Library of pH responsive polymers and nanoprobes thereof

Patent metadata

Field	Value
Publication number	US-11013818-B2
Application number	US-201816114187-A
Country	US
Kind code	B2
Filing date	Aug 27, 2018
Priority date	Jun 6, 2014
Publication date	May 25, 2021
Grant date	May 25, 2021

Abstract

The present disclosure relates to polymers which contain a hydrophobic and hydrophilic segment which is sensitive to pH. In some aspects, the polymers form a micelle which is sensitive to pH and results in a change in fluorescence based upon the particular pH. In some aspects, the disclosure also provides methods of using the polymers for the imaging of cellular or extracellular environment or delivering a drug.

First claim

What is claimed is:

1. A polymer of the formula:

wherein:
R 1 is hydrogen, alkyl (C≤12) , cycloalkyl (C≤12) , substituted alkyl (C≤12) , substituted cycloalkyl (C≤12) , or

or a metal chelating group;
n is an integer from 1 to 500;
R 2 and R 2 ′ are each independently selected from hydrogen, alkyl (C≤12) , cycloalkyl (C≤12) , substituted alkyl (C≤12) , or substituted cycloalkyl (C≤12) ;
R 3 is a group of the formula:

wherein:
n x is 1-10;
X 1 , X 2 , and X 3 are each independently selected from hydrogen, alkyl (C≤12) , cycloalkyl (C≤12) , substituted alkyl (C≤12) , or substituted cycloalkyl (C≤12) ;
X 4 is pentyl, n-propyl, or ethyl and X 5 is pentyl or n-propyl; or X 4 and X 5 are taken together and are alkanediyl (C≤12) or substituted alkanediyl (C≤12) ;
x is an integer from 1 to 150;
R 4 is a group of the formula:

wherein:
n z is 1-10;
Y 1 , Y 2 , and Y 3 are each independently selected from hydrogen, alkyl (C≤12) , cycloalkyl (C≤12) , substituted alkyl (C≤12) , or substituted cycloalkyl (C≤12) ; and
Y 4 is a dye with the following structure:

y is an integer from 1 to 6; and
R 5 is hydrogen, halo, hydroxy, alkyl (C≤12) , or substituted alkyl (C≤12) .

2. The polymer of claim 1 , wherein R 1 is alkyl (C≤12) .

3. The polymer of claim 2 , wherein R 1 is methyl.

4. The polymer of claim 1 , wherein R 2 and R 2 ′ are each alkyl (C≤12) .

5. The polymer of claim 4 , wherein R 2 and R 2 ′ are each methyl.

6. The polymer of claim 1 , wherein R 3 is:

7. The polymer of claim 6 , wherein X 4 and X 5 are each pentyl or n-propyl, or X 4 and X 5 are taken together and are alkanediyl (C≤12) or substituted alkanediyl (C≤12) .

8. The polymer of claim 6 , wherein X 4 is ethyl and X 5 is n-propyl.

9. The polymer of claim 6 , wherein X 4 and X 5 are taken together and are —CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 .

10. The polymer of claim 1 , wherein R 4 is:

11. The polymer of claim 1 , wherein X 1 or Y 1 is alkyl (C≤12) .

12. The polymer of claim 11 , wherein X 1 is methyl.

13. The polymer of claim 11 , wherein Y 1 is methyl.

14. The polymer of claim 1 , wherein the polymer is PEO 114 -P(D5A 80 ), PEO 114 -P(D5A 100 ), PEO 114 -P(DPA 80 ), PEO 114 -P(DPA 100 ), PEO 114 -P(EPA 40 ), PEO 114 -P(EPA 60 ), PEO 114 -P(EPA 80 ), PEO 114 -P(EPA 100 ), or PE 114 -P(EPA 120 ).

15. The polymer of claim 1 , wherein the polymer is PEO 114 -P(EPA 40 -r-ICG 1 ), PEO 114 -P(EPA 60 -r-ICG 1 ), PEO 114 -P(EPA 80 -r-ICG 1 ), PEO 114 -P(EPA 100 -r-ICG 1 ), or PEO 114 -P(EPA 120 -r-ICG 1 ).

16. The polymer of claim 1 , wherein the polymer is PEO 114 -P(C7A 40 -r-ICG 3 ), PEO 114 -P(C7A 60 -r-ICG 3 ), PEO 114 -P(C7A 80 -r-ICG 3 ), PEO 114 -P(C7A 100 -r-ICG 3 ), or PEO 114 -P(C7A 120 -r-ICG 3 ).

17. The polymer of claim 1 , wherein the polymer is:

wherein: x is an integer from 30 to 150, y is an integer from 1 to 2.

18. The polymer of claim 1 , wherein the polymer is:

wherein: x is an integer from 30 to 150, y is an integer from 1, 2 or 3.

19. A composition, comprising a micelle formed from a plurality of polymers according to claim 1 .

20. The composition of claim 19 , wherein the micelle has a pH transition point and an emission spectra, wherein the micelle dissociates at a pH below the pH transition point.

21. A method of imaging pH of an intracellular or extracellular environment comprising:
(a) contacting the intracellular or extracellular environment with a composition according to claim 20 ; and
(b) detecting one or more optical signals from the intracellular or extracellular environment, wherein the detection of the optical signal indicates that the micelle has reached its pH transition point and disassociated.

22. The method according to claim 21 , wherein the intracellular environment is part of a cell.

23. The method according to claim 21 , wherein the extracellular environment is of a tumor or vascular cell.

24. A method of resecting a tumor in a patient comprising:
(a) administering to the patient an effective dose of a composition according to claim 23 ;
(b) detecting one or more optical signals for the patient; wherein the optical signals indicate the presence of a tumor; and
(c) resecting the tumor via surgery.

25. The method of claim 24 , wherein the tumor is a cancer and the cancer is a breast cancer, a head and neck cancer, or colorectal peritoneal metastases.

Assignees

• Univ Texas

Inventors

• Gao Jinming
• Huang Gang
• Zhao Tian
• Ma Xinpeng
• Wang Yiguang
• Li Yang
• Sumer Baran D

Classifications

• G01N33/582

  with fluorescent label · CPC title

• G01N21/6428

  Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" (in vivo A61B5/00; immunoassay G01N33/53) · CPC title

• G01N2021/6441

  with two or more labels · CPC title

• C08F8/32

  by reaction with amines · CPC title

• A61K49/0021

  the fluorescent group being a small organic molecule · CPC title