Biomolecule-polymer-pharmaceutical agent conjugates for delivering the pharmaceutical agent

1. An end-functionalized polymer of Formula (III):

or a tautomer, isotopically labeled polymer, or salt thereof, wherein:

B 1 is a brush polymer or star polymer;

L 1 is substituted or unsubstituted, C 1-1000 alkylene, substituted or unsubstituted, C 2-1000 alkenylene, substituted or unsubstituted, C 2-1000 alkynylene, substituted or unsubstituted, C 1-1000 heteroalkylene, substituted or unsubstituted, C 2-1000 heteroalkenylene, or substituted or unsubstituted, C 2-1000 heteroalkynylene;

optionally wherein one or more backbone carbon atoms of the C 1-1000 alkylene, C 2-1000 alkenylene, C 2-1000 alkynylene, C 1-1000 heteroalkylene, C 2-1000 heteroalkenylene, or C 2-1000 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits;

E 1 is a thiophile, a first click-chemistry handle, a nucleophile, an electrophile, or a leaving group, H, halogen, substituted or unsubstituted, C 1-6 alkyl, substituted or unsubstituted, C 2-6 alkenyl, substituted or unsubstituted, C 2-6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —NO 2 , —N 3 , —NR a C(═O)R a ,—NR a C(═O)OR a ,—NR a C(═O)N(R a ) 2 ,—NR a C(═NR a )R a , —NR a C(═NR a )OR a ,—NR a C(═NR a )N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , —OC(═O)N(R a ) 2 , —OC(═NR a )R a , —OC(═NR a )OR a , —OC(═NR a )N(R a ) 2 ,—NR a S(═O) 2 R a , —NR a S(═O) 2 OR a , —NR a S(═O) 2 N(R a ) 2 , —OS(═O)R a , —OS(═O)OR a , —OS(═O)N(R a ) 2 , —S(═O)R a , —S(═O)OR a , —S(═O)N(R a ) 2 , —OS(═O) 2 R a , —OS(═O) 2 OR a , —OS(═O) 2 N(R a ) 2 , —S(═O) 2 R a , —S(═O) 2 OR a , —S(═O) 2 N(R a ) 2 , or —P(═O)(R a ) 2 ; and

each instance of R a is independently H, substituted or unsubstituted, C 1-6 alkyl, substituted or unsubstituted, C 2-6 alkenyl, substituted or unsubstituted, C 2-6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R a attached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl.

2. A method of preparing an end-functionalized polymer of claim 1 , or a tautomer, isotopically labeled polymer, or salt thereof, the method comprising reacting a living polymer of Formula (B):

with an enyne of Formula II:

or a tautomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof, wherein:

X 1 is S, O, Se, or a single bond;

R 11 is substituted or unsubstituted, C 1-18 alkyl;

each of R 12 , R 13 , R 14 , and R 15 is independently H, halogen, substituted or unsubstituted, C 1-6 alkyl, —O-(substituted or unsubstituted, C 1-6 alkyl), substituted or unsubstituted carbocyclyl, or substituted or unsubstituted aryl;

R 16 is H or substituted or unsubstituted, C 1-6 alkyl;

R 18 is H or substituted or unsubstituted, C 1-6 alkyl;

each instance of R 17 is independently H or substituted or unsubstituted, C 1-6 alkyl;

or R 16 and one instance of R 17 are joined with their intervening atoms to form substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;

L 2 is —C(═O)—, —S(═O) 2 —, —S(═O)—, or a single bond;

L 3 is substituted or unsubstituted, C 1-1000 alkylene, substituted or unsubstituted, C 2-1000 alkenylene, substituted or unsubstituted, C 2-1000 alkynylene, substituted or unsubstituted, C 1-1000 heteroalkylene, substituted or unsubstituted, C 2-1000 heteroalkenylene, substituted or unsubstituted, C 2-1000 heteroalkynylene, or a single bond;

optionally wherein one or more backbone carbon atoms of the C 1-1000 alkylene, C 2-1000 alkenylene, C 2-1000 alkynylene, C 1-1000 heteroalkylene, C 2-1000 heteroalkenylene, or C 2-1000 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits; and

at least one of L 2 and L 3 is not a single bond.

3. The end-functionalized polymer or a tautomer, isotopically labeled polymer, or salt thereof of claim 1 prepared by a method comprising:

(a) metathesis polymerizing one or more types of monomers in the presence of a metathesis catalyst to form a living polymer of Formula (B):

wherein each instance of the monomers comprises one or more non-aromatic alkenyl and/or one or more alkynyl; and

(b) reacting the living polymer with an enyne of Formula II:

or a tautomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof, wherein:

X 1 is S, O, Se, or a single bond;

R 11 is substituted or unsubstituted, C 1-18 alkyl;

each of R 12 , R 13 , R 14 , and R 15 is independently H, halogen, substituted or unsubstituted, C 1-6 alkyl, —O-(substituted or unsubstituted, C 1-6 alkyl), substituted or unsubstituted carbocyclyl, or substituted or unsubstituted aryl;

R 16 is H or substituted or unsubstituted, C 1-6 alkyl;

R 18 is H or substituted or unsubstituted, C 1-6 alkyl;

each instance of R 17 is independently H or substituted or unsubstituted, C 1-6 alkyl;

or R 16 and one instance of R 17 are joined with their intervening atoms to form substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;

L 2 is —C(═O)—, —S(═O) 2 —, —S(═O)—, or a single bond;

L 3 is substituted or unsubstituted, C 1-1000 alkylene, substituted or unsubstituted, C 2-1000 alkenylene, substituted or unsubstituted, C 2-1000 alkynylene, substituted or unsubstituted, C 1-1000 heteroalkylene, substituted or unsubstituted, C 2-1000 heteroalkenylene, substituted or unsubstituted, C 2-1000 heteroalkynylene, or a single bond;

optionally wherein one or more backbone carbon atoms of the C 1-1000 alkylene, C 2 -1000 alkenylene, C 2-1000 alkynylene, C 1-1000 heteroalkylene, C 2-1000 heteroalkenylene, or C 2-1000 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits; and

at least one of L 2 and L 3 is not a single bond.

4. The end-functionalized polymer of claim 1 , or a tautomer, isotopically labeled polymer, or salt thereof, wherein B 1 is a brush polymer.

5. The end-functionalized polymer of claim 3 , or a tautomer, isotopically labeled polymer, or salt thereof, wherein at least one instance of the monomers is of Formula (A):

or a tautomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof, wherein:

each instance of R A is independently H, halogen, or substituted or unsubstituted, C 1-6 alkyl;

each instance of a is independently an integer from 0 to 20, inclusive;

each instance of R 1 is independently H, halogen, or substituted or unsubstituted, C 1-6 alkyl, or two R 1 attached to the same carbon atom are taken together to form oxo;

each instance of R 2 is independently H, halogen, or substituted or unsubstituted, C 1-6 alkyl, or two R 2 attached to the same carbon atom are taken together to form oxo;

each instance of L is substituted or unsubstituted, C 1-1000 alkylene, substituted or unsubstituted, C 2-1000 alkenylene, substituted or unsubstituted, C 2-1000 alkynylene, substituted or unsubstituted, C 1-1000 heteroalkylene, substituted or unsubstituted, C 2-1000 heteroalkenylene, or substituted or unsubstituted, C 2-1000 heteroalkynylene;

optionally wherein one or more backbone carbon atoms of the C 1-1000 alkylene, C 2 -1000 alkenylene, C 2-1000 alkynylene, C 1-1000 heteroalkylene, C 2-1000 heteroalkenylene, or C 2-1000 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as valency permits;

each instance of M is independently a pharmaceutical agent;

each instance of m is independently an integer from 1 to 10, inclusive;

each instance of RB is independently H, halogen, or substituted or unsubstituted, C 1-6 alkyl;

each instance of b is independently an integer from 0 to 20, inclusive;

each instance of e is independently an integer from 1 to 10, inclusive;

each instance of X is —ORC or —N(R D ) 2 ;

each instance of R C is independently H, substituted or unsubstituted, C 1-1000 alkyl, substituted or unsubstituted, C 2-1000 alkenyl, substituted or unsubstituted, C 2-1000 alkynyl, substituted or unsubstituted, C 1-1000 heteroalkyl, substituted or unsubstituted, C 2-1000 heteroalkenyl, substituted or unsubstituted, C 2-1000 heteroalkynyl, an oxygen protecting group, or a leaving group; and

each instance of R D is independently H, substituted or unsubstituted, C 1-1000 alkyl, substituted or unsubstituted, C 2-1000 alkenyl, substituted or unsubstituted, C 2-1000 alkynyl, substituted or unsubstituted, C 1-1000 heteroalkyl, substituted or unsubstituted, C 2-1000 heteroalkenyl, substituted or unsubstituted, C 2-1000 heteroalkynyl, or a nitrogen protecting group, or two R D attached to the same nitrogen atom are taken together with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl.

6. The end-functionalized polymer of claim 4 , or a tautomer, isotopically labeled polymer, or salt thereof, wherein L 1 is

wherein:

each instance of q is independently an integer from 1 to 10, inclusive;

each instance of r1 is independently an integer from 2 to 40, inclusive;

each instance of s is independently 0 or 1;

each instance of t is independently an integer from 0 to 10, inclusive; and

the attachment point marked with “*” is attached to E 1 .

7. The end-functionalized polymer claim 4 , or a tautomer, isotopically labeled polymer, or salt thereof, wherein E 1 is

or —OS(═O) 2 (substituted or unsubstituted phenyl or substituted or unsubstituted, C 1-6 alkyl).

8. The end-functionalized polymer of claim 4 , or a tautomer, isotopically labeled polymer, or salt thereof, wherein E 1 is a first click-chemistry handle.

9. The end-functionalized polymer of claim 4 , or a tautomer, isotopically labeled polymer, or salt thereof, wherein E 1 is —N 3 .

10. The end-functionalized polymer of claim 4 , or a tautomer, isotopically labeled polymer, or salt thereof, wherein E 1 is trans-cyclooctenyl.

11. The end-functionalized polymer of claim 4 , or a tautomer, isotopically labeled polymer, or salt thereof, wherein E 1 is

wherein R 19 is H, halogen, unsubstituted C 1-6 alkyl, or —O-(unsubstituted C 1-6 alkyl).

12. The end-functionalized polymer of claim 4 , or a tautomer, isotopically labeled polymer, or salt thereof, wherein L 1 is unsubstituted C 1-1000 heteroalkylene.

13. The end-functionalized polymer of claim 12 , or a tautomer, isotopically labeled polymer, or salt thereof, wherein E 1 is substituted or unsubstituted carbocyclyl.

14. The end-functionalized polymer of claim 12 , or a tautomer, isotopically labeled polymer, or salt thereof, wherein E 1 is a thiophile or a first click-chemistry handle.

15. The end-functionalized polymer of claim 5 , or a tautomer, isotopically labeled polymer, or salt thereof, wherein L 1 is unsubstituted C 1-1000 heteroalkylene.

16. The end-functionalized polymer of claim 15 , or a tautomer, isotopically labeled polymer, or salt thereof, wherein E 1 is substituted or unsubstituted carbocyclyl.

17. The end-functionalized polymer of claim 15 , or a tautomer, isotopically labeled polymer, or salt thereof, wherein E 1 is a thiophile or a first click-chemistry handle.

18. The end-functionalized polymer of claim 4 , or a tautomer, isotopically labeled polymer, or salt thereof, wherein end-functionalized polymer is of the formula:

19. The end-functionalized polymer of claim 18 , or a tautomer, isotopically labeled polymer, or salt thereof, wherein the end-functionalized polymer is of the formula:

20. The end-functionalized polymer of claim 7 , or a tautomer, isotopically labeled polymer, or salt thereof, wherein L 1 is

wherein:

each instance of q is independently an integer from 1 to 10, inclusive;

each instance of r1 is independently an integer from 2 to 40, inclusive;

each instance of s is independently 0 or 1;

each instance of t is independently an integer from 0 to 10, inclusive; and

the attachment point marked with “*” is attached to E 1 .

21. The end-functionalized polymer of claim 8 , or a tautomer, isotopically labeled polymer, or salt thereof, wherein L 1 is

wherein:

each instance of q is independently an integer from 1 to 10, inclusive;

each instance of r1 is independently an integer from 2 to 40, inclusive;

each instance of s is independently 0 or 1;

each instance of t is independently an integer from 0 to 10, inclusive; and

the attachment point marked with “*” is attached to E 1 .

22. The end-functionalized polymer of claim 9 , or a tautomer, isotopically labeled polymer, or salt thereof, wherein L 1 is

wherein:

each instance of q is independently an integer from 1 to 10, inclusive;

each instance of r1 is independently an integer from 2 to 40, inclusive;

each instance of s is independently 0 or 1;

each instance of t is independently an integer from 0 to 10 , inclusive; and

the attachment point marked with “*” is attached to E 1 .

23. The end-functionalized polymer of claim 10 , or a tautomer, isotopically labeled polymer, or salt thereof, wherein L 1 is

wherein:

each instance of q is independently an integer from 1 to 10, inclusive;

each instance of r1 is independently an integer from 2 to 40, inclusive;

each instance of s is independently 0 or 1;

each instance of t is independently an integer from 0 to 10, inclusive; and

the attachment point marked with “*” is attached to E 1 .

24. The end-functionalized polymer of claim 11 , or a tautomer, isotopically labeled polymer, or salt thereof, wherein L 1 is

wherein:

each instance of q is independently an integer from 1 to 10, inclusive;

each instance of r1 is independently an integer from 2 to 40, inclusive;

each instance of s is independently 0 or 1;

each instance of t is independently an integer from 0 to 10, inclusive; and

the attachment point marked with “*” is attached to E 1 .

25. The end-functionalized polymer of claim 5 , or a tautomer, isotopically labeled polymer, or salt thereof, wherein L 1 is:

wherein:

each instance of q is independently an integer from 1 to 10, inclusive;

each instance of r1 is independently an integer from 2 to 40, inclusive;

each instance of s is independently 0 or 1;

each instance of t is independently an integer from 0 to 10, inclusive; and

the attachment point marked with “*” is attached to E 1 .

26. The end-functionalized polymer of claim 25 , or a tautomer, isotopically labeled polymer, or salt thereof, wherein E 1 is

—OS(═O) 2 (substituted or unsubstituted phenyl or substituted or unsubstituted, C 1-6 alkyl).

27. The end-functionalized polymer of claim 25 , or a tautomer, isotopically labeled polymer, or salt thereof, wherein E 1 is a first click-chemistry handle.

28. The end-functionalized polymer of claim 25 , or a tautomer, isotopically labeled polymer, or salt thereof, wherein E 1 is −N 3 .

29. The end-functionalized polymer of claim 25 , or a tautomer, isotopically labeled polymer, or salt thereof, wherein E 1 is trans-cyclooctenyl.

30. The end-functionalized polymer of claim 25 , or a tautomer, isotopically labeled polymer, or salt thereof, wherein E 1 is

wherein R 19 is H, halogen, unsubstituted C 1-6 alkyl, or —O—(unsubstituted C 1-6 alkyl).