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

Patent metadata

Field	Value
Publication number	US-9393306-B2
Application number	US-201314396802-A
Country	US
Kind code	B2
Filing date	Apr 24, 2013
Priority date	Apr 24, 2012
Publication date	Jul 19, 2016
Grant date	Jul 19, 2016

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 linker selected from the group consisting of aminoacrylate, aminoacrylthioate, and aminoacrylamide, the at least one linker linked to the at least one functional moiety, wherein the at least one functional moiety is inactive when linked to the linker, and wherein the at least one linker is cleavable by singlet oxygen; and
a sensitizer linked via the at least one linker to the functional moiety, wherein exposure of the sensitizer to an activator results in generation of singlet oxygen by the sensitizer, which causes cleavage of the at least one linker and thus activation of the at least one functional moiety.

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 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 linker and the sensitizer and/or between the linker and the functional moiety.

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

8. The activatable composition of claim 7 , 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.

9. 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-bromopropyl)piperazine, 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. The activatable composition of claim 1 , wherein at least one component thereof is further defined as a detectable moiety.

13. A kit, comprising:
at least one linker selected from the group consisting of aminoacrylate, aminoacrylthioate, and aminoacrylamide, the at least one linker capable of being linked to at least one functional moiety, wherein the at least one functional moiety is inactive when linked to the linker, and wherein the at least one linker is cleavable by singlet oxygen; and
a sensitizer capable of being linked via the at least one linker to the functional moiety, wherein exposure of the sensitizer to an activator results in generation of singlet oxygen by the sensitizer, which causes cleavage of the at least one linker and the at least one functional moiety and thus activation of the at least one functional moiety.

14. The kit of claim 13 , further comprising at least one of:
(a) a therapeutic moiety and/or a detectable moiety as the at least one functional moiety;
(b) at least one targeting/delivery moiety capable of being linked to the at least one functional moiety; and
(c) at least one spacer positioned between any two of the linker, the functional moiety, the sensitizer, and the targeting/delivery moiety.

15. 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 linker selected from the group consisting of aminoacrylate, aminoacrylthioate, and aminoacrylamide, the at least one linker linked to the at least one functional moiety, wherein the at least one functional moiety is inactive when liked to the linker, and wherein the at least one linker is cleavable by singlet oxygen; and
a sensitizer linked via the at least one linker to the functional moiety, wherein exposure of the sensitizer to an activator results in generation of singlet oxygen by the sensitizer, which causes cleavage of the at least one linker and thus activation of the at least one functional moiety; and
exposing at least a portion of the patient to an activator, whereby singlet oxygen is generated, resulting in cleavage of the at least one linker and activation of the at least one functional moiety.

16. The method of claim 15 , 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.

17. The method of claim 16 , wherein the activator comprises irradiation with light in a range of from about 380 nm to about 1200 nm.

18. The method of claim 15 , wherein the at least one functional moiety, the at least one linker, and the sensitizer of the activatable composition are linked to one another.

19. The method of claim 15 , 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 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 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.

20. The method of claim 15 , 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.

21. The method of claim 15 , further comprising a spacer between the linker and the sensitizer and/or between the liker and the functional moiety.

22. The method of claim 15 , wherein the activatable composi

Assignees

• Univ Oklahoma

Inventors

• You Youngjae
• Bio Moses
• Hossion Abugafar
• Nkepang Gregory

Classifications

• A61K47/546

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

• A61N2005/0662

  Visible light · CPC title

• A61N2005/0659

  infrared · 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

• A61K41/0042 Primary

  Photocleavage of drugs in vivo, e.g. cleavage of photolabile linkers in vivo by UV radiation for releasing the pharmacologically-active agent from the administered agent; photothrombosis or photoocclusion · CPC title