Polyacetal polymers, conjugates, particles and uses thereof

1. A conjugate, comprising:

a polyacetal polymer;

an agent, and

(optionally) a targeting moiety;

wherein the polyacetal polymer, and the agent and/or a targeting moiety are coupled; and

the conjugate has a hydrodynamic diameter of about 10 nm to 50 nm, and has at least one of the following properties:

(i) the conjugate shows a ratio of release or degradation rate at pH=6.7 relative to pH=7.4 that is greater than 1.5;

(ii) the conjugate shows increased pH-sensitivity in a hypoxic microenvironment;

(iii) the conjugate is sparingly soluble or slightly soluble in water; or

(iv) the polyacetal polymer has a melting temperature (T m ) of about 35° C. or greater,

wherein the polyacetal polymer comprises a structure according to Formula (I-c):

wherein:

each of A 1 and A 2 is independently represented by a structure of Formula (II-d), Formula (II-e), Formula (II-f), Formula (II-g), Formula (II-h), Formula (II-i), or Formula (II-j);

each of B 1 and B 2 is independently represented by a structure of Formula (III-a);

each of C 1 and C 2 is heteroalkyl, cyclyl, or heterocyclyl, each of which is optionally substituted with 1-6 R 3 ;

each of R 3 is independently alkyl, alkenyl, alkynyl, hydroxyl, halo, heteroalkyl, keto, alkoxy, ester, cyclyl, heterocyclyl, cycloalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, a linker, an agent, a targeting moiety, or a branching point;

each of m or n is independently an integer from 1 to 200; and

wherein the structures of Formula (II-d), Formula (II-e), Formula (II-f), Formula (II-g), Formula (II-h), Formula (II-i), and Formula (II j) are represented by:

wherein:

X 1 is C 1 -C 12 alkylene, C 1 -C 12 heteroalkylene, C 3 -C 8 cyclyl, or C 3 -C 8 heterocyclyl, wherein each alkylene, heteroalkylene, cyclyl, and heterocyclyl is optionally substituted with 1-6 R 4b ;

R 4a is C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, O, (C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-C(O)—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-C(O)O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-NR 6 —(C 1 -C 6 alkylene)-O—, (C 1 -C 6 alkylene)-C(O)NR 6 —(C 1 -C 6 alkylene)-O, or (C 1 -C 6 alkylene)-NR 6 C(O)—(C 1 -C 6 alkylene)-O, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, or alkylene is optionally substituted with 1-6 R 7 ;

each R 4b is independently C 1 -C 6 alkyl, (C 1 -C 6 alkylene)-O-L-losartan, (C 1 -C 6 alkylene)-O-L-valsartan, (C 1 -C 6 alkylene)-O-L-telmisartan, (C 1 -C 6 alkylene)-O-L-candesartan, or (C 1 -C 6 alkylene)-O-L-olmesartan;

L is absent or comprises an acetal, ketal, anhydride, ester, hydrazone, or silyl ether;

R 6 is hydrogen or C 1 -C 6 alkyl; and

each R 7 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, halo, O-L-losartan, O-L-valsartan, O-L-telmisartan, O-L-candesartan, O-L-olmesartan, (C 1 -C 6 alkylene)-O-L-losartan, (C 1 -C 6 alkylene)-O-L-valsartan, (C 1 -C 6 alkylene)-O-L-telmisartan, (C 1 -C 6 alkylene)-O-L-candesartan, (C 1 -C 6 alkylene)-O-L-olmesartan, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O-L-losartan, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O-L-valsartan, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O-L-telmisartan, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O-L-candesartan, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O-L-olmesartan, cyano, cyclyl, heterocyclyl, aryl, or heteroaryl;

and the structure of Formula (III-a) is represented by:

wherein:

Z 1 is O, C 3 -C 8 cyclyl, or C(R 22 )(R 23 );

each of X 4 and X 5 is independently C 1 -C 6 alkylene;

each of R 20 and R 21 is independently C 1 -C 6 alkyl or OR 20 ;

each of R 22 and R 23 is independently hydrogen, C 1 -C 6 alkyl, or (C 1 -C 6 alkylene)-OR 26 ;

and each R 26 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, a linker, an agent, a targeting moiety, a protecting group, or a branching point, and

wherein: (i) for Formula (II-e), Formula (II-f), Formula (II-g), Formula (II-h), or Formula (II-i), X 1 is C 3 -C 6 cyclyl, optionally substituted with 1-6 R 4 ; or (ii) for Formula (II-e), Formula (II-f), Formula (II-g), Formula (II-h), or Formula (II-i), each R 4a is independently C 1 -C 6 alkyl, O, (C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-C(O)—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-C(O)O—(C 1 -C 6 alkylene)-O, or (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-O.

2. The conjugate of claim 1 comprised in a particle, wherein the particle has a hydrodynamic diameter of less than about 100 nm and has at least one of the following properties:

(i) the particle shows a ratio of release or degradation rate at pH=6.7 relative to pH=7.4 that is greater than 1.5;

(ii) the particle shows increased pH-sensitivity in a hypoxic microenvironment;

(iii) the particle is slightly soluble or very slightly soluble in water; or

(iv) the polyacetal polymer has a melting temperature (T m ) of about 35° C. or greater.

3. The conjugate of claim 1 , wherein for Formula (II-e), Formula (II-f), Formula (II-g), Formula (II-h), or Formula (II-i), X 1 is C 3 -C 6 cyclyl, optionally substituted with 1-6 R 4 .

4. The conjugate of claim 1 , wherein for Formula (II-e), Formula (II-f), Formula (II-g), Formula (II-h), or Formula (II-i), each R 4a is independently C 1 -C 6 alkyl, O, (C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-C(O)—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-OC(O)—(C 1 -C 6 alkylene)-O, (C 1 -C 6 alkylene)-C(O)O—(C 1 -C 6 alkylene)-O, or (C 1 -C 6 alkylene)-OC(O)O—(C 1 -C 6 alkylene)-O.

5. The conjugate of claim 1 , wherein for Formula Z 1 is C(R 23 )(R 24 ) and each of R 22 and R 23 is independently hydrogen, C 1 -C 6 alkyl, or (C 1 -C 6 alkylene)-OR 26 .

6. The conjugate of claim 1 , wherein for Formula (III-a), R 22 is hydrogen or C 1 -C 6 alkyl, R 23 is independently C 1 -C 6 alkyl or C 1 -C 2 alkylene)-OR 26 and R 26 is C 2 -C 6 alkenyl or a branching point.

7. The conjugate of claim 1 , wherein a precursor to each of B 1 and B 2 is independently selected from the following vinyl ethers:

8. The conjugate of claim 1 wherein each of C 1 and C 2 is independently a polyethylene glycol (PEG) and is between about 200 and 4000 Da in size.

9. The conjugate of claim 1 , wherein the polymer, the linker, the agent and/or targeting moiety in the conjugate are covalently coupled via a linker.

10. The conjugate of claim 9 , wherein the linker is a polyacetal polymer.

11. The conjugate of claim 1 , wherein the agent is a therapeutic agent and/or a diagnostic agent.

12. The conjugate of claim 1 , wherein the conjugate has at least two of the following properties:

(i) the conjugate shows a ratio of release or degradation rate at pH=6.7 relative to pH=7.4 that is greater than 1.5;

(ii) the conjugate shows increased pH-sensitivity in a hypoxic microenvironment;

(iii) the conjugate is sparingly soluble or slightly soluble in water; or

(iv) the polyacetal polymer has a melting temperature (T m ) of about 35° C. or greater.

13. A composition comprising one or more of the conjugates of claim 1 and a pharmaceutically acceptable carrier.

14. A method of treating a hyperproliferative and/or fibrotic disorder in a subject, or of improving the delivery and/or efficacy of a therapy-in a subject, the method comprising:

administering a particle according to claim 2 , as a single agent or in combination, to the subject;

administering the therapy,

under conditions sufficient to treat or prevent the disorder or condition in the subject, or to improve the delivery and/or efficacy of the therapy provided to the subject.