IP Library › Granted Patent US 12,116,458

Granted Patent B2

US 12,116,458 · App. 17/287,978 · Granted Oct 15, 2024

Cationic polymer with alkyl side chains and use for biomolecule delivery

Inventors: Kunwoo Lee (South San Francisco, CA); Santanu Maity (South San Francisco, CA)

C08G69/10 A61K47/595 C08G69/48

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Quick Facts

Patent No.: US 12,116,458
App. No.: 17/287,978
Granted: Oct 15, 2024
Kind: B2

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Abstract

Provided is a polymer comprising a structure of Formula 1 or Formula 3 as provided herein, as well as a method of making the same; a composition comprising the polymer and a nucleic acid and/or polypeptide; and a method of delivering a nucleic acid and/or polypeptide to a cell.

Claims (414)

1. A polymer comprising a structure of Formula 1:

wherein,

m 1 is an integer from 1 to 2000;

R 1 is a methylene or ethylene group;

R 14 is hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group;

X is a C 1 -C 12 alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, aryl group, heteroalkyl group, or heterocyclic group;

A 1 is a group of formula

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 2 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 2 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —]r 2 R 2 }; or

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 2 ] 2 } 2 ,

wherein p1 to p4, q1 to q6, and r1 and r2 are each independently an integer of 1 to 5; and

each instance of R 2 is independently hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group.

2. The polymer of claim 1 , having the structure of Formula 1A:

wherein,

c is an integer from 0 to 50;

L is optionally present and is a cleavable linker;

m 1 is an integer from 1 to 2000;

R 1 is a methylene or ethylene group;

R 6 is hydrogen, an amino group, an aryl group, a heterocyclic group, a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group, a C 1 -C 12 linear or branched alkyl group optionally substituted with one or more amines; or a tissue-specific or cell-specific targeting moiety;

R 7 is hydrogen, an aryl group, a heterocyclic group, a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group, or a C 1 -C 12 linear or branched alkyl group optionally substituted with one or more substituents;

R 14 is hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group;

X is a C 1 -C 12 alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, aryl group, heteroalkyl group, or heterocyclic group;

A 1 is a group of formula

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 2 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 2 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —]r 2 R 2 }; or

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 2 ] 2 } 2 ,

wherein p1 to p4, q1 to q6, and r1 and r2 are each independently an integer of 1 to 5; and

each instance of R 2 is independently hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group.

3. The polymer of claim 1 , comprising a structure of Formula 2:

wherein,

m 1 is an integer from 1 to 1000;

m 2 is an integer from 1 to 1000;

the symbol “/” indicates that the units separated thereby are linked randomly or in any order;

each R 1 independently is a methylene or ethylene group;

each instance of R 14 is independently hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group;

each instance of X is independently a C 1 -C 12 alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, aryl group, heteroalkyl group, or heterocyclic group;

A 1 is a group of formula

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 2 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 2 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —]r 2 R 2 }; or

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 2 ] 2 } 2 ,

B 1 is a group of formula

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 —(CH 2 ) 2 —R 4 —R 5 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 —(CH 2 ) 2 —R 4 —R 5 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —]12(CH 2 ) 2 —R 4 —R 5 };

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 —(CH 2 ) 2 —R 4 —R 5 ] 2 } 2 ;

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 —CH 2 —CHOH—R 5 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 —CH 2 —CHOH—R 5 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —] r2 —CH 2 —CHOH—R 5 ;

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 —CH 2 —CHOH—R 5 ] 2 } 2 ;

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 —(CH 2 ) 2 —R 5 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 —(CH 2 ) 2 —R 5 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —]2(CH 2 ) 2 —R 5 }; or

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 —(CH 2 ) 2 —R 5 ] 2 } 2 ,

wherein p1 to p4, q1 to q6, and r1 and r2 are each independently an integer of 1 to 5; each instance of R 2 is independently hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group; each instance of R 4 is independently —C(O)O—, —C(O)NH—, or —S(O)(O)—; and each instance of R 5 is independently an alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, aryl group, heteroalkyl group, or heterocyclic group optionally comprising from 2 to 8 tertiary amines or a substituent comprising a tissue-specific or cell-specific targeting moiety.

4. The polymer of claim 3 , having the structure of Formula 2A:

wherein,

c is an integer from 0 to 50;

L is optionally present and is a cleavable linker;

m 1 is an integer from 1 to 1000;

m 2 is an integer from 1 to 1000;

the symbol “/” indicates that the units separated thereby are linked randomly or in any order;

each R 1 independently is a methylene or ethylene group;

each instance of R 14 is independently hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group;

each instance of X is independently a C 1 -C 12 alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, aryl group, heteroalkyl group, or heterocyclic group;

A 1 is a group of formula

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 2 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 2 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —]r 2 R 2 }; or

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 2 ] 2 } 2 ,

B 1 is a group of formula

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 —(CH 2 ) 2 —R 4 —R 5 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 —(CH 2 ) 2 —R 4 —R 5 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —]12(CH 2 ) 2 —R 4 —R 5 };

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 —(CH 2 ) 2 —R 4 —R 5 ] 2 } 2 ;

—(CH 2 ) p1 —[NR 2 _(CH 2 ) q1 —] r1 NR 2 —CH 2 —CHOH—R 5 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 —CH 2 —CHOH—R 5 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —] r2 —(CH 2 ) 2 —R 4 —R 5 };

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 —CH 2 —CHOH—R 5 ] 2 } 2 ;

—(CH 2 ) p1 —[NR 2 _(CH 2 ) q1 —] r1 NR 2 —(CH 2 ) 2 —R 5 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 —(CH 2 ) 2 —R 5 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —] r2 (CH 2 ) 2 —R 5 }; or

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 —(CH 2 ) 2 —R 5 ] 2 } 2 ,

5. A method of preparing a polymer according to claim 3 comprising a structure of Formula 2:

wherein,

m 1 is an integer from 1 to 1000;

m 2 is an integer from 1 to 1000;

the symbol “/” indicates that the units separated thereby are linked randomly or in any order;

each R 1 independently is a methylene or ethylene group;

each instance of R 14 is independently hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group;

each instance of X is independently a C 1 -C 12 alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, aryl group, heteroalkyl group, or heterocyclic group;

A 1 is a group of formula

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 2 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 2 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —]r 2 R 2 }; or

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 2 ] 2 } 2 ,

B 1 is a group of formula

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 —(CH 2 ) 2 —R 4 —R 5 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 —(CH 2 ) 2 —R 4 —R 5 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —] r2 (CH 2 ) 2 —R 4 —R 5 };

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 —(CH 2 ) 2 —R 4 —R 5 ] 2 } 2 ;

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 —CH 2 —CHOH—R 5 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 —CH 2 —CHOH—R 5 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —] r2 —CH 2 —CHOH—R 5 ;

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 —CH 2 —CHOH—R 5 ] 2 } 2 ;

—(CH 2 ) p1 —[NR 2 _(CH 2 ) q1 —] r1 NR 2 —(CH 2 ) 2 —R 5 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 —(CH 2 ) 2 —R 5 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —]12(CH 2 ) 2 —R 5 }; or

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 —(CH 2 ) 2 —R 5 ] 2 } 2 ,

wherein p1 to p4, q1 to q6, and r1 and r2 are each independently an integer of 1 to 5;

each instance of R 2 is independently hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group; each instance of R 4 is independently —C(O)O—, —C(O)NH—, or —S(O)(O)—; and each instance of R 5 is independently an alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, aryl group, heteroalkyl group, or heterocyclic group optionally comprising from 2 to 8 tertiary amines or a substituent comprising a tissue-specific or cell-specific targeting moiety

from a polymer comprising a structure of Formula 1:

wherein,

m 1 is an integer from 1 to 2000;

R 1 is a methylene or ethylene group;

R 14 is hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group;

X is a C 1 -C 12 alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, aryl group, heteroalkyl group, or heterocyclic group;

A 1 is a group of formula

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 2 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 2 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —]r 2 R 2 }; or

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 2 ] 2 } 2 ,

wherein p1 to p4, q1 to q6, and r1 and r2 are each independently an integer of 1 to 5; and

each instance of R 2 is independently hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group,

the method comprising modifying at least a portion of groups designated A 1 to produce groups designated B 1 .

6. The method of claim 5 , wherein the polymer comprising a structure of Formula 2 is a polymer of Formula 2A:

wherein,

c is an integer from 0 to 50;

L is optionally present and is a cleavable linker;

m 1 is an integer from 1 to 1000;

m 2 is an integer from 1 to 1000;

the symbol “/” indicates that the units separated thereby are linked randomly or in any order;

each R 1 independently is a methylene or ethylene group;

each instance of R 14 is independently hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group;

each instance of X is independently a C 1 -C 12 alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, aryl group, heteroalkyl group, or heterocyclic group;

A 1 is a group of formula

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 2 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 2 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —]r 2 R 2 }; or

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 2 ] 2 } 2 ,

B 1 is a group of formula

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 —(CH 2 ) 2 —R 4 —R 5 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 —(CH 2 ) 2 —R 4 —R 5 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —] r2 (CH 2 ) 2 —R 4 —R 5 };

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 —(CH 2 ) 2 —R 4 —R 5 ] 2 } 2 ;

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 —CH 2 —CHOH—R 5 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 —CH 2 —CHOH—R 5 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —] r2 —CH 2 —CHOH—R 5 ;

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 —CH 2 —CHOH—R 5 ] 2 } 2 ;

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 —(CH 2 ) 2 —R 5 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 —(CH 2 ) 2 —R 5 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —]12(CH 2 ) 2 —R 5 }; or

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 —(CH 2 ) 2 —R 5 ] 2 } 2 ,

7. A composition comprising the polymer of claim 1 and a nucleic acid and/or polypeptide.

8. A method of delivering a nucleic acid and/or polypeptide to a cell, the method comprising administering the composition of claim 7 to the cell.

9. A polymer comprising a structure of Formula 3:

wherein,

each of m 1 and n 1 is an integer from 0 to 1000; provided that the sum of m 1 +n 1 is greater than 5;

the symbol “/” indicates that the units separated thereby are linked randomly or in any order;

R 1 and R 3 each independently are a methylene or ethylene group;

each instance of R 14 is independently hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group;

each instance of X is independently a C 1 -C 12 alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, aryl group, heteroalkyl group, or heterocyclic group;

A 1 and A 2 are each independently a group of formula

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 2 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 2 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —]r 2 R 2 }; or

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 2 ] 2 } 2 ,

wherein p1 to p4, q1 to q6, and r1 and r2 are each independently an integer of 1 to 5; and

each instance of R 2 is independently hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group.

10. The polymer of claim 9 , having the structure of Formula 3A:

wherein,

c is an integer from 0 to 50;

L is optionally present and is a cleavable linker;

each of m 1 and n 1 is an integer from 0 to 1000; provided that the sum of m 1 +n 1 is greater than 5;

the symbol “/” indicates that the units separated thereby are linked randomly or in any order;

R 1 and R 3 each independently are a methylene or ethylene group;

each instance of R 14 is independently hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group;

A 1 and A 2 are each independently a group of formula

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 2 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 2 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —]r 2 R 2 }; or

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 2 ] 2 } 2 ,

wherein p1 to p4, q1 to q6, and r1 and r2 are each independently an integer of 1 to 5; each instance of X is independently a C 1 -C 12 alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, aryl group, heteroalkyl group, or heterocyclic group; and each instance of R 2 is independently hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group.

11. The polymer of claim 9 , comprising a structure of Formula 4:

wherein,

each of m 1 and n 1 is an integer from 0 to 1000;

each of m 2 and n 2 is an integer from 0 to 1000, provided that the sum of m 2 +n 2 is greater than 5;

the symbol “/” indicates that the units separated thereby are linked randomly or in any order;

each instance of R 1 and R 3 independently is a methylene or ethylene group;

each instance of R 14 is independently hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group;

each instance of X is independently a C 1 -C 12 alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, aryl group, heteroalkyl group, or heterocyclic group;

A 1 and A 2 are each independently a group of formula

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 2 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 2 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —]r 2 R 2 }; or

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 2 ] 2 } 2 ,

B 1 and B 2 are each independently

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 —(CH 2 ) 2 —R 4 —R 5 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 —(CH 2 ) 2 —R 4 —R 5 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —] r2 (CH 2 ) 2 —R 4 —R 5 };

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 —(CH 2 ) 2 —R 4 —R 5 ] 2 } 2 ;

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 —CH 2 —CHOH—R 5 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 —CH 2 —CHOH—R 5 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —] r2 —CH 2 —CHOH—R 5 ;

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 —CH 2 —CHOH—R 5 ] 2 } 2 ;

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 —(CH 2 ) 2 —R 5 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 —(CH 2 ) 2 —R 5 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —] r2 (CH 2 ) 2 —R 5 }; or

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 —(CH 2 ) 2 —R 5 ] 2 } 2 ,

wherein p1 to p4, q1 to q6, and r1 and r2 are each independently an integer of 1 to 5;

12. The polymer of claim 11 , having the structure of Formula 4A:

wherein,

c is an integer from 0 to 50;

L is optionally present and is a cleavable linker;

each of m 1 and n 1 is an integer from 0 to 1000;

each of m 2 and n 2 is an integer from 0 to 1000, provided that the sum of m 2 +n 2 is greater than 5;

the symbol “/” indicates that the units separated thereby are linked randomly or in any order;

each instance of R 1 and R 3 independently is a methylene or ethylene group;

each instance of R 14 is independently hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group;

each instance of X is independently a C 1 -C 12 alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, aryl group, heteroalkyl group, or heterocyclic group;

A 1 and A 2 are each independently a group of formula

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 2 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 2 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —]r 2 R 2 }; or

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 2 ] 2 } 2 ,

B 1 and B 2 are each independently

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 —(CH 2 ) 2 —R 4 —R 5 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 —(CH 2 ) 2 —R 4 —R 5 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —] r2 (CH 2 ) 2 —R 4 —R 5 };

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 —(CH 2 ) 2 —R 4 —R 5 ] 2 } 2 ;

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 —CH 2 —CHOH—R 5 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 —CH 2 —CHOH—R 5 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —] r2 —CH 2 —CHOH—R 5 ;

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 —CH 2 —CHOH—R 5 ] 2 } 2 ;

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 —(CH 2 ) 2 —R 5 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 —(CH 2 ) 2 —R 5 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —]12(CH 2 ) 2 —R 5 }; or

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 —(CH 2 ) 2 —R 5 ] 2 } 2 ,

wherein p1 to p4, q1 to q6, and r1 and r2 are each independently an integer of 1 to 5;

13. A method of preparing a polymer according to claim 11 comprising a structure of Formula 4:

wherein,

each of m 1 and n 1 is an integer from 0 to 1000;

each of m 2 and n 2 is an integer from 0 to 1000, provided that the sum of m 2 +n 2 is greater than 5;

the symbol “/” indicates that the units separated thereby are linked randomly or in any order;

each instance of R 1 and R 3 independently is a methylene or ethylene group;

each instance of R 14 is independently hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group;

each instance of X is independently a C 1 -C 12 alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, aryl group, heteroalkyl group, or heterocyclic group;

A 1 and A 2 are each independently a group of formula

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 2 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 2 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —]r 2 R 2 }; or

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 2 ] 2 } 2 ,

B 1 and B 2 are each independently

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 —(CH 2 ) 2 —R 4 —R 5 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 —(CH 2 ) 2 —R 4 —R 5 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —] r2 (CH 2 ) 2 —R 4 —R 5 };

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 —(CH 2 ) 2 —R 4 —R 5 ] 2 } 2 ;

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 —CH 2 —CHOH—R 5 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 —CH 2 —CHOH—R 5 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —] r2 —CH 2 —CHOH—R 5 ;

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 —CH 2 —CHOH—R 5 ] 2 } 2 ;

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 —(CH 2 ) 2 —R 5 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 —(CH 2 ) 2 —R 5 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —]12(CH 2 ) 2 —R 5 }; or

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 —(CH 2 ) 2 —R 5 ] 2 } 2 ,

wherein p1 to p4, q1 to q6, and r1 and r2 are each independently an integer of 1 to 5;

from a polymer comprising a structure of Formula 3:

wherein,

each of m 1 and n 1 is an integer from 0 to 1000; provided that the sum of m 1 +n 1 is greater than 5;

the symbol “/” indicates that the units separated thereby are linked randomly or in any order;

R 1 and R 3 each independently are a methylene or ethylene group;

each instance of R 14 is independently hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group;

A 1 and A 2 are each independently a group of formula

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 2 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 2 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —]r 2 R 2 }; or

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 2 ] 2 } 2 ,

the method comprising modifying at least a portion of groups designated A 1 and/or A 2 to produce groups designated B 1 and/or B 2 .

14. The method of claim 13 , wherein the polymer comprising a structure of Formula 4 is a polymer of Formula 4A:

wherein,

c is an integer from 0 to 50;

L is optionally present and is a cleavable linker;

each of m 1 and n 1 is an integer from 0 to 1000;

each of m 2 and n 2 is an integer from 0 to 1000, provided that the sum of m 2 +n 2 is greater than 5;

the symbol “/” indicates that the units separated thereby are linked randomly or in any order;

each instance of R 1 and R 3 independently is a methylene or ethylene group;

each instance of R 14 is independently hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group;

each instance of X is independently a C 1 -C 12 alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, aryl group, heteroalkyl group, or heterocyclic group;

A 1 and A 2 are each independently a group of formula

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 2 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 2 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —]r 2 R 2 }; or

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 2 ] 2 } 2 ,

B 1 and B 2 are each independently

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 —(CH 2 ) 2 —R 4 —R 5 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 —(CH 2 ) 2 —R 4 —R 5 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —]12(CH 2 ) 2 —R 4 —R 5 };

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 —(CH 2 ) 2 —R 4 —R 5 ] 2 } 2 ;

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 —CH 2 —CHOH—R 5 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 —CH 2 —CHOH—R 5 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —] r2 —CH 2 —CHOH—R 5 ;

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 —CH 2 —CHOH—R 5 ] 2 } 2 ;

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 —(CH 2 ) 2 —R 5 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 —(CH 2 ) 2 —R 5 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —] r2 (CH 2 ) 2 —R 5 }; or

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 —(CH 2 ) 2 —R 5 ] 2 } 2 ,

wherein p1 to p4, q1 to q6, and r1 and r2 are each independently an integer of 1 to 5;

15. A composition comprising the polymer of claim 9 and a nucleic acid and/or polypeptide.

16. A method of delivering a nucleic acid and/or polypeptide to a cell, the method comprising administering the composition of claim 15 to the cell.

17. A method of preparing a polymer according to claim 1 comprising a structure of Formula 1:

wherein,

m 1 is an integer from 1 to 2000;

R 1 is a methylene or ethylene group;

R 14 is hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group;

X is a C 1 -C 12 alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, aryl group, heteroalkyl group, or heterocyclic group;

A 1 is a group of formula

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 2 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 2 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —]r 2 R 2 }; or

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 2 ] 2 } 2 ,

wherein p1 to p4, q1 to q6, and r1 and r2 are each independently an integer of 1 to 5; and each instance of R 2 is independently hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group,

from a compound of Formula A:

wherein,

R 1 is a methylene or ethylene group;

X is a C 1 -C 12 alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, aryl group, heteroalkyl group, or heterocyclic group;

Y is —NR 14 — or —O—, wherein R 14 is hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group;

Z is A 1 , or an alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, aryl group, arylalkyl group, heteroalkyl group, or heterocyclic group optionally comprising from 2 to 8 tertiary amines or a substituent comprising a tissue-specific or cell-specific targeting moiety;

A 1 is a group of formula

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 2 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 2 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —]r 2 R 2 }; or

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 2 ] 2 } 2 ,

wherein p1 to p4, q1 to q6, and r1 and r2 are each independently an integer of 1 to 5; and

each instance of R 2 is independently hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group,

the method comprising a ring-opening polymerization of the compound Formula A.

18. The method of claim 17 , wherein the polymer comprising a structure of Formula 1 is a polymer of Formula 1A:

wherein,

c is an integer from 0 to 50;

L is optionally present and is a cleavable linker;

m 1 is an integer from 1 to 2000;

R 1 is a methylene or ethylene group;

R 14 is hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group;

X is a C 1 -C 12 alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, aryl group, heteroalkyl group, or heterocyclic group;

A 1 is a group of formula

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 2 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 2 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —]r 2 R 2 }; or

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 2 ] 2 } 2 ,

19. A method of preparing a polymer according to claim 9 comprising a structure of Formula 3:

wherein,

each of m 1 and n 1 is an integer from 0 to 1000; provided that the sum of m 1 +n 1 is greater than 5;

the symbol “/” indicates that the units separated thereby are linked randomly or in any order;

R 1 and R 3 each independently are a methylene or ethylene group;

each instance of R 14 is independently hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group;

each instance of X is independently a C 1 -C 12 alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, aryl group, heteroalkyl group, or heterocyclic group;

A 1 and A 2 are each independently a group of formula

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 2 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 2 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —]r 2 R 2 }; or

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 2 ] 2 } 2 ,

from a compound of Formula B:

wherein,

R 1 is a methylene or ethylene group;

X is a C 1 -C 12 alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, aryl group, heteroalkyl group, or heterocyclic group;

Y is —NR 14 — or —O—, wherein R 14 is hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group;

A 1 is a group of formula

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 2 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 2 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —]r 2 R 2 }; or

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 2 ] 2 } 2 ,

wherein p1 to p4, q1 to q6, and r1 and r2 are each independently an integer of 1 to 5; and

each instance of R 2 is independently hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group,

the method comprising a ring-opening polymerization of the compound formula B.

20. The method of claim 19 , wherein the polymer comprising a structure of Formula 3 is a polymer of Formula 3A:

wherein,

c is an integer from 0 to 50;

L is optionally present and is a cleavable linker;

each of m 1 and n 1 is an integer from 0 to 1000; provided that the sum of m 1 +n 1 is greater than 5;

the symbol “/” indicates that the units separated thereby are linked randomly or in any order;

R 1 and R 3 each independently are a methylene or ethylene group;

each instance of R 14 is independently hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group;

A 1 and A 2 are each independently a group of formula

—(CH 2 ) p1 —[NR 2 —(CH 2 ) q1 —] r1 NR 2 2 ;

—(CH 2 ) p2 —N[—(CH 2 ) q2 —NR 2 2 ] 2 ;

—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NR 2 2 ][—(CH 2 ) q4 —NR 2 —]r 2 R 2 }; or

—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NR 2 2 ] 2 } 2 ,

wherein p1 to p4, q1 to q6, and r1 and r2 are each independently an integer of 1 to 5;

each instance of X is independently a C 1 -C 12 alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, aryl group, heteroalkyl group, or heterocyclic group, or cycloalkenyl group; and each instance of R 2 is independently hydrogen or a C 1 -C 12 alkyl group, alkenyl group, cycloalkyl group, or cycloalkenyl group.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 2, 2021

From: LEE, KUNWOO; MAITY, SANTANU

To: GENEDIT INC.

Reel/Frame 056419/0903 →

Continuity (2)

Provisional Application 62750123 · Oct 24, 2018

Related Publication 20210371590A1 · Dec 2, 2021

Cited By (2)

US 12,344,709 US 12,415,891