Porphyrin modified telodendrimers

Patent metadata

Field	Value
Publication number	US-10238750-B2
Application number	US-201314651860-A
Country	US
Kind code	B2
Filing date	Dec 12, 2013
Priority date	Dec 12, 2012
Publication date	Mar 26, 2019
Grant date	Mar 26, 2019

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 method of treating a disease via photodynamic or photothermal therapy, comprising administering to a subject in need thereof, a therapeutically effective amount of a nanocarrier, and exposing the subject to radiation, thereby treating the disease via photodynamic or photothermal therapy,
wherein
the nanocarrier comprises a plurality of first conjugates wherein each conjugate is a compound of formula (I):

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 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,
each Y 2 is absent or a crosslinking group independently selected from the group consisting of boronic acid, dihydroxybenzene and a thiol, wherein at least two crosslinking groups are present;
each L 2 is independently a bond or a linker; and
each R is independently selected from the group consisting of cholic acid, (3α,5β,7α,12α)-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), (3α,5β,7α,12α)-7,12-dihydroxy-3-(3-amino-2-hydroxy-1-propoxy)-cholic acid (CA-3OH—NH 2 ), cholesterol formate, doxorubicin, rhein, and porphyrin,
wherein at least one R group is a porphyrin,

wherein each conjugate self-assembles in an aqueous solvent to form the nanocarrier such that a hydrophobic pocket is formed in the interior of the nanocarrier by the orientation of the hydrophobic face of each amphiphilic compound towards each other, wherein the PEG of each conjugate self-assembles on the exterior of the nanocarrier.

2. The method of claim 1 , wherein the disease is cancer.

3. The method of claim 1 , wherein the disease is selected from the group consisting of bladder cancer and ovarian cancer.

4. A method of imaging, comprising administering to a subject to be imaged, an effective amount of a nanocarrier, wherein the nanocarrier comprises a plurality of first conjugates wherein each conjugate is a compound of formula (I):

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 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;
each Y 2 is absent or a crosslinking group independently selected from the group consisting of boronic acid, dihydroxybenzene and a thiol, wherein at least two crosslinking groups are present;
each L 2 is independently a bond or a linker;
each R is independently selected from the group consisting of cholic acid, (3α,5β,7α, 12α)-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), (3α,3OH—NH 2 ), cholesterol formate, doxorubicin, rhein, and porphyrin,
wherein at least one R group is a porphyrin;

wherein each conjugate self-assembles in an aqueous solvent to form the nanocarrier such that a hydrophobic pocket is formed in the interior of the nanocarrier by the orientation of the hydrophobic face of each amphiphilic compound towards each other, wherein the PEG of each conjugate self-assembles on the exterior of the nanocarrier, and
wherein the nanocarrier further comprises an imaging agent.

5. The method of claim 1 , wherein the nanocarrier further comprises a hydrophobic drug or an imaging agent, such that the hydrophobic drug or imaging agent is sequestered in the hydrophobic pocket of the nanocarrier.

6. The method of claim 1 , wherein at least one of X is optionally linked to a member selected from the group consisting of an optical probe, a radionuclide, a paramagnetic agent, a metal chelate and a drug.

7. The method of claim 5 , wherein the hydrophobic drug is selected from the group consisting of bortezomib, paclitaxel, SN38, camptothecin, etoposide and doxorubicin, docetaxel, daunorubicin, VP16, prednisone, dexamethasone, vincristine, vinblastine, temsirolimus, carmusine, sorafinib, lapatinib, and bortezomiob.

8. The method of claim 1 , wherein the conjugates are crosslinked via the crosslinking groups.

9. The method of claim 1 , wherein each conjugate comprises:
at least two cholic acids;
at least two pyropheophorbide-a groups; and
at least two crosslinking groups, wherein the conjugates of the nanocarrier are crosslinked via the crosslinking groups.

10. The method of claim 1 , wherein each X is lysine.

11. The method of claim 1 , wherein each linker L 2 , when present, is independently selected from the group consisting of polyethylene glycol, polyserine, polyglycine, poly(serine-glycine), aliphatic amino acids, 6-amino hexanoic acid, 5-amino pentanoic acid, 4-amino butanoic acid and beta-alanine or have the formula:

12. The method of claim 1 , wherein each remaining R is cholic acid.

13. The method of claim 1 , wherein the compound of formula I has 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
each R is a cholic acid or a porphyrin.

14. The method of claim 13 , wherein the compound is selected from the group consisting of:

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-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 ); and
each R″ is a porphyrin selected from the group consisting of pyropheophorbide-a, pheophorbide, chlorin e6, purpurin and purpurinimide.

15. The method of claim 14 , wherein the porphyrin is pyropheophorbide-a.

16. The method of claim 14 , 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, each R″ is pyropheophorbide-a;
(2) each L 2 is the linker Ebes, each Y 2 is cysteine, each R′ is cholic acid, each R″ is pyropheophorbide-a.

Assignees

• Univ California

Inventors

• Lam Kit
• Li Yuanpei
• Pan Chongxian

Classifications

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P33/00

  Antiparasitic agents · 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

• A61K41/0033

  Sonodynamic cancer therapy with sonochemically active agents or sonosensitizers, having their cytotoxic effects enhanced through application of ultrasounds (ultrasound therapy per se A61N7/00) · CPC title