Poly(Beta-Thioester) Polymers and Polymeric Nanoparticles

A method of identifying a polymer-based adjuvant for a vaccine comprising:

• selecting one or more test polymers with unknown activity in the activation of dendritic cells;
• determining a set of molecular descriptors for the one or more test polymers;
• by machine, accessing a body of data comprising molecular descriptors and dendritic cell activation data of a set of training polymers, wherein the body of data has been configured to derive an algorithm for determining the ability of a polymer to activate a dendritic cell based on its molecular descriptors;
• applying the set of molecular descriptors for the one or more test polymers to the algorithm;
• identifying a polymer from the one or more test polymers for development into an adjuvant for a vaccine.

A method of preparing an adjuvant for a vaccine comprising:

• by machine, accessing a body of data comprising molecular descriptors and dendritic cell activation data of a set of training polymers, wherein the body of data has been configured to derive an algorithm for predicting the ability of a polymer to activate a dendritic cell based on its molecular descriptors;
• using said algorithm to select a polymer with predicted activity in the activation of dendritic cells;
• synthesizing the polymer;
• precipitating the polymer into nanoparticles.

A high throughput method of synthesizing a nanoparticle library comprising:

• (1) selecting a dithiol and a diacrylate;
• (2) reacting the dithiol and the diacrylate with triethylamine to produce a polymer;
• (3) precipitating the polymer;
• (4) washing the polymer;
• (5) preparing a mixture comprising the polymer and PLGA-PEG in solvent;
• (6) precipitating the mixture to produce nanoparticles;
• (7) repeating steps 2-6 at least one more time, selecting, during each repetition, a different combination of dithiol and diacrylate.

The method of claim 21, further comprising the following steps after step (4):

• (4.1) selecting a monothiol;
• (4.2) reacting the polymer with the monothiol and triethylamine to produce a capped polymer;
• (4.3) precipitating the capped polymer;
• (4.4) washing the capped polymer;
• wherein, the capped polymer is used in place of the polymer in subsequent steps 5-7.

A polymer of Formula (I):

• or a pharmaceutically acceptable salt thereof, wherein,
• R1 is
• Y1 is C1-3 alkyl, (C1-6 alkyl)-NHC(═O), C═O, 5 to 10-membered heteroaryl, or absent, wherein heteroaryl is optionally substituted, independently for each occurrence, one, two, or three times with C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, halogen, or 6 to 10-membered aryl;
• Y2 is C1-6 alkyl, 6 to 10-membered aryl, biphenyl, 5 to 10-membered heteroaryl, (CH2CH2O)pCH2CH2, C═N—(C1-6 alkyl)-N═C, O, S, or SO2, wherein the alkyl, aryl, biphenyl, and heteroaryl are optionally substituted, independently for each occurrence, one, two, or three times with C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, (C0-3 alkyl)-OH, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, halogen, or carboxylic acid;
• R2 is C1-6 alkyl, 6 to 10-membered aryl, O, or
• Z1 is C1-6 alkyl or 6 to 10-membered aryl;
• Z2 is O, O(C═O)O, or absent;
• Z3 is 6 to 10-membered aryl, 5 to 10-membered heteroaryl, or absent;
• Z4 is C1-6 alkyl, 5 to 15-membered cycloalkyl, 5 to 15-membered heterocyclyl, 6 to 14-membered aryl, 5 to 15-membered heteroaryl, or (C═O)O-(6 to 10-membered aryl)-O(C═O), each of which are optionally substituted, independently for each occurrence, one, two, or three times with C1-3 alkyl, C1-3 haloalkyl, or halogen;
• n is 25-250;
• p is 1, 2, 3, or 4;
• and
• wherein R1, R2, Y1, Y2, Z1, Z2, Z3, and Z4 are each, independently, the same for every occurrence in the polymer.

A polymer of Formula (II):

• or a pharmaceutically acceptable salt thereof, wherein,
• R1 is
• Y1 is C1-3 alkyl, (C1-6 alkyl)-NHC(═O), C═O, 5 to 10-membered heteroaryl, or absent, wherein heteroaryl is optionally substituted, independently for each occurrence, one, two, or three times with C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, halogen, or 6 to 10-membered aryl;
• Y2 is C1-6 alkyl, 6 to 10-membered aryl, biphenyl, 5 to 10-membered heteroaryl, (CH2CH2O)pCH2CH2, C═N—(C1-6 alkyl)-N═C, O, S, or SO2, wherein the alkyl, aryl, biphenyl, and heteroaryl are optionally substituted, independently for each occurrence, one, two, or three times with C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, (C0-3 alkyl)-OH, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, halogen, or carboxylic acid;
• R2 is C1-6 alkyl, 6 to 10-membered aryl, O, or
• Z1 is C1-6 alkyl or 6 to 10-membered aryl;
• Z2 is O, O(C═O)O, or absent;
• Z3 is 6 to 10-membered aryl, 5 to 10-membered heteroaryl, or absent;
• Z4 is C1-6 alkyl, 5 to 15-membered cycloalkyl, 5 to 15-membered heterocyclyl, 6 to 14-membered aryl, 5 to 15-membered heteroaryl, or (C═O)O-(6 to 10-membered aryl)-O(C═O), each of which are optionally substituted, independently for each occurrence, one, two, or three times with C1-3 alkyl, C1-3 haloalkyl, or halogen;
• R3 is C1-6 alkyl, C(═O)—C1-6 alkyl, 6 to 10-membered aryl, 5 to 10-membered heteroaryl, (C1-6 alkyl)-(6 to 10-membered aryl), (C1-6 alkyl)-(5 to 10-membered heteroaryl), and 5 to 15-membered heterocyclyl, each of which is optionally substituted, independently for each occurrence, one, two, or three times, independently, with C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, acetamide, carboxylic acid, silyl, hydroxyl, cyano, nitro, and halogen;
• n is 25-250;
• p is 1, 2, 3, or 4;
• and
• wherein R1, R2, R3, Y1, Y2, Z1, Z2, Z3, and Z4 are each, independently, the same for every occurrence in the polymer.