Prodrug compositions, prodrug nanoparticles, and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10201500-B2
Application number	US-201615179626-A
Country	US
Kind code	B2
Filing date	Jun 10, 2016
Priority date	Apr 15, 2010
Publication date	Feb 12, 2019
Grant date	Feb 12, 2019

Abstract

The present invention encompasses prodrug compositions, nanoparticles comprising one or more prodrugs, and methods of use thereof.

First claim

The invention claimed is:

1. A composition for in vivo delivery of a taxane to a target cell, the composition comprising a non-liposomal particle and at least one taxane prodrug, wherein
(a) the particle has an outer surface that is a membrane comprised of the at least one prodrug, about 100 mol % to about 60 mol % phospholipid, and a homing ligand, and an inner core comprising a surfactant selected from polysorbate 80, sorbitan monooleate, sorbitan sesquioleate, or sorbitan monolaurate
(b) the particle has a hydrodynamic diameter that is about 20 nm or less as measured by dynamic light scattering; and
(c) the taxane prodrug comprises a taxane of less than about 3000 da linked to an acyl moiety of a phosphoglyceride,
wherein the taxane may be released from the phosphoglyceride backbone via enzyme cleavage, and wherein the particle can leave blood vessels while circulating through the body.

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

3. The composition of claim 1 , wherein the non-liposomal particle is a micelle.

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

5. The composition of claim 1 , wherein the outer surface is not pegylated except for the homing ligand.

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

8. The composition of claim 1 , wherein the taxane is linked to the sn-2 acyl moiety of the phosphoglyceride.

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

10. The composition of claim 1 , wherein the taxane is docetaxel or paclitaxel.

11. The composition of claim 1 , wherein the prodrug comprises a compound selected from the group consisting of

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

13. The composition of claim 1 , wherein the particle has a hydrodynamic diameter that is between about 10 nm to about 20 nm as measured by dynamic light scattering.

14. The corn position of claim 1 , wherein the outer surface of the particle is comprised of about 0.1 mol % of the prodrug to about 9% of the prodrug.

15. A method for in vivo delivery of a taxane to a target cell, the method comprising administering a composition to a subject, the composition comprising a non-liposomal particle and at least one prodrug in a pharmaceutically acceptable carrier, wherein
(a) the particle has an outer surface that is a membrane comprised of the at least one prodrug, about 100 mol % to about 60 mol % phospholipid, and a homing ligand, and an inner core comprising a surfactant selected from polysorbate 80, sorbitan monooleate, sorbitan sesquioleate, or sorbitan monolaurate;
(b) the particle has a hydrodynamic diameter that is about 20 nm or less as measured by dynamic light scattering; and
(c) the taxane prodrug comprises a taxane of less than about 3000 da linked to an acyl moiety of a phosphoglyceride,
wherein the taxane may be released from the phosphoglyceride backbone via enzyme cleavage, and wherein the particle can leave blood vessels while circulating through the body.

16. The method of claim 15 , wherein the composition is administered intravenously.

17. The method of claim 15 , wherein the taxane is docetaxel or paclitaxel.

Assignees

• Univ Washington

Inventors

• Lanza Gregory M
• Pan Dipanjan

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K47/6907

  the form being a microemulsion, nanoemulsion or micelle · 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

• A61K47/555

  pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells · CPC title