ß-cyclodextrin-based star-shaped polymer, a preparation method therefor and an integrated unimolecular micelle system for diagnosis and treatment thereof

Patent metadata

Field	Value
Publication number	US-10874609-B2
Application number	US-201616080355-A
Country	US
Kind code	B2
Filing date	Dec 14, 2016
Priority date	Apr 5, 2016
Publication date	Dec 29, 2020
Grant date	Dec 29, 2020

Abstract

Disclosed is a β-cyclodextrin-based star-shaped polymer and a preparation method therefor, and an integrated unimolecular micelle system for diagnosis and treatment based on the star-shaped polymer and the use thereof. The polymer has a structure represented by the following formula (I):

wherein x=4-15, y=3-20, and z=10-30.

First claim

What is claimed is:

1. An amphipathic pH-responsive β-cyclodextrin-based star-shaped polymer with the structure represented by the following formula (I):

wherein x=4-15, y=3-20, z=10-30.

2. A method for preparing the amphipathic pH-responsive β-cyclodextrin-based star-shaped polymer according to claim 1 , comprising:
(1) preparation of a pH-responsive monomer precursor (tBAM), wherein tert-butyl N-(2-hydroxyethyl)carbamate, N,N-diisopropylethylamine are mixed in a solvent, and methacryloyl chloride is added under ice bath condition; the reaction is carried out under ice bath condition and subsequently at room temperature to obtain the precursive pH-responsive monomer t-butyl methacrylate-2-carbamate (tBAM);
(2) preparation of a polymer containing polycaprolactone β-CD-(PCL-OH) 21 , wherein β-CD, ε-CL and a catalyst are mixed and heated to react, so as to obtain the polymer β-CD-(PCL-OH) 21 ;
(3) preparation of a macroinitiator β-CD-(PCL-Br) 21 , wherein the β-CD-(PCL-OH) 21 prepared in step (2) is dissolved in a solvent; triethylamine (TEA) and initiator 2-bromoisobutyryl bromide (BIBB) are then added under ice bath; the reaction is carried out under ice bath condition and subsequently at room temperature to obtain the macroinitiator β-CD-(PCL-Br) 21 ;
(4) preparation of a pH-responsive polymer precursor β-CD-(PCL-b-PtBAM) 21 : the macroinitiator β-CD-(PCL-Br) 21 prepared in step (3), the precursor tBAM prepared in step (1) and a catalyst are dissolved in a solvent, after which a ligand 1,1,4,7,10,10-hexamethyltriethylenetetramine (HMTETA) is further added; then a reducing agent is introduced and the solution is heated to react to obtain the pH-responsive polymer β-CD-(PCL-b-PtBAM) 21 ;
(5) preparation of an amphipathic star-shaped polymer β-CD-(PCL-b-tBAM-b-PPEGMA) 21 , wherein the pH-responsive polymer precursor β-CD-(PCL-b-PtBAM) 21 prepared in step (4), poly(ethylene glycol) methyl ether methacrylate (PEGMA), a ligand 1,1,4,7,10,10-hexamethyltriethylenetetramine (HMTETA) and a catalyst are dissolved in a solvent; after mixing homogeneously, a reducing agent is added and the solution is heated to react to obtain the amphipathic star-shaped polymer β-CD-(PCL-b-tBAM-b-PPEGMA) 21 ;
(6) preparation of an amphipathic pH-responsive β-cyclodextrin-based star-shaped polymer β-CD-(PCL-b-PAEMA-b-PPEGMA) 21 , wherein the amphiphilic star-shaped polymer prepared in step (5) is dissolved in a solvent, and after addition of trifluoroacetic acid (TFA), the reaction is carried out under ice bath condition and subsequently at room temperature to obtain the amphipathic pH-responsive O-cyclodextrin-based star-shaped polymer β-CD-(PCL-b-PAEMA-b-PPEGMA) 21 .

3. The method for preparing the amphipathic pH-responsive β-cyclodextrin-based star-shaped polymer according to claim 2 , wherein
the molar parts of the reactants in step (1) are:

tert-butyl N-(2-hydroxyethyl)carbamate
1

N,N-diisopropylethylamine
1-3

methacryloyl chloride
1-3

the molar parts of the reactants in step (2) are:

β-CD
1

ε-CL
84-315

the molar parts of the reactants in step (3) are:

β-CD-(PCL-OH) 21
1

TEA
21-84

BIBB
21-84

the molar parts of the reactants in step (4) are:

macroinitiator (β-CD-(PCL-Br) 21 )
1

tBAM
63-420

HMTETA
8-12

the molar parts of the reactants in step (5) are:

pH-responsive polymer precursor
1

PEGMA
210-630

HMTETA
 8-12

the molar parts of the reactants in step (6) are:

amphipathic star-shaped polymer
1

TFA
30-60.

4. The method for preparing the amphipathic pH-responsive β-cyclodextrin-based star-shaped polymer according to claim 2 , wherein, in step (1), the reaction is carried out under ice bath condition for 0.5-4 h, and subsequently at room temperature for 24-48 h.

5. The method for preparing the amphipathic pH-responsive β-cyclodextrin-based star-shaped polymer according to claim 2 , wherein: in step (2) the solution is heated to 90-130° C. to react for 24-48 h; in step (3) the reaction is carried out under ice bath condition for 4-6 h, and sub

Assignees

• Univ South China Tech

Inventors

• Zhang Lijuan
• Lin Wenjing
• Yao Na
• Zhang Xiaofang

Classifications

• C08F220/34

  Esters containing nitrogen {, e.g. N,N-dimethylaminoethyl (meth)acrylate} · CPC title

• C08F220/286

  and containing polyethylene oxide in the alcohol moiety, e.g. methoxy polyethylene glycol (meth)acrylate · CPC title

• A61K9/1075 Primary

  Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers (A61K9/0026 takes precedence) · CPC title

• A61K33/242

  Gold; Compounds thereof · CPC title

• A61K47/22

  Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones · CPC title