Cationic mucic acid polymer-based delivery system

Patent metadata

Field	Value
Publication number	US-10717825-B2
Application number	US-201916351168-A
Country	US
Kind code	B2
Filing date	Mar 12, 2019
Priority date	Jul 1, 2015
Publication date	Jul 21, 2020
Grant date	Jul 21, 2020

Abstract

The present disclosure is directed to nanoparticle delivery systems for delivering biological agents, pharmaceutical compositions of comprising these nanoparticles, and methods of using these compositions. Certain embodiments of the present disclosure provide nanoparticles comprising polymers comprising alternating charged and uncharged segments comprising one or more of the following structural units of Formula (I) Formula (III):

wherein A is an uncharged segment comprising polyalkylene glycol; and B is a cationically charged segment comprising at least one polyhydroxy linkage.

First claim

What is claimed:

1. A nanoparticle comprising a first polymer comprising alternating charged and uncharged segments comprising one or more of the following structural units of Formula (I) or Formula (III):

wherein
A is the uncharged segment comprising a poly-C 1-6 -alkylene glycol;
B is the charged segment comprising at least one cationic charged moiety and at least one polyhydroxy linkage comprising at least one pair of vicinal diols.

2. The nanoparticle of claim 1 , wherein A comprises polyethylene glycol and an appropriate linking group, wherein the polyethylene glycol has a nominal weight in a range of from about 1000 Daltons to about 10,000 Daltons.

3. The nanoparticle of claim 1 , where B is a cationically charged segment comprising at least one mucic acid linkage comprising the at least one pair of vicinal diols and comprising at least one repeating subunit comprising a structure of Formula (IV):

and at least one repeating subunit comprising a structure of Formula (V):

wherein m is 1, 2, 3, 4, 5, or 6.

4. The nanoparticle of claim 1 , wherein B comprises at least one repeating subunit comprising cMAP, whose subunit structure is represented as Formula (VI):

wherein
m is independently at each occurrence 4, 5, or 6; and
n is independently at each occurrence 1, 2, or 3.

5. The nanoparticle of claim 1 , described by a structure of Formula (VII):

wherein
Chain A is

Chain B is

cMAP is

p and q are sufficient to provide a number average molecular weight for the subunits comprising cMAP and PEG, respectively, independently in a range of from 1000 Da to 10,000 Da;
m is independently at each occurrence 4, 5, or 6;
n and r are independently at each occurrence 0, 1, 2, 3, 4, or 5; and
X 1 and X 2 are independently at each occurrence C 1-4 alkyl, optionally substituted with —COOH, —C(═O)O(alkyl), —NH 2 , —NH(alkyl), —N(alkyl) 2 , or a salt or protected analog thereof.

6. The nanoparticle of claim 1 , described by a structure of Formula (VII):

wherein
cMAP is

Chain B is

Chain C is

End Group D is:

p and q are sufficient to provide a number average molecular weight for the subunits comprising cMAP and PEG, respectively, independently in a range of from 1000 Da to 10,000 Da;
m is independently at each occurrence 4, 5, or 6;
n and r are independently at each occurrence 1, 2, or 3;
z is equal to or greater than 1 and up to 10; and
X 2 is independently at each occurrence C 1-6 alkyl, optionally substituted with OH, —COOH, —C(═O)O(alkyl), —NH 2 , —NH(alkyl), —N(alkyl) 2 , or a salt or protected analog thereof; and
X 3 is —NH 2 , —COOH, —C(═O)O(alkyl), or a salt or protected analog thereof.

7. The nanoparticle of claim 1 , described by a structure of Formula (IX):

wherein
End Group D is:

cMAP is

Chain C is

p and q are sufficient to provide a number average molecular weight for the subunits comprising cMAP and PEG, respectively, independently in a range of from about 500 Da to about 50,000 Da;
m is independently at each occurrence 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
n and r are independently at each occurrence 0, 1, 2, 3, 4, or 5;
z is equal to or greater than 1 up to 10 and
X 3 and X 4 are independently at each occurrence —NH 2 , —COOH, —C(═O)O(alkyl), or a salt or protected analog thereof.

8. The nanoparticle of claim 1 , further comprising a polymer comprising a boronic acid-containing structure of Formula (X)

conjugated to the first polymer by a borate condensation linkage between the boronic acid moieties of Formula (X) and the at least one pair of vicinal diols of the polyhydroxy linkages of Formula (I) or (III), X 5 being at a distal end thereof;
R A is nitro;
n is 1;
s is 20-1200
L is —NH—C(═O)—, —C(═O)—NH—, —O—C(═O)—, or —C(═O)—O—; and
X 5 is C 1-6 alkyl, optionally substituted with —OH, —COOH, —C(═O)O(alkyl), —C(═O)O(aryl), —NH 2 , —NH(alkyl), —N(alkyl) 2 , or a salt or protected analog thereof.

9. The nanoparticle of claim 5 , further comprising a polymer comprising a boronic acid-containing structure of Formula (X)

conjugated to the first polymer by a borate condensation linkage between the boronic acid moieties of Formula (X) and the at least one pair of vicinal diols of the polyhydroxy linkages of Formula (I) or (III), X 5 being at a distal end thereof;
R A is nitro;
n is 1;
s is 20-1200
L is —NH—C(═O)—, —C(═O)—NH—, —O—C(═O)—, or —C(═O)—O—; and
X 5 is C 1-6 alkyl, optionally substituted with —OH, —COOH, —C(═O)O(alkyl), —C(═O)O(aryl), —NH 2 , —NH(alkyl), —N(alkyl) 2 , or a salt or protected analog thereof.

10. The nanoparticle of claim 6 , further comprising a polymer comprising a boronic acid-containing structure of Formula (X)

conjugated to the first polymer by a borate condensation linkage between the boronic acid moieties of Formula (X) and at the least one pair of vicinal diols of the polyhydroxy linkages of Formula (I) or (III), X 5 being at the distal end thereof;
R A is nitro;
n is 1;
s is 20-1200
L is —NH—C(═O)—, —C(═O)—NH—, —O—C(═O)—, or —C(═O)—O—; and
X 5 is C 1-6 alkyl, optionally substituted with —OH, —COOH, —C(═O)O(alkyl), —C(═O)O(aryl), —NH 2 , —NH(alkyl), —N(alkyl) 2 , or a salt or protected analog thereof.

11. The nanoparticle of claim 7 , further comprising a polymer comprising a boronic acid-

Assignees

• California Inst Of Techn
• California Instite Of Tech

Inventors

• Davis Mark E
• Pan Dorothy

Classifications

• A61K47/34

  Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence) · CPC title

• A61K31/7088

  Compounds having three or more nucleosides or nucleotides · CPC title

• A61K9/5031 Primary

  obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide) · CPC title

• A61K9/5146 Primary

  obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides · CPC title

• A61P35/00

  Antineoplastic agents · CPC title