Porphyrin modified telodendrimers

Patent metadata

Field	Value
Publication number	US-11219692-B2
Application number	US-201916355123-A
Country	US
Kind code	B2
Filing date	Mar 15, 2019
Priority date	Dec 12, 2012
Publication date	Jan 11, 2022
Grant date	Jan 11, 2022

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 nanocarrier having an interior and an exterior, the nanocarrier comprising 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 nanocarrier 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.

3. The nanocarrier of claim 2 , 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.

4. The nanocarrier of claim 1 , wherein the nanocarrier further comprises a metal cation chelated to the porphyrin.

5. The nanocarrier of claim 1 , wherein the nanocarrier further comprises a radio-metal cation selected from the group consisting of 64 Cu, 67 Cu, 177 Lu, 67 Ga, 111 In, and 90 Yt, wherein the radio-metal is chelated to the porphyrin.

6. The nanocarrier of claim 1 , wherein the conjugates are crosslinked via the crosslinking groups.

7. The nanocarrier 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.

8. The nanocarrier of claim 7 , further comprising a metal chelated to at least one of the pyropheophorbide-a groups.

9. 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 of claim 4 , and exposing the subject to radiation, thereby treating the disease via photodynamic or photothermal therapy.

10. A method of imaging, comprising administering to a subject to be imaged, an effective amount of a nanocarrier of claim 1 , wherein the nanocarrier further comprises an imaging agent.

11. A method of treating a disease via sonodynamic therapy, comprising administering to a subject in need thereof, a therapeutically effective amount of a nanocarrier of claim 4 , and exposing the subject to a sonic wave, thereby treating the disease via sonodynamic therapy.

12. A method of detecting a tumor in a subject, comprising
administering to the subject, an effective amount of a nanocarrier of claim 1 ;
exposing the subject to radiation at a first wavelength, wherein the radiation excites porphyrins present on the nanocarrier such that the porphyrins emit radiation at a second wavelength; and
detecting the radiation emitted by the excited porphyrins, thereby detecting the tumor.

13. The nanocarrier of claim 1 , wherein each branched monomer unit X is lysine.

14. The nanocarrier of claim 1 , wherein 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.

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

16. The nanocarrier of claim 1 , wherein each remaining 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, and rhein.

17. The nanocarrier of claim 1 , wherein each remaining R is cholic acid.

18. The nanocarrier 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; and
each R is a cholic acid or a porphyrin, wherein at least one R group is a porphyrin.

19. The nanocarrier of claim 18 , 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.

20. The nanocarrier of claim 19 , wherein the porphyrin is pyropheophorbide-a.

21. The nanocarrier of claim 19 , wherein the compound is selected from the group consisting of:
(1) each L 2 is a bond, each Y 2 is absent, each R′ is cholic acid, each R″ is pyropheophorbide-a, and subscript k is 0;
(2) each L 2 is the linker Ebes, each Y 2 is absent, each R′ is cholic acid, each R″ is pyropheophorbide-a, and subscript k is 0;
(3) each L 2 is a bond, each Y 2 is cysteine, each R′ is cholic acid, each R″ is pyropheophorbide-a, and subscript k is 0;
(4) each L 2 is the linker Ebes, each Y 2 is cysteine, each R′ is cholic acid, each R″ is pyropheophorbide-a, and subscript k is 0;
(5) each L 2 is a bond, each Y 2 is absent, each R′ is cholic acid, each R″ is pyropheophorbide-a, and subscript k is 1;
(6) each L 2 is the linker Ebe

Assignees

• Univ California

Inventors

• Lam Kit S
• Li Yuanpei
• Pan Chong-Xian

Classifications

• A61K49/0423

  Nanoparticles, nanobeads, nanospheres, nanocapsules, i.e. having a size or diameter smaller than 1 micrometer · CPC title

• A61K49/1809

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

• A61K49/0002

  General or multifunctional contrast agents, e.g. chelated 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

• A61K41/0052

  Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy · CPC title