrin-phospholipid conjugate.

15. The method of claim 14 , wherein the nanoparticle further comprises a pegylated material selected from PEG, PEG-lipid, and PEG-DSPE.

16. The method of claim 15 , wherein the pegylated material is present in an amount of about 5 molar %.

17. The method of claim 14 , wherein the nanoparticle is a bilayered vesicle or a monolayered vesicle.

18. The method of claim 14 , wherein the nanoparticle is substantially spherical and between about 3 nm and about 200 nm in diameter.

19. The method of claim 14 , further comprising encapsulating an active agent therein.

20. The method of claim 14 , wherein the nanoparticle further comprises a targeting molecule.

Assignees

• Univ Health Network

Inventors

• Zheng Gang
• Keca Joseph

Classifications

• A61K49/227 Primary

  Liposomes, lipoprotein vesicles, e.g. LDL or HDL lipoproteins, micelles, e.g. phospholipidic or polymeric · CPC title

• C07F9/6561

  containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings · CPC title

• C07D487/22

  in which the condensed system contains four or more hetero rings · CPC title

• C07F9/106

  Adducts, complexes, salts of phosphatides · CPC title

• C12P17/182

  Heterocyclic compounds containing nitrogen atoms as the only ring heteroatoms in the condensed system (alloxazine or isoalloxazine, e.g. riboflavine C12P25/00) · CPC title