Singlet oxygen-labile linkers and methods of production and use thereof

Patent metadata

Field	Value
Publication number	US-9839690-B2
Application number	US-201615187227-A
Country	US
Kind code	B2
Filing date	Jun 20, 2016
Priority date	Apr 24, 2012
Publication date	Dec 12, 2017
Grant date	Dec 12, 2017

Abstract

Activatable compositions that include at least one functional moiety and at least one cleavable linker directly or indirectly linked to the at least one functional moiety are disclosed. The at least one functional moiety is inactive when linked to the linker and activated upon cleavage of the linker. Methods of production and use of the activatable composition are also disclosed.

First claim

What is claimed is:

1. An activatable composition, comprising:
at least one functional moiety;
at least one singlet oxygen-labile linker selected from the group consisting of aminoacrylate, aminoacrylthioate, and aminoacrylamide, the at least one singlet oxygen-labile linker linked to the at least one functional moiety, wherein the at least one functional moiety is inactive until the at least one singlet oxygen-labile linker is cleaved by singlet oxygen, whereby the at least one functional moiety becomes activated; and
a sensitizer, which when exposed to an activator results in generation of singlet oxygen by the sensitizer.

2. The activatable composition of claim 1 , further defined as comprising at least one of a prodrug, a nano-carrier, and a micro-carrier in which the at least one functional moiety is encapsulated, and wherein the at least one singlet oxygen-labile linker is incorporated into a portion of the structure of the at least one prodrug, nano-carrier, or micro-carrier.

3. The activatable composition of claim 2 , wherein the nano-carrier is selected from the group consisting of liposomes, polymers, nanospheres, nanocapsules, micelles, solid lipid nanoparticles, and combinations thereof.

4. The activatable composition of claim 2 , further defined as being in the form of a dendrimer.

5. The activatable composition of claim 1 , wherein the sensitizer is a photosensitizer selected from the group consisting of porphyrin, phthalocyanines, boron-dipyrromethene (BODIPY) or aza-BODIPY-type photosensitizers, chlorins, bacteriochlorins, non-porphyrin-based photosensitizers, and combinations thereof.

6. The activatable composition of claim 1 , further comprising a spacer between the at least one singlet oxygen-labile linker and the at least one functional moiety.

7. The activatable composition of claim 6 , wherein the spacer is selected from the group consisting of piperidin-4-ylmethanol, pyrrolidine-2-carboxylic acid, pyrrolidine-3-carboxylic acid, piperidin-4-ylmethyl-2-bromoacetate, 1-(3-bromoporpyl) piperazine, and combinations thereof.

8. The activatable composition of claim 1 , further comprising at least one targeting/delivery moiety linked to the at least one functional moiety.

9. The activatable composition of claim 8 , wherein the at least one targeting/delivery moiety is selected from the group consisting of antibodies, ligands, tumor markers, aptamers, polyethylene glycol, albumin, tumor specific peptides, affibodies, vitamins, carbohydrates, hormones, low density lipoproteins (LDL), and combinations thereof.

10. The activatable composition of claim 1 , wherein the at least one functional moiety is a therapeutic moiety and/or a detectable moiety.

11. The activatable composition of claim 1 , further defined as comprising two or more functional moieties, wherein the two or more functional moieties are the same or are different.

12. A method of inhibiting and/or decreasing the occurrence and/or severity of at least one condition/disorder in a patient, the method comprising the steps of:
administering an effective amount of an activatable composition to the patient, the activatable composition comprising:
at least one functional moiety, wherein the functional moiety is a therapeutic moiety and/or a detectable moiety;
at least one singlet oxygen-labile linker selected from the group consisting of aminoacrylate, aminoacrylthioate, and aminoacrylamide, the at least one singlet oxygen-labile linker linked to the at least one functional moiety, wherein the at least one functional moiety is inactive until the at least one singlet oxygen-labile linker is cleaved by singlet oxygen, whereby the at least one functional moiety becomes activated; and
a sensitizer, which when exposed to an activator results in generation of singlet oxygen by the sensitizer; and

exposing at least a portion of the patient to the activator, whereby singlet oxygen is generated, resulting in cleavage of the at least one singlet oxygen-labile linker and activation of the at least one functional moiety.

13. The method of claim 12 , wherein the activator is selected from the group consisting of irradiation with visible/near IR light, irradiation with ionizing radiation, exposure to electromagnetic waves/materials, exposure to luminescence, exposure to fluorescence, and combinations thereof.

14. The method of claim 12 , wherein the activator comprises irradiation with light in a range of from about 380 nm to about 1200 nm.

15. The method of claim 12 , wherein the activatable composition is further defined as comprising at least one of a prodrug, a nano-carrier, and a micro-carrier in which the at least one functional moiety is encapsulated, and wherein the at least one singlet oxygen-labile linker is incorporated into a portion of the structure of the at least one prodrug, nano-carrier, or micro-carrier, thereby indirectly linking the at least one functional moiety and the at least one singlet oxygen-labile linker to one another, and wherein at least one of:
(a) the nano-carrier is selected from the group consisting of liposomes, polymers, nanospheres, nanocapsules, micelles, solid lipid nanoparticles, and combinations thereof;
(b) the nano-carrier is further defined as being in the form of a dendrimer;
(c) the activatable composition comprises a prodrug, and the sensitizer is a photosensitizer; and
(d) the activatable composition comprises a prodrug which comprises a targeting group.

16. The method of claim 12 , wherein the sensitizer of the activatable composition is a photosensitizer selected from the group consisting of porphyrin, phthalocyanines, boron-dipyrromethene (BODIPY) or aza-BODIPY-type photosensitizers, chlorins, bacteriochlorins, non-porphyrin-based photosensitizers, and combinations thereof.

17. The method of claim 12 , further comprising a spacer between the at least one singlet oxygen-labile linker and the at least one functional moiety.

18. The method of claim 17 , wherein the spacer is selected from the group consisting of piperidin-4-ylmethanol, pyrrolidine-2-carboxylic acid, pyrrolidine-3-carboxylic acid, piperidin-4-ylmethyl-2-bromoacetate, 1-(3-bromoporpyl)piperazine, and combinations thereof.

19. The method of claim 12 , wherein the activatable composition further comprises at least one targeting/delivery moiety linked to the at least one functional moiety, wherein the targeting/delivery moiety is selected from the group consisting of antibodies, ligands, tumor markers, aptamers, polyethylene glycol, albumin, tumor specific peptides, affibodies, vitamins, carbohydrates, hormones, low density lipoproteins (LDL), and combinations thereof.

20. The method of claim 12 , wherein the activatable composition is further defined as comprising two or more functional moieties, wherein the two or more functional moieties are the same or are different.

21. The method of claim 12 , wherein:
the at least one functional moiety is a therapeutic moiety having at least one targeting/delivery moiety linked thereto;
at least one of the at least one singlet oxygen-labile linker, the at least one targeting/delivery moiety, and the sensitizer is further defined as comprising a detectable moiety; and
the method further comprises detecting the presence of the activatable composition at a desired delivery site.

Assignees

• Univ Oklahoma

Inventors

• You Youngjae
• Bio Moses
• Hossion Abu Gafar
• Nkepang Gregory

Classifications

• A61N5/062

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

• A61K31/4745

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · CPC title

• A61K31/09

  having two or more such linkages · CPC title

• A61K49/0006

  Skin tests, e.g. intradermal testing, test strips, delayed hypersensitivity · CPC title

• A61K47/546

  Porphyrines; Porphyrine with an expanded ring system, e.g. texaphyrine · CPC title