Core-to-surface polymerization for the synthesis of star polymers and uses thereof

Patent metadata

Field	Value
Publication number	US-10973847-B2
Application number	US-201816024665-A
Country	US
Kind code	B2
Filing date	Jun 29, 2018
Priority date	Jun 30, 2017
Publication date	Apr 13, 2021
Grant date	Apr 13, 2021

Abstract

Disclosed are methods, compositions, reagents, systems, and kits to prepare star polymers, as well as compositions and uses thereof. Various embodiments show that synthesis of these polymers contain low metal concentration to provide polymers for diverse biomedical applications including in vivo applications.

First claim

What is claimed is:

1. A ring-opening-metathesis-polymerization-out brush-arm star polymer (ROMP-out BASP) formed by a method comprising the steps of:
(a) providing a first macromonomer comprising one or more polymeric sidechains and one or more olefin moieties;
(b) providing a metal complex;
(c) reacting the first macromonomer and the metal complex under conditions suitable to effect ring-opening metathesis polymerization (ROMP) to yield a polymer;
(d) providing a crosslinker, wherein the crosslinker comprises more than one olefin moiety;
(e) reacting the polymer and the crosslinker under conditions suitable to effect ROMP to yield a ring-opening-metathesis-polymerization-in brush-arm star polymer (ROMP-in BASP);
(f) providing a second macromonomer comprising one or more polymeric sidechains and one or more olefin moieties; and
(g) reacting the ROMP-in BASP and the second macromonomer under conditions suitable to effect ROMP to yield a ROMP-out BASP;

provided that the metal concentration of the ROMP-out BASP is less than about 450 ppm by weight.

2. A pharmaceutical composition comprising a ring-opening-metathesis-polymerization-out brush-arm star polymer (ROMP-out BASP) of claim 1 , and a pharmaceutically acceptable excipient.

3. A kit comprising a ring-opening-metathesis-polymerization-out brush-arm star polymer of claim 1 , and instructions for use.

4. The ROMP-out BASP of claim 1 , wherein the metal is ruthenium, and the metal complex is a ruthenium complex.

5. The pharmaceutical composition of claim 2 , wherein the ROMP-out BASP comprises one or more therapeutic agents.

6. The ROMP-out BASP of claim 1 , wherein the metal complex is dichloro[1,3-bis(2,6-isopropylphenyl)-2-imidazolidinylidene](benzylidene)(tricyclohexylphosphine) ruthenium(II), dichloro[1,3-bis(2-methylphenyl)-2-imidazolidinylidene](benzylidene) (tricyclohexylphosphine)ruthenium(II), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][3-(2-pyridinyl)propylidene]ruthenium(II), dichloro(3-methyl-2-butenylidene)bis (tricyclopentylphosphine)ruthenium(II), dichloro[1,3-bis(2-methylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II), dichloro(benzylidene)bis(tricyclohexylphosphine)ruthenium(II), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](benzylidene)(tricyclohexylphosphine) ruthenium(II), or dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene] (benzylidene)bis(3-bromopyridine)ruthenium(II), or is of the formula:

7. The ROMP-out BASP of claim 1 , wherein the method further comprises the step of purifying the ROMP-out BASP via addition of an additive, dialysis, and/or lyophilization.

8. The ROMP-out BASP of claim 1 , wherein the method further comprises the step of purifying the ROMP-out BASP via addition of an additive, wherein the additive is dimethyl sulfoxide, triphenylphosine oxide, lead tetraacetate, activated carbon, mesoporous silicate, isocyanide, or trishydroxymethylphosphine.

9. The ROMP-out BASP of claim 1 , wherein the ROMP-out BASP comprises a polymeric core of repeating units covalently linked to backbone polymeric arms of repeating units each covalently linked to polymeric sidechains.

10. The ROMP-out BASP of claim 9 , wherein the polymeric sidechains are each independently selected from polyethers, polyesters, polyacrylamides, polycarbonates, polysiloxanes, polyfluorocarbons, polysulfones, and polystyrenes.

11. The ROMP-out BASP of claim 9 , wherein the backbone polymeric arms are of Formula (I):

or a salt thereof, wherein:
G A is optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof;
each of L 1 , L 2 , L 3 , L 4 , L A , and L B is independently a linker selected from the group consisting of a bond, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, and combinations thereof;
each of T 1 and T 2 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted hydroxyl, optionally substituted amino, optionally substituted thiol, a structure of Formula (I), and a bond to the polymeric core;
n is an integer between 5 and 10000, inclusive;
y is an integer between 1 and 20, inclusive;
A is a polymeric sidechain having a number average molecular weight of about 1000 Da to about 100000 Da, and selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted hydroxyl, optionally substituted amino, and optionally substituted thiol; and
B is hydrogen, an agent, or a polymeric sidechain having a number average molecular weight of about 1000 Da to about 100000 Da.

12. The ROMP-out BASP of claim 9 , wherein the polymeric core is of Formula (II):

or a salt thereof, wherein:
G A is optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof;
each of L 1 , L 3 , and L 4 , is independently a linker selected from the group consisting of a bond, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, and combinations thereof;
each of T 1 , T 2 , T 3 , and T 4 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted hydroxyl, optionally substituted amino, optionally substituted thiol, a structure of Formula (I), and a structure of Formula (II); and
b and c are independently an integer between 1 and 10000, inclusive.

13. The ROMP-out BASP of claim 11 , wherein the backbone polymeric arms are of Formula (I-a):

or a salt thereof.

14. The ROMP-out BASP of claim 11 , wherein the backbone polymeric arms are of formula:

Assignees

• Massachusetts Inst Technology

Inventors

• Johnson Jeremiah A
• Golder Matthew R

Classifications

• C08F291/06

  on to oxygen-containing macromolecules · CPC title

• C08G2261/354

  containing hetero atoms · CPC title

• C08G2261/1432

  containing amide groups · CPC title

• C08G2261/1426

  containing carboxy groups (COOH) and/or -C(=O)O-moieties · CPC title

• C08G2261/3225

  containing one or more Se atoms as the only heteroatom · CPC title