Porphyrin modified telodendrimers

Patent metadata

Field	Value
Publication number	US-9642916-B2
Application number	US-201313803878-A
Country	US
Kind code	B2
Filing date	Mar 14, 2013
Priority date	Dec 12, 2012
Publication date	May 9, 2017
Grant date	May 9, 2017

Abstract

The present invention provides amphiphilic telodendrimers that aggregate to form nanocarriers characterized by a hydrophobic core and a hydrophilic exterior. The nanocarrier core may include amphiphilic functionality such as cholic acid or cholic acid derivatives, and the exterior may include branched or linear poly(ethylene glycol) segments. Nanocarrier cargo such as hydrophobic drugs and other materials may be sequester in the core via non-covalent means or may be covalently bound to the telodendrimer building blocks. Telodendrimer structure may be tailored to alter loading properties, interactions with materials such as biological membranes, and other characteristics.

First claim

What is claimed is:

1. A compound having a structure:

wherein
each PEG is a polyethyleneglycol (PEG) polymer having a molecular weight of 1-100 kDa;
A comprises at least one branched monomer unit X and is linked to at least one PEG group;
X is a diamino carboxylic acid;
each Y 2 is independently:
absent; or
a crosslinkable group independently selected from the group consisting of boronic acid, dihydroxybenzene and a thiol,

wherein at least two Y 2 are present;
each L 2 is independently a bond or a linker; and at least one R group is a porphyrin, and each remaining R is independently selected from the group consisting of cholic acid, (3a,5b,7a,12a)-7,12-dihydroxy-3-(2,3-dihydroxy-1-propoxy)-cholic acid (CA-4OH), (3α, 5β, 7α, 12α)-7-hydroxy-3,12-di(2,3-dihydroxy-1-propoxy)-cholic acid (CA-5OH), and (3α, 5β, 7α, 12α)-7,12-dihydroxy-3-(3-amino-2-hydroxy-1-propoxy)-cholic acid (CA-3OH—NH 2 ).

2. The compound of claim 1 , wherein A comprises at least one branched monomer unit X independently selected from the group consisting of a diamino carboxylic acid, a dihydroxy carboxylic acid and a hydroxyl amino carboxylic acid.

3. The compound of claim 1 , wherein each diamino carboxylic acid is independently selected from the group consisting of 2,3-diamino propanoic acid, 2,4-diaminobutanoic acid, 2,5-diaminopentanoic acid (ornithine), 2,6-diaminohexanoic acid (lysine), (2-Aminoethyl)-cysteine, 3-amino-2-aminomethyl propanoic acid, 3-amino-2-aminomethyl-2-methyl propanoic acid, 4-amino-2-(2-aminoethyl) butyric acid and 5-amino-2-(3-aminopropyl) pentanoic acid.

4. The compound of claim 1 , wherein each branched monomer unit X is lysine.

5. The compound of claim 1 , wherein linker L 2 when present has the formula:

6. The compound of claim 1 , wherein each remaining R is cholic acid.

7. The compound of claim 1 , having the structure:

wherein
PEG is PEG5k;
each branched monomer unit X is lysine;
A is lysine;
each L 2 is a bond or linker Ebes;
each Y 2 is absent or is cysteine, wherein at least two Y 2 groups are cysteine; and at least one R group is a porphyrin, and each remaining R is independently selected from the group consisting of cholic acid (CA), (3α, 5β, 7α, 12α)-7,12-dihydroxy-3-(2,3-dihydroxy-1-propoxy)-cholic acid (CA-40H), (3α, 5β, 7α, 12α)-7-hydroxy-3,12-di(2,3-dihydroxy-1-propoxy)-cholic acid (CA-50H) and (3α, 5β, 7α, 12α)-7,12-dihydroxy-3-(3-amino-2-hydroxy-1-propoxy)-cholic acid (CA-3OH—NH 2 ).

8. The compound of claim 7 , wherein the compound has the structure

wherein
each R′ is selected from the group consisting of cholic acid (CA), (3α, 5β, 7α, 12α)-7,12-dihydroxy-3-(2,3-dihydroxy-1-propoxy)-cholic acid (CA-40H), (3α, 5β, 7α, 12α)-7-hydroxy-3,12-di(2,3-dihydroxy-1-propoxy)-cholic acid (CA-50H), (3α, 5β, 7α, 12α)-7,12-dihydroxy-3-(3-amino-2-hydroxy-1-propoxy)-cholic acid (CA-3OH—NH 2 ); and
each R″ is a porphyrin selected from the group consisting of pyropheophorbide-a, pheophorbide, chlorin e6, purpurin and purpurinimide.

9. The compound of claim 8 , wherein the compound is selected from the group consisting of:
(1) each L 2 is a bond, each Y 2 is cysteine, each R′ is cholic acid, and each R″ is pyropheophorbide-a; and
(2) each L 2 is the linker Ebes, each Y 2 is cysteine, each R′ is cholic acid, and each R″ is pyropheophorbide-a.

Assignees

• Univ California

Inventors

• Lam Kit S
• Li Yuanpei
• Pan Chong-Xian
• Lin Tzu-Yin

Classifications

• A61P33/00

  Antiparasitic agents · CPC title

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61N5/062

  Photodynamic therapy, i.e. excitation of an agent · CPC title

• A61K49/1809

  Micelles, e.g. phospholipidic or polymeric micelles · CPC title