Prodrug compositions, prodrug nanoparticles, and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9498439-B2
Application number	US-201113641252-A
Country	US
Kind code	B2
Filing date	Apr 15, 2011
Priority date	Apr 15, 2010
Publication date	Nov 22, 2016
Grant date	Nov 22, 2016

Abstract

Nanoparticles comprising a prodrug and prodrugs linked to phospholipids, wherein the linkages facilitate release of the prodrugs from the nanoparticles to sites within a target cell or cell membrane by fusion of the particle and the cell membrane are disclosed. Also disclosed are methods for producing and using the nanoparticles and their constituents.

First claim

What is claimed is:

1. A composition for in vivo delivery of a compound to a target cell, the composition comprising a non-liposomal particle and at least one prodrug, wherein
(a) the particle has an outer surface that is a membrane comprised of the at least one prodrug, and is further comprised of about 100 mol % to about 60 mol % phospholipid, and
(b) the prodrug comprises fumagillol or a derivative of fumagillol in which the spiro epoxide at C4 is ring opened to afford a tertiary alcohol and a ClCH 2 group wherein the fumagillol or said derivative thereof is linked to an acyl moiety of a phosphoglyceride either directly or indirectly via a linker, wherein the linker is

and the phosphoglyceride is attached at the amine, and
wherein the fumagillol may be released from the phosphoglyceride backbone via enzyme cleavage.

2. The composition of claim 1 , wherein the outer surface of the particle is comprised of not more than 3 mol % of a prodrug.

3. The composition of claim 1 , wherein less than about 10% of the outer surface of the particle is cross-linked.

4. The composition of claim 1 , wherein the outer surface further comprises a homing ligand.

5. The composition of claim 4 , wherein the outer surface is not pegylated except for the homing ligand.

6. The composition of claim 4 , wherein the homing ligand is selected from the group consisting of antibodies, antibody fragments, peptides, asialoglycoproteins, polysaccharides, nucleic acids, small molecules, and peptidomimetics.

7. The composition of claim 1 , wherein the fumagillol is linked to an sn-2 acyl moiety of the phosphoglyceride.

8. The composition of claim 7 , wherein the sn-2 acyl moiety is at least 4 carbon atoms in length from the glycerol backbone sn-2 ester bond.

9. The composition of claim 1 , wherein the prodrug is

10. The composition of claim 1 , wherein the phosphoglyceride of the prodrug is selected from the group consisting of phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl inositol, and phosphatidyl serine.

11. The composition of claim 1 , wherein the particle is between about 10 nm and 10 micrometers.

12. The composition of claim 1 , wherein the composition is formulated for intravenous administration.

13. The composition of claim 4 , wherein the homing ligand is selected from the group consisting of integrins αvβ3, α5β1, ICAM-1, VCAM-1 and VLA-4.

14. The composition of claim 8 , wherein the phosphoglyceride of the prodrug is selected from the group consisting of phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl inositol, and phosphatidyl serine.

15. The composition of claim 10 , wherein the phosphatidyl choline is 1-palmitoyl-2-(9′-oxo-nonanoyl)-sn-glycero-3-phosphocholine or 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine.

16. The composition of claim 1 , wherein the outer surface of the particle is comprised of about 10 mol % of a prodrug.

17. The composition of claim 1 , wherein the particle is a micelle.

Assignees

• Lanza Gregory M
• Pan Dipanjan
• Univ Washington

Inventors

• Lanza Gregory M
• Pan Dipanjan

Classifications

• A61K9/145 Primary

  with organic compounds · CPC title

• A61K41/0071

  PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines · CPC title

• Y10S977/773

  Nanoparticle, i.e. structure having three dimensions of 100 nm or less · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• Y10S977/906

  Drug delivery · CPC title