A CATION POLYMER CAPABLE OF REMOVING POSITIVE CHARGES THROUGH OXIDATIVE RESPONSE, A PREPARATION METHOD AND APPLICATION

• US 20180312617A1
• Filed: 10/13/2015
• Published: 11/01/2018
• Est. Priority Date: 10/13/2015
• Status: Active Grant

• Current Assignee: Zhejiang University
• Original Assignee: Zhejiang University
• Inventors: SHEN, YOUQING, LIU, XIN, TANG, JIANBIN, LIU, XIANGRUI
• Granted Patent: US 10,640,592 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 47/58 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
• CPC Class Codes: A61K 47/585 Ion exchange resins, e.g. polystyrene sulfonic acid resin
• CPC Class Codes: A61K 47/59 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
• CPC Class Codes: A61K 47/595 Polyamides, e.g. nylon polyamino acids A61K47/62
• CPC Class Codes: A61K 48/0041 the non-active part being polymeric
• CPC Class Codes: C08F 120/34 Esters containing nitrogen , e.g. N,N-dimethylaminoethyl (meth)acrylate
• CPC Class Codes: C08F 120/36 containing oxygen in addition to the carboxy oxygen , e.g. 2-N-morpholinoethyl (meth)acrylate or 2-isocyanatoethyl (meth)acrylate
• CPC Class Codes: C08F 130/06 containing boron
• CPC Class Codes: C08F 8/06 Oxidation
• CPC Class Codes: C08F 8/12 Hydrolysis
• CPC Class Codes: C08F 8/42 Introducing metal atoms or metal-containing groups
• CPC Class Codes: C08F 8/44 Preparation of metal salts or ammonium salts
• CPC Class Codes: C08G 73/0206 Polyalkylene(poly)amines
• CPC Class Codes: C08G 73/028 Polyamidoamines
• CPC Class Codes: C08G 83/004 After treatment of dendrimers
• CPC Class Codes: C12N 15/88 using microencapsulation, e.g. using amphiphile liposome vesicle

Abstract

Disclosed are the cation polymers capable of removing their positive charges in oxidative conditions, preparation methods, and applications as gene delivery carriers. The oxidation-responsive unit is the p-(boronic acid or ester)benzylammonium, which upon oxidation eliminates p-hydroxymethlphenol and thus converts in a tertiary amine. Compared with the prior art, different from a common quaternary amination carrier, the synthesized charge reversal type gene delivery carrier for oxidative response of the present invention has a large quantity of positive charges and can well coat a DNA, but the positive charges can be removed under the condition of intracellular oxidation when the charge reversal type gene delivery carrier enters a cell, a charge reverse is triggered, the positive charges turn to negative charges, and the DNA is quickly released for transfection. The carrier is efficient, low in toxicity, and good in application prospect.

Claims

1. A cationic polymer capable of removing positive charges through oxidative response, comprising the following moiety:

2. The cationic polymer of claim 1, wherein the cationic polymer is obtained from reactions between polyacrylate, polymethacrylate or other primary or secondary amino-containing polymers and the compound containing benzylboronic acid or ester.

3. The cationic polymer of claim 2, wherein the primary or secondary amino-containing polymers comprise poly[2-(N,N-disubstituted-amino)ethyl acrylate], polyethyleneimine (PEI) and poly(amidoamine) dendrimers (PAMAM).

4. The cationic polymer of claim 1, wherein R₃ and R₄ are selected from hydrogen, ethylene or 2,3-dimethylbutylene, and R₁ and R₂ are methyl or ethyl.

5. The cationic polymer of claim 1, wherein the cationic polymer is selected from one or more the following (1)-(4):

6. The cationic polymer of claim 5, wherein compound (1) and (2) are obtained by either of the methods as follows:

method 1;

polymerization of 2-(N,N-disubstituted-amino)ethyl acrylate or 2-(N,N-disubstituted-amino)ethyl methacrylate to produces poly[2-(N,N-disubstituted-amino)ethyl acrylate] or poly[2-(N,N-disubstituted-amino)ethyl methacrylate], which is then reacted with p-bromomethylphenylboronic acid, p-bromomethylphenylboronic ester, p-chloromethylphenylboronic acid or p-chloromethylphenylboronic ester to produce the desired compound; and

method 2;

2-(N,N-disubstituted-amino)ethyl acrylate or 2-(N,N-disubstituted-amino)ethyl methacrylate first reacts with p-bromomethylphenylboronic acid, p-bromomethylphenylboronic ester, p-chloromethylphenylboronic acid or p-chloromethylphenylboronic ester to obtain the corresponding ammonium-based cationic monomer, 2-[(meth)acryloyloxy]ethyl-[p-(boronic acid)benzyl]-di-substituted ammonium bromide (or chloride) or 2-[(meth)acryloyloxy]ethyl-[p-(boronic ester)benzyl]-diethyl ammonium bromide (or chloride), which is then polymerized to produce the desired compound.

7. The cationic polymer of claim 5, wherein compound (3) and (4) are prepared by Michael addition reaction of the acrylate monomers with PEI or PAMAM;

the acrylate monomers are selected from one of 2-acryloyloxyethyl-[p-(boronic acid)benzyl]-di-substituted ammonium bromide (or chloride) or 2-acryloyloxyethyl-[p-(boronic ester)benzyl]-diethyl ammonium bromide (or chloride).

8. The cationic polymer of claim 5, wherein n is from 5 to 500 and generation of PAMAM is from 2 to 5.

9. The cationic polymer of claim 1, wherein the polymer is used for the delivery of deoxyribonucleic acids and oligonucleotides.

10. The cationic polymer of claim 1, wherein the polymer is used for the delivery of taxol.