Compositions and methods for delivery of macromolecules

Patent metadata

Field	Value
Publication number	US-12059407-B2
Application number	US-201816766226-A
Country	US
Kind code	B2
Filing date	Dec 3, 2018
Priority date	Dec 4, 2017
Publication date	Aug 13, 2024
Grant date	Aug 13, 2024

Abstract

The present disclosure provides endosomal disruptors, which are useful for facilitating delivery of a macromolecule to the cytoplasm of a cell. The present disclosure provides compositions comprising an endosomal disruptor and a macromolecule. The present disclosure provides methods of delivering a macromolecule to the cytoplasm of a cell.

First claim

What is claimed is:

1. An endosomal disruptor of the formula (I):
(M-Z-A-T)-Y  (I)

wherein:
M is a hydrophilic masking group;
Z is a cleavable linker capable of cleavage with an endosome to release M and produce an endosomal disrupting surfactant;
A is a masked hydrophobic group comprising:
(a) a cyclic group selected from:

wherein:
R 2 and R 3 are each independently selected from the group consisting of OH, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, —OCF 3 , halogen, amine, substituted amine, amide, azide, heterocycle and substituted heterocycle;
X 1 and X 2 are each independently selected from a carbon atom and a heteroatom selected from S, O and N;
m is an integer from 0 to 4; and
p is an integer from 0 to 8; and
(b) a hydrophobic chain comprising:
a linear or branched hydrophobic chain selected from, alkyl, alkenylene, alkynylene, arylene, alkarylene, aralkylene, alkoxy and alkamine; or
(c) a hydrophobic chain selected from:

wherein:
R 4 , R 5 , R 6 and R 7 are each independently selected from alkyl and substituted alkyl; and
q, q 1 , q 2 and q 3 are each independently an integer from 1 to 20;

T is a hydrophilic tail group; and
Y is an optional group selected from a terminal group, a linker, a chemoselective tag, a member of a specific binding pair, a linked biomolecule and a linked cell delivery agent;
or a pharmaceutically acceptable salt.

2. The endosomal disruptor of claim 1 , wherein M is an inert hydrophilic masking group.

3. The endosomal disruptor of claim 1 , of the formula (II):

wherein:
R 1 and R 1′ are independently selected from alkyl, alkenyl, heterocycle, substituted heterocycle, substituted heterocycle, carbocycle, substituted carbocycle, polyethylene glycol (PEG), substituted PEG, alkyl-Y 1 and alkenyl-Y 1 , wherein Y 1 is selected from the group consisting of, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, carbocycle, substituted carbocycle, polyethylene glycol (PEG), modified PEG, and wherein each Y 1 group is optionally substituted with one or more additional groups selected from alkyl, substituted alkyl, PEG and modified PEG;
or R 1 and R 1′ together with the carbon to which they are attached form a group selected from heterocycle and substituted heterocycle;
X is O or S;
A is a masked hydrophobic group comprising:
(a) a cyclic group selected from:

wherein:
R 2 and R 3 are each independently selected from the group consisting of OH, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, —OCF 3 , halogen, amine, substituted amine, amide, azide, heterocycle and substituted heterocycle;
X 1 and X 2 are each independently selected from a carbon atom and a heteroatom selected from S, O and N;
m is an integer from 0 to 4; and
p is an integer from 0 to 8; and
(b) a hydrophobic chain comprising:
a linear or branched hydrophobic chain selected from, alkyl, alkenylene, alkynylene, arylene, alkarylene, aralkylene, alkoxy and alkamine; or
(c) a hydrophobic chain selected from:

wherein:
R 4 , R 5 , R 6 and R 7 are each independently selected from alkyl and substituted alkyl; and
q, q 1 , q 2 and q 3 are each independently an integer from 1 to 20;

T is a hydrophilic tail selected from a polyethylene glycol (PEG), a modified PEG, a oligoethyleneglycol, a phosphate, a phosphonate, a boric acid, a carboxylate, a sulfate, a sulfonate, an amine, a glycerol, a sugar, an amino acid, a substituted amino acid; and
Y 1 is an optional group selected from a terminal group, a linker, a chemoselective tag, a member of a specific binding pair, a linked biomolecule and a linked cell delivery agent;
or a pharmaceutically acceptable salt.

4. The endosomal disruptor of claim 3 , of the formula (III)

wherein:
R 1 and R 1′ are independently selected from alkyl, alkenyl, heterocycle, substituted heterocycle, substituted heterocycle, carbocycle, substituted carbocycle, polyethylene glycol (PEG), substituted PEG, alkyl-Y 1 and alkenyl-Y 1 , wherein Y 1 is selected from the group consisting of, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, carbocycle, substituted carbocycle, polyethylene glycol (PEG), modified PEG, and wherein each Y 1 group is optionally substituted with one or more additional groups selected from alkyl, substituted alkyl, PEG and modified PEG;
or R 1 and R 1′ together with the carbon to which they are attached form a group selected from heterocycle and substituted heterocycle;
X is O or S;
A is a masked hydrophobic group comprising:
(a) a cyclic group selected from:

wherein:
R 2 and R 3 are each independently selected from the group consisting of OH, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, —OCF 3 , halogen, amine, substituted amine, amide, azide, heterocycle and substituted heterocycle;
X 1 and X 2 are each independently selected from a carbon atom and a heteroatom selected from S, O and N;
m is an integer from 0 to 4; and
p is an integer from 0 to 8; and
(b) a hydrophobic chain comprising:
a linear or branched hydrophobic chain selected from, alkyl, alkenylene, alkynylene, arylene, alkarylene, aralkylene, alkoxy and alkamine; or
(c) a hydrophobic chain selected from:

wherein:
R 4 , R 5 , R 6 and R 7 are each independently selected from alkyl and substituted alkyl; and
q, q 1 , q 2 and q 3 are each independently an integer from 1 to 20;

n is an integer up to 500 Da; and
Y 1 is selected from a terminal group, a linker, a chemoselective tag, a member of a specific binding pair, a linked biomolecule and a linked cell delivery agent;
or a pharmaceutically acceptable salt.

5. The endosomal disruptor of claim 1 , of the formula (IV):

wherein:
R 1 and R 1′ are independently selected from alkyl, alkenyl, heterocycle, substituted heterocycle, substituted heterocycle, carbocycle, substituted carbocycle, polyethylene glycol (PEG), substituted PEG, alkyl-Y 1 and alkenyl-Y 1 , wherein Y 1 is selected from the group consisting of, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, carbocycle, substituted carbocycle, polyethylene glycol (PEG), modified PEG, and wherein each Y 1 group i

Assignees

• Univ California
• Murthy Niren
• Roeise Joachim Justad
• Taing Chung Hak

Inventors

• Murthy Niren
• Roeise Joachim Justad
• Taing Chung Hak

Classifications

• A61K38/465

  acting on ester bonds (3.1), e.g. lipases, ribonucleases · CPC title

• A61K47/61

  the organic macromolecular compound being a polysaccharide or a derivative thereof · CPC title

• A61K47/6455

  Polycationic oligopeptides, polypeptides or polyamino acids, e.g. for complexing nucleic acids · CPC title

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title