Drug loaded peptide brush polymers

1 . A polymer comprising:

a plurality of repeating units, each repeating unit comprising a polymer backbone group directly or indirectly covalently linked to one or two side chain moieties, the polymer is of formula FX1:

Q 1 -[M(Z) u ] n -Q 2   (FX1);

wherein:

n is an integer selected from a range of 2 to 1000;

u is 1 or 2;

each M is independently the polymer backbone group of one of the repeating units and each M is independently a ROMP-polymerized monomer;

each Z is independently one of the one or two side chain moieties and each Z independently comprises a peptide moiety or a non-peptide therapeutic moiety;

each Z is independently directly or indirectly covalently attached to an M;

each M is covalently attached to at least one other M and each M is independently directly or indirectly covalently attached to one or two of Z, such that 100% of the ROMP-polymerized monomers (M) are each individually attached to one or two side chain moieties (Z);

Q 1 is a first polymer-terminating group;

Q 2 is a second polymer-terminating group;

the polymer comprises a plurality of peptide moieties;

at least one Z of the polymer comprises a non-peptide therapeutic moiety, Q 1 comprises a non-peptide therapeutic moiety, and/or Q 2 comprises a non-peptide therapeutic moiety;

wherein the polymer comprises at least two peptide moieties; and

wherein the at least two peptide moieties include at least two unique peptide moieties.

2 . The polymer of claim 1 , wherein n and a fraction (“P”) of all side chain moieties in the polymer that are side chain moieties comprising a peptide moiety are selected to provide for cellular uptake.

3 . The polymer of claim 2 , wherein cellular uptake of the polymer is provided by a combination of parameters n, P, and peptide moiety charge.

4 . The polymer of claim 1 , wherein Q 1 , Q 2 , or a combination thereof, comprises a non-peptide therapeutic moiety.

5 . The polymer of claim 1 , wherein at least one of the plurality of peptide moieties is a non-cell-penetrating peptide or a therapeutic peptide.

6 . The polymer of claim 1 , wherein at least one of the plurality of peptide moieties comprises a sequence having 80% or greater sequence homology of GGSGSGS (SEQ ID NO:1), GGSGSGE (SEQ ID NO:2), GGSGSGK (SEQ ID NO:3), GGSGSGR (SEQ ID NO:4), GGSGSGRR (SEQ ID NO:5), or a combination thereof.

7 . The polymer of claim 1 , wherein at least one of the plurality of peptide moieties has a positive charge.

8 . The polymer of claim 1 , wherein the polymer has a net positive charge.

9 . The polymer of claim 1 , wherein at least one of the plurality of peptide moieties is a positively charged peptide moiety, and wherein a cell uptake efficiency of the polymer is higher due to the presence of the at least one positively charged peptide moiety, compared to a cell uptake efficiency of an equivalent polymer free of a positively charged group.

10 . The polymer of claim 1 , wherein each of a number of peptide moieties corresponding to at least a fraction of the plurality of peptide moieties is a hydrophilic peptide such that the polymer is hydrophilic.

11 . The polymer of claim 1 , wherein each M is independently a ROMP-polymerized substituted or unsubstituted norbornene or a ROMP-polymerized substituted or unsubstituted oxanorbornene monomer.

12 . The polymer of claim 1 , wherein the polymer is of formula FX2a or FX2b:

wherein:

each of L 1 and L 2 is independently a covalent linking group;

each of Z, Z 1 , and Z 2 is independently one of the one or two side chain moieties;

n is an integer selected from a range of 2 to 1000; and

w is 1 or 0.

13 . The polymer of claim 12 , wherein each of L 1 and L 2 is independently selected from a single bond, an oxygen, and one or more substituted or unsubstituted groups having an alkyl group, an alkenylene group, an arylene group, an alkoxy group, an acyl group, a carboxyl group, an aliphatic group, an amide group, an aryl group, an amine group, an ether group, a ketone group, an ester group, a triazole group, a diazole group, a pyrazole group, or combinations thereof.

14 . The polymer of claim 1 , wherein each M covalently attached to one or two side chain moieties is of formula FX3a, FX3b, FX3c, FX3d, FX3e, FX3f, FX3g, or FX3h:

wherein each of L 3 and L 4 is optionally present, and is independently a covalent linking group; and

wherein each of Z 1 and Z 2 is independently one of the one or two side chain moieties.

15 . The polymer of claim 14 , wherein each of L 3 and L 4 is independently selected from a single bond, an oxygen, and one or more substituted or unsubstituted groups having an alkyl group, an alkenylene group, an arylene group, an alkoxy group, an acyl group, a carboxyl group, an aliphatic group, an amide group, an aryl group, an amine group, an ether group, a ketone group, an ester group, a triazole group, a diazole group, a pyrazole group, or combinations thereof.

16 . The polymer of claim 1 , wherein Q 1 and/or Q 2 is of formula FX4a or FX4b:

wherein:

T is a non-peptide therapeutic moiety; and

L 6 is a covalent linking group selected from a single bond, an oxygen, and one or more substituted or unsubstituted groups having an alkyl group, an alkenylene group, an arylene group, an alkoxy group, an acyl group, a carboxyl group, an aliphatic group, an amide group, an aryl group, an amine group, an ether group, a ketone group, an ester group, a triazole group, a diazole group, a pyrazole group, or combinations thereof.

17 . The polymer of claim 16 , wherein L 6 is of formula FX5a, FX5b, FX5c, FX5d, FX5e, FX5f, FX5g, or any combination thereof:

wherein:

q is an integer selected from a range of 1 to 10; and

L 5 is a covalent linking group.

18 . The polymer of claim 1 , wherein Q 1 and/or Q 2 is of formula FX6a, FX6b, FX6c, or FX6d:

wherein T is a non-peptide therapeutic moiety.

19 . The polymer of claim 1 , wherein the non-peptide therapeutic moiety is a therapeutic agent and is not a diagnostic agent.

20 . The polymer of claim 1 , wherein the non-peptide therapeutic moiety is a cell growth or proliferation inhibitory agent, an anti-inflammatory agent, an anti-tumor or anti-cancer agent, an anti-apoptotic agent, anti-diabetic agent, anti-obesity agent, anti-infective agent, anti-bacterial agent, anti-viral agent, an agent for promoting cell growth and differentiation, an agent for preventing pain, an agent for preventing or treating neural degeneration, an agent for promoting neurogenesis; an immunosuppressant agent, an immunostimulant agent, an MMP-inhibitor agent, a corticosteroid, an anti-angiogenic agent, a pro-angiogenic agent, an NSAID, paclitaxel, or a combination thereof.

21 . The polymer of claim 1 , wherein each non-peptide therapeutic moiety is released from the polymer when the polymer is exposed to an acidic solution.

22 . The polymer of claim 1 , wherein the polymer has a polydispersity index of less than 1.5.

23 . A liquid composition comprising an aqueous plurality of polymers, each polymer is according to claim 1 , wherein the liquid composition is a therapeutic formulation having a therapeutically effective concentration of the aqueous plurality of polymers, wherein the therapeutic formulation is free of polymers that do not include the non-peptide therapeutic moiety.

24 . The liquid composition of claim 23 , wherein each polymer of the aqueous plurality of polymers is individually solvated by water.

25 . A method of treating or managing a condition in a subject comprising:

administering to a subject an effective amount of a polymer comprising:

a plurality of repeating units, each repeating unit comprising a polymer backbone group directly or indirectly covalently linked to one or two side chain moieties, the polymer is of formula FX1:

Q 1 -[M(Z) u ] n -Q 2   (FX1);

wheren:

n is an integer selected from a range of 2 to 1000;

u is 1 or 2;

each M is independently the polymer backbone group of one of the repeating units and each M is independently a ROMP-polymerized monomer;

each Z is independently one of the one or two side chain moieties (Z) and each Z independently comprises a peptide moiety or a non-peptide therapeutic moiety; wherein the polymer comprises a plurality of peptide moieties;

each Z is independently directly or indirectly covalently attached to an M;

each M is covalently attached to at least one other M and each M is independently directly or indirectly covalently attached to one or two of Z, such that 100% of the ROMP-polymerized monomers are each individually attached to one or two side chain moieties;

Q 1 is a first polymer-terminating group;

Q 2 is a second polymer-terminating group;

at least one Z of the polymer comprises a non-peptide therapeutic moiety, Q 1 comprises a non-peptide therapeutic moiety, and/or Q 2 comprises a non-peptide therapeutic moiety;

wherein the polymer comprises at least two peptide moieties; and

wherein the at least two peptide moieties include at least two unique peptide moieties.

26 . The method of claim 25 , wherein the condition is myocardial ischemia, acute myocardial infarction, heart failure, rheumatoid arthritis, articular cartilage damage, acute and/or chronic epidermal wound, liver failure, nerve damage, acute brain injury, spinal disk injury, or a combination thereof.

27 . A method of treating or managing a condition in a subject comprising:

administering to the subject an effective amount of a liquid composition having water and a plurality of aqueous polymers; wherein each of the aqueous polymers independently comprises:

a plurality of repeating units, each repeating unit comprising a polymer backbone group directly or indirectly covalently linked to one or two side chain moieties, the polymer is of formula FX1:

Q 1 -[M(Z) u ] n -Q 2   (FX1);

wherein:

n is an integer selected from a range of 2 to 1000;

u is 1 or 2;

each M is independently the polymer backbone group of one of the repeating units and each M is independently a ROMP-polymerized monomer;

each Z is independently one of the one or two side chain moieties (Z) and each Z independently comprises a peptide moiety or a non-peptide therapeutic moiety; wherein the polymer comprises a plurality of peptide moieties;

each Z is independently directly or indirectly covalently attached to an M;

each M is covalently attached to at least one other M and each M is independently directly or indirectly covalently attached to one or two of Z, such that 100% of the ROMP-polymerized monomers are each individually attached to one or two side chain moieties;

Q 1 is a first polymer-terminating group;

Q 2 is a second polymer-terminating group;

at least one Z of the polymer comprises a non-peptide therapeutic moiety, Q 1 comprises a non-peptide therapeutic moiety, and/or Q 2 comprises a non-peptide therapeutic moiety;

wherein the polymer comprises at least two peptide moieties; and

wherein the at least two peptide moieties include at least two unique peptide moieties.

28 . A method for synthesizing a polymer, the method comprising steps of:

ROMP-polymerizing of a plurality of monomers, each monomer being directly or indirectly covalently attached to at least one side chain moiety; and

terminating ROMP-polymerization with a chain termination agent, wherein the chain termination agent comprises a non-peptide therapeutic moiety;

wherein a synthesized polymer comprises:

a plurality of repeating units, each repeating unit comprising a polymer backbone group directly or indirectly covalently linked to one or two side chain moieties, the polymer is of formula FX1:

Q 1 -[M(Z) u ] n -Q 2   (FX1);

where:

n is an integer selected from a range of 2 to 1000;

u is 1 or 2;

each M is independently the polymer backbone group of one of the repeating units and each M is independently a ROMP-polymerized monomer;

each Z is independently one of the one or two side chain moieties and each Z independently comprises a peptide moiety or a non-peptide therapeutic moiety; wherein the polymer comprises a plurality of peptide moieties;

each Z is independently directly or indirectly covalently attached to an M;

each M is covalently attached to at least one other M and each M is independently directly or indirectly covalently attached to one or two of Z, such that 100% of the ROMP-polymerized monomers are each individually attached to one or two side chain moieties;

Q 1 is a first polymer-terminating group;

Q 2 is a second polymer-terminating group; and

Q 1 comprises a non-peptide therapeutic moiety and/or Q 2 comprises a non-peptide therapeutic moiety;

wherein the polymer comprises at least two peptide moieties; and

wherein the at least two peptide moieties include at least two unique peptide moieties.

29 . The method of claim 28 , wherein the chain termination agent is of formula FX7a or FX7b:

wherein:

r is 0 or 1;

if r is 1, each of L 1 and L 2 is independently a covalent linker group selected from a single bond, oxygen, C 2 -C 10 alkenylene, C 3 -C 10 arylene, and one or more substituted or unsubstituted groups having an alkyl group, an alkenylene group, an arylene group, an alkoxy group, an acyl group, a carboxyl group, an aliphatic group, an amide group, an aryl group, an amine group, an ether group, a ketone group, an ester group, a triazole group, a diazole group, a pyrazole group, or combinations thereof;

if r is 0, each of L 2 is selected from a C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 acyl, or combinations thereof, and

each of T 1 and T 2 is independently a non-peptide therapeutic moiety.

30 . The method of claim 29 , wherein the chain termination agent is of formula FX7c, FX7d, FX7e, FX7f, FX7g, FX7h, FX7i, or FX7j: