Polymyxin derived cell penetrating scaffolds

Patent metadata

Field	Value
Publication number	US-10449230-B2
Application number	US-201715727397-A
Country	US
Kind code	B2
Filing date	Oct 6, 2017
Priority date	Oct 6, 2016
Publication date	Oct 22, 2019
Grant date	Oct 22, 2019

Abstract

Provided are transporters based on polymyxin B. Also provided are methods of using the transporters for intracellular delivery of cargo and methods of enhancing intracellular uptake of cargo.

First claim

What is claimed is:

1. A compound of formula (Ia)

wherein each R 1 is independently selected from an ammonium group and a guanidinium group.

2. A method of delivering cargo into mammalian cells, comprising:
a) coupling the cargo with a compound of Formula (Ia)

to form a conjugate, wherein:
each R 1 is independently selected from among an ammonium group (—NH 3 + ) and a guanidinium group (—NH—C(═NH 2 + )—NH 2 );
and
b) contacting the cells with the conjugate.

3. The method of claim 2 , wherein each R 1 is —NH 3 + .

4. The method of claim 2 , wherein each R 1 is —NH—C(═NH 2 + )—NH 2 .

5. The method of claim 2 , wherein the cargo has limited cellular uptake.

6. The method of claim 2 , wherein the cargo is selected from among a large biomolecule, a protein, an oligonucleotide, a drug, a liposome, a liposomal assembly, and combinations thereof.

7. The method of claim 6 , wherein the cargo has a molecular weight of greater than about 30, 50, 100, 200, 300, 500, or 1000 kDa.

8. The method of claim 7 , wherein the cargo has a molecular weight of greater than about 300 kDa.

9. The method of claim 2 , wherein the compound of Formula (Ia) is present at nanomolar concentrations.

10. The method of claim 2 , wherein following step b), the conjugate is internalized by the cells.

11. The method of claim 10 , wherein internalization depends on cell surface heparan sulfate.

12. The method of claim 10 , wherein internalization occurs through caveolae-mediated pathways.

13. A method of enhancing the intracellular uptake of liposomes, comprising:
a) incorporating into a liposome or liposomal assembly a compound of Formula (Ia)

wherein:
each R 1 is independently selected from among an ammonium group (—NH 3 + ) and a guanidinium group (—NH—C(═NH 2 + )—NH 2 );
and
b) contacting mammalian cells with the liposome or liposomal assembly comprising the compound of Formula (Ia).

14. The method of claim 13 , wherein the liposome or liposomal assembly comprises cargo.

15. The method of claim 14 , wherein the cargo is selected from among a large biomolecule, a protein, an oligonucleotide, a drug, and combinations thereof.

16. The method of claim 15 , wherein the cargo has a molecular weight of greater than about 30, 50, 100, 200, 300, 500, or 1000 kDa.

17. The method of claim 16 , wherein the cargo has a molecular weight of greater than about 300 kDa.

Assignees

• Univ California

Inventors

• Hamill Kristina
• Esko Jeffrey D
• McCoy Lisa
• Tor Yitzhak

Classifications

• G01R33/46

  NMR spectroscopy · CPC title

• C07K7/62

  Polymyxins; Related peptides · CPC title

• A61K38/12 Primary

  Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)} · CPC title

• A61K47/6939

  the polymer being a polysaccharide, e.g. starch, chitosan, chitin, cellulose or pectin · CPC title

• A61K47/6911 Primary

  the form being a liposome · CPC title