# US 11,433,136 B2 · Polyacetal polymers, conjugates, particles and uses thereof

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- Number: US 11,433,136 B2
- Document ID: US11433136B2
- Status: Granted
- Kind: B2
- Application number: 16/063,353
- Filed: 2016-12-16
- Published: 2018-12-20
- Granted: 2022-09-06
- Earliest claimed: 2015-12-18
- Assignees: The General Hospital Corporation; Massachusetts Institute of Technology; Xtuit Pharmaceuticals, Inc.
- Applicants: The General Hospital Corporation; Massachusetts Institute of Technology; Xtuit Pharmaceuticals, Inc.
- Inventors: Peter Blume-Jensen; Donald E. Chickering, III; Paul W. Kopesky; Lawrence A. Reiter; Alan Crane; Robert S. Langer; Rong Tong; Rakesh K. Jain; Vikash Pal Singh Chauhan; Joao Incio; Dai Fukumura
- Web page: https://patentgrep.com/patent/US11433136B2

## CPC

- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61K 9/146: {with organic macromolecular compounds}
- A61K 31/41: having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61P 35/00: Antineoplastic agents
- C08G 65/48: Polymers modified by chemical after-treatment
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS

## Abstract

Provided herein are polymers, pH-sensitive polymers and/or linkers; conjugates comprising said polymers and/or linkers, optionally, coupled to one or more agents and/or targeting moieties; and particles (e.g., nanoparticles comprising the aforesaid polymers, linkers and/or conjugates), which can be used to enhance the delivery and/or efficacy of one or more agents in a subject.

## Claims

### Claim 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 (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.

### Claim 2 (depends on 1)

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 (Tm) of about 35° C. or greater.

### Claim 3 (depends on 1)

The conjugate of claim 1, wherein 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.

### Claim 4 (depends on 1)

The conjugate of claim 1, wherein 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.

### Claim 5 (depends on 1)

The conjugate of claim 1, wherein for Formula Z1 is C(R23)(R24) and each of R22 and R23 is independently hydrogen, C1-C6 alkyl, or (C1-C6 alkylene)-OR26.

### Claim 6 (depends on 1)

The conjugate of claim 1, wherein for Formula (III-a), R22 is hydrogen or C1-C6 alkyl, R23 is independently C1-C6 alkyl or C1-C2 alkylene)-OR26 and R26 is C2-C6 alkenyl or a branching point.

### Claim 7 (depends on 1)

The conjugate of claim 1, wherein a precursor to each of B1 and B2 is independently selected from the following vinyl ethers:

### Claim 8 (depends on 1)

The conjugate of claim 1 wherein each of C1 and C2 is independently a polyethylene glycol (PEG) and is between about 200 and 4000 Da in size.

### Claim 9 (depends on 1)

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.

### Claim 10 (depends on 9)

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

### Claim 11 (depends on 1)

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

### Claim 12 (depends on 1)

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 (Tm) of about 35° C. or greater.

### Claim 13 (depends on 1)

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

### Claim 14 (depends on 2)

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.