Polyacetal polymers, conjugates, particles and uses thereof

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 (Tm) of about 35° C. or greater,
• wherein the polyacetal polymer comprises a structure according to Formula (I-c):
• wherein:
• each of A1 and A2 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 B1 and B2 is independently represented by a structure of Formula (III-a);
• each of C1 and C2 is heteroalkyl, cyclyl, or heterocyclyl, each of which is optionally substituted with 1-6 R3;
• each of R3 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:
• X1 is C1-C12 alkylene, C1-C12 heteroalkylene, C3-C8 cyclyl, or C3-C8 heterocyclyl, wherein each alkylene, heteroalkylene, cyclyl, and heterocyclyl is optionally substituted with 1-6 R4b;
• R4a is C2-C6 alkenyl, C1-C6 heteroalkyl, O, (C1-C6 alkylene)-O, (C1-C6 alkylene)-O—(C1-C6 alkylene)-O, (C1-C6 alkylene)-C(O)—(C1-C6 alkylene)-O, (C1-C6 alkylene)-OC(O)—(C1-C6 alkylene)-O, (C1-C6 alkylene)-C(O)O—(C1-C6 alkylene)-O, (C1-C6 alkylene)-OC(O)O—(C1-C6 alkylene)-O, (C1-C6 alkylene)-NR6—(C1-C6 alkylene)-O—, (C1-C6 alkylene)-C(O)NR6—(C1-C6 alkylene)-O, or (C1-C6 alkylene)-NR6C(O)—(C1-C6 alkylene)-O, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, or alkylene is optionally substituted with 1-6 R7;
• each R4b is independently C1-C6 alkyl, (C1-C6 alkylene)-O-L-losartan, (C1-C6 alkylene)-O-L-valsartan, (C1-C6 alkylene)-O-L-telmisartan, (C1-C6 alkylene)-O-L-candesartan, or (C1-C6 alkylene)-O-L-olmesartan;
• L is absent or comprises an acetal, ketal, anhydride, ester, hydrazone, or silyl ether;
• R6 is hydrogen or C1-C6 alkyl;
• and
• each R7 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, halo, O-L-losartan, O-L-valsartan, O-L-telmisartan, O-L-candesartan, O-L-olmesartan, (C1-C6 alkylene)-O-L-losartan, (C1-C6 alkylene)-O-L-valsartan, (C1-C6 alkylene)-O-L-telmisartan, (C1-C6 alkylene)-O-L-candesartan, (C1-C6 alkylene)-O-L-olmesartan, (C1-C6 alkylene)-O—(C1-C6 alkylene)-O-L-losartan, (C1-C6 alkylene)-O—(C1-C6 alkylene)-O-L-valsartan, (C1-C6 alkylene)-O—(C1-C6 alkylene)-O-L-telmisartan, (C1-C6 alkylene)-O—(C1-C6 alkylene)-O-L-candesartan, (C1-C6 alkylene)-O—(C1-C6 alkylene)-O-L-olmesartan, cyano, cyclyl, heterocyclyl, aryl, or heteroaryl;
• and the structure of Formula (III-a) is represented by:
• wherein:
• Z1 is O, C3-C8 cyclyl, or C(R22)(R23);
• each of X4 and X5 is independently C1-C6 alkylene;
• each of R20 and R21 is independently C1-C6 alkyl or OR20;
• each of R22 and R23 is independently hydrogen, C1-C6 alkyl, or (C1-C6 alkylene)-OR26;
• and each R26 is C1-C6 alkyl, C2-C6 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), X1 is C3-C6 cyclyl, optionally substituted with 1-6 R4;
• or (ii) for Formula (II-e), Formula (II-f), Formula (II-g), Formula (II-h), or Formula (II-i), each R4a is independently C1-C6 alkyl, O, (C1-C6 alkylene)-O, (C1-C6 alkylene)-O—(C1-C6 alkylene)-O, (C1-C6 alkylene)-C(O)—(C1-C6 alkylene)-O, (C1-C6 alkylene)-OC(O)—(C1-C6 alkylene)-O, (C1-C6 alkylene)-C(O)O—(C1-C6 alkylene)-O, or (C1-C6 alkylene)-OC(O)O—(C1-C6 alkylene)-O.