Cyclic peptides with enhanced nerve-binding selectively, nanoparticles bound with said cyclic peptides, and use of same for real-time in vivo nerve tissue imaging

Patent metadata

Field	Value
Publication number	US-10940216-B2
Application number	US-201916414874-A
Country	US
Kind code	B2
Filing date	May 17, 2019
Priority date	Dec 15, 2014
Publication date	Mar 9, 2021
Grant date	Mar 9, 2021

Abstract

Described herein are cyclic peptides, nanoparticles bound with cyclic peptides, and methods for using said cyclic peptides and/or said nanoparticles bound with cyclic peptides for intraoperative nerve tissue imaging.

First claim

What is claimed is:

1. An imaging method comprising:
exposing tissue of a subject to excitation light, a formulation comprising a cyclic nerve-binding peptide conjugate having been administered to the subject,
wherein the cyclic nerve-binding peptide conjugate comprises
from one to twenty cyclic nerve-binding peptide ligands, each having from 5 to 20 amino acid residues and/or a 15 atom to 60 atom macrocycle, wherein the one to twenty cyclic nerve-binding peptide ligands comprise the peptide sequence NTQTLAKAPEHT (SEQ ID NO: 1);
a silica-based nanoparticle, wherein the silica-based nanoparticle has a diameter less than 10 nm;
a fluorescent agent; and
a linker moiety attached to the silica-based nanoparticle, thereby coating the nanoparticle, wherein the one to twenty cyclic nerve-binding peptide ligands are attached to the coated silica-based nanoparticle; and
detecting light emitted by the fluorescent agent of the cyclic nerve-binding peptide conjugate.

2. The method of claim 1 , wherein the detecting step comprises detecting light emitted by the fluorescent agent of the cyclic nerve-binding peptide conjugate to create an image and displaying the image.

3. The method of claim 1 , wherein light emitted from the nerve tissue is more intense than light emitted from surrounding tissue such that the nerve tissue is visually distinguishable from the surrounding tissue.

4. The imaging method of claim 1 , wherein light emitted from the nerve tissue is detectable at least as early as 15 minutes following administration of the formulation to the subject.

5. The method of claim 1 , wherein light emitted from the nerve tissue is detectable at least as long as 1 hour following administration of the formulation to the subject.

6. The method of claim 1 , the formulation having been administered by topical application to a peripheral nerve trunk adjacent to or within the vicinity of a metastatic lymph node or primary tumor after surgical exposure.

7. The method of claim 1 , the formulation having been administered by topical application to a peripheral nerve trunk such that the cyclic nerve-binding peptide conjugate of the formulation has diffused from the nerve trunk to smaller branches of the nerve tissue, wherein the method comprises detecting light emitted by the fluorescent agent of the cyclic nerve-binding peptide conjugate to create an image of the smaller branches of the nerve tissue.

8. The method of claim 1 , wherein the formulation is administered intravenously.

9. The method of claim 1 , wherein the formulation is locally administered.

10. The method of claim 1 , wherein exposing the tissue of the subject to excitation light occurs during a surgical procedure.

11. The method of claim 1 , wherein the detecting step comprises detecting light emitted by the fluorescent agent of the cyclic nerve-binding peptide conjugate to create an image and displaying the image, wherein the image is a video and/or still image and/or real-time video.

12. The method of claim 11 , wherein the image is displayed to a surgeon during a surgical procedure conducted on the subject.

13. The method of claim 3 , wherein the surrounding tissue is muscle tissue, and wherein the nerve-to-muscle signal ratio is at least 2.

14. The method of claim 1 , wherein the silica-based nanoparticle comprises:
a silica-based core;
the fluorescent agent within the core; and
a silica shell surrounding at least a portion of the core.

15. The method of claim 1 , wherein the linker moiety comprises one or more members selected from the group consisting of polyethylene glycol (PEG), PEG 2 , and para-aminobenzyloxy carbamate (PABC).

16. The method of claim 1 , wherein each of the from one to twenty cyclic nerve-biding peptide ligands is bound to the silica-based nanoparticle via the linker moiety.

17. The method of claim 1 , wherein the fluorescent agent comprises a cyanine dye.

18. The method of claim 1 , wherein the nerve-binding peptide conjugate has 17 amino acid residues and/or a 51 atom macrocycle.

19. The method of claim 1 , wherein a macrocycle is formed by cyclizing the peptide head-to-tail, or by introducing a covalent bond internal to the sequence.

Assignees

• Memorial Sloan Kettering Cancer Center
• Univ Cornell

Inventors

• Bradbury Michelle S
• Yoo Barney
• Wiesner Ulrich
• Chen Peiming
• Ma Kai
• Patel Snehal G
• Zanoni Daniella Karassawa

Classifications

• A61K49/0065 Primary

  the luminescent/fluorescent agent having itself a special physical form, e.g. gold nanoparticle · CPC title

• A61B5/0071

  by measuring fluorescence emission · CPC title

• A61B5/4893

  Nerves · CPC title

• A61K9/0014

  Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00) · CPC title

• A61K49/0032

  Methine dyes, e.g. cyanine dyes · CPC title