Polymyxin derived cell penetrating scaffolds

• US 10,449,230 B2
• Filed: 10/06/2017
• Issued: 10/22/2019
• Est. Priority Date: 10/06/2016
• Status: Active Grant

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Hamill, Kristina, Esko, Jeffrey D., McCoy, Lisa, Tor, Yitzhak
• Primary Examiner(s): Bradley, Christina
• Application Number:
  US15/727,397
• Publication Number:
  US 20180099022A1
• Time in Patent Office: 746 Days
• Field of Search: None
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/12 Cyclic peptides , e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61K 47/6911 the form being a liposome
• CPC Class Codes: A61K 47/6939 the polymer being a polysaccharide, e.g. starch, chitosan, chitin, cellulose or pectin
• CPC Class Codes: C07K 7/62 Polymyxins; Related peptides
• CPC Class Codes: G01R 33/46 NMR spectroscopy

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.

Claims

1. A compound of formula (Ia)

2. A method of delivering cargo into mammalian cells, comprising:

a) coupling the cargo with a compound of Formula (Ia)

3. The method of claim 2, wherein each R¹ is —

NH₃⁺.

4. The method of claim 2, wherein each R¹ is —

NH—

C(═

NH₂⁺)—

NH₂.

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)

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.