Ph-activated nanoparticles

Patent metadata

Field	Value
Publication number	US-2022117917-A1
Application number	US-201917289425-A
Country	US
Kind code	A1
Filing date	Oct 30, 2019
Priority date	Oct 30, 2018
Publication date	Apr 21, 2022
Grant date	—

Abstract

Disclosed herein is a pH activated nanoparticle that can be used to deliver labile therapeutic or diagnostic agents to the cytoplasm of cells. These nanoparticles allow the agents to escape the endosome by releasing a gas in an amount effective to disrupt the endosome and release the agents into the cytoplasm. The disclosed nanoparticles have a shell, such as a phospholipid bilayer shell, and a core containing a gas bound to a substrate by a pH sensitive interaction. Also disclosed herein is are methods for delivering a pH sensitive cargo to the cytoplasm of a cell, treating triple negative breast cancer (TNBC) in a subject, and treating HER2+ breast cancer in a subject.

First claim

1 . A pH activated nanoparticle, comprising
a shell comprising a phospholipid bilayer, and a core comprising a gas bound to a substrate by a pH sensitive interaction.

2 . The nanoparticle of claim 1 , wherein the substrate comprises chitosan-guanidine (CG) or chitosan-arginine (CA).

3 . The nanoparticle of claim 1 , wherein the substrate comprises metformin.

4 . The nanoparticle of claim 1 , wherein the substrate comprises calcium carbonate.

5 . The nanoparticle of claim 1 , wherein the gas comprises carbon dioxide.

6 . The nanoparticle of claim 1 , wherein the core further comprises a pH sensitive therapeutic or diagnostic agent.

7 . The nanoparticle of claim 6 , wherein the pH sensitive therapeutic or diagnostic agent is an RNA or DNA oligonucleotide.

8 . The nanoparticle of claim 7 , wherein the pH sensitive therapeutic or diagnostic agent is an mRNA, ncRNA, siRNA, miRNA, or shRNA oligonucleotide.

9 . The nanoparticle of claim 6 , wherein the pH sensitive therapeutic or diagnostic agent is peptide.

10 . The nanoparticle of claim 6 , wherein the pH sensitive therapeutic or diagnostic agent is a labile small molecule.

11 . The nanoparticle of claim 7 , wherein the pH sensitive therapeutic agent is a POLR2A-targeting siRNA (siPol2).

12 . The nanoparticle of claim 7 , wherein the pH sensitive therapeutic agent is an anti-miR-21 oligonucleotide.

13 . The nanoparticle of claim 12 , further comprising a small molecule inhibitor against WIP1.

14 . The nanoparticle of claim 13 , wherein the small molecule inhibitor against WIP1 comprises GSK2830371.

15 . The nanoparticle of claim 1 , further comprising paclitaxel, camptothecin, doxorubicin, or any combination thereof.

16 . The nanoparticle of claim 1 , wherein the phospholipid bilayer comprises dipalmitoyl phosphatidylcholine (DPPC) or dioleoyl phosphatidylcholine (DOPC).

17 . The nanoparticle of claim 1 , wherein the shell further comprises poly(lactic-co-glycolic acid) (PLGA).

18 . The nanoparticle of claim 17 , wherein the PLGA is PEGylated.

19 . The nanoparticle of claim 1 , wherein the shell further comprises a poloxamer.

20 . The nanoparticle of claim 19 , wherein the poloxamer is poloxamer 407.

21 . A method for treating triple negative breast cancer (TNBC) in a subject, comprising administering to the subject a therapeutically effective amount of the pH activated nanoparticle of claim 11 .

22 . The method of claim 21 , wherein the TNBC has a TP53 gene mutation or deletion.

23 . A method for delivering a pH sensitive cargo to the cytoplasm of a cell, comprising loading the pH sensitive cargo into the pH activated nanoparticle of claim 1 , and contacting the cell with the loaded nanoparticle.

24 . A method for treating HER2+ breast cancer in a subject, comprising administering to the subject a therapeutically effective amount of an anti-miR-21 oligonucleotide and a small molecule inhibitor against WIP1.

25 - 32 . (canceled)

Assignees

• Ohio State Innovation Foundation
• Univ Maryland
• Univ Indiana Res & Tech Corp

Inventors

• Lu Xiongbin
• He Xiaoming
• Xu Jiangsheng

Classifications

• C12Y207/07048

  RNA-directed RNA polymerase (2.7.7.48), i.e. RNA replicase · CPC title

• C12Y207/07006

  DNA-directed RNA polymerase (2.7.7.6) · CPC title

• C12N2320/32

  Special delivery means, e.g. tissue-specific · CPC title

• C12N2320/31

  Combination therapy · CPC title

• C12N2310/3517

  Marker; Tag · CPC title