Environmental pH stimuli-responsive type tumor targeting and controlled drug release nano-carrier and preparation method of nano-carrier

A tumor-targeting, stimuli-responsive technology, applied in the field of biopolymer materials and nanometers, can solve the problems of high cytotoxicity, nucleic acid is easy to be hydrolyzed, and cannot distinguish cancer cells from normal cells, etc., so as to prolong the circulation time and not easily release effect

Inactive Publication Date: 2018-01-19
WUHAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main disadvantages of cancer treatment methods are: drugs or treatment methods are not highly targeted to cancer cells, and cannot distinguish cancer cells from normal cells, especially chemotherapy and some protein drugs have high cytotoxicity, and are also harmful to normal body damage
However, the new gene therapy also has problems in practical application due to the fact that nucleic acids are easily decomposed by enzymes in the body or viral vectors are toxic.

Method used

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  • Environmental pH stimuli-responsive type tumor targeting and controlled drug release nano-carrier and preparation method of nano-carrier
  • Environmental pH stimuli-responsive type tumor targeting and controlled drug release nano-carrier and preparation method of nano-carrier
  • Environmental pH stimuli-responsive type tumor targeting and controlled drug release nano-carrier and preparation method of nano-carrier

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] [Example 1] Preparation of dendritic nano-prodrugs

[0033] (1) Amphiphilic block copolymer (PBLA-b-PEG-OCH 3 ) Synthesis: The copolymer of polybenzyl aspartate and PEG was synthesized by NCA method, and N-carboxy-L-aspartic acid was prepared by reacting benzyl L-aspartate (BLA) with trimer phosgene -Benzyl ester-cyclic anhydride (BLA-NCA). Using methoxypolyethylene glycol amine (MPEG-NH2) as an initiator to initiate ring-opening polymerization of NCA, poly(ethylene glycol)-poly(benzyl aspartate) amphiphilic block copolymers with different molecular weights were synthesized.

[0034] Dissolve 80 mg-100 mg BLA-NCA in 6 mL of anhydrous DMF solution at room temperature. Subsequently, 100mg-200mg of methoxyl PEG-NH 2 (MPEG-NH 2 ) (or MAL-PEG-NH 2 ) was added to the solution. Pour in 0 O The precipitate was separated in diethyl ether of C. The precipitate was collected by filtration and washed. Finally dry under vacuum.

[0035] (2) A multifunctional tumor-targetin...

Embodiment 2

[0041] [Example 2] Preparation of Hyperbranched Nanomicelles

[0042] The polymer prodrug obtained in Example 1 can be self-assembled in an aqueous medium to form nanomicelles with a core-shell structure. After entering the target tumor tissue, due to the pH sensitivity of the hydrazone bond, the hydrazone bond is in the It can be broken in an acidic environment, but will not break in the pH environment of normal tissues, so as to realize the intelligent controlled release of drugs.

[0043] PAMAM-P(LA-HYD-DOX)-b-PEG-OCH 3 / F3 copolymer dissolved in DI water. Dialysis for 96 hours followed by lyophilization yielded PAMAM-P(LA-Hyd-DOX)-b-PEG-OCH 3 / F3 micelles.

Embodiment 3

[0044] [Example 3] Preparation and Characterization of DOX-loaded Polymer Prodrug

[0045] Preparation of amphiphilic polymer prodrug PAMAM–P (LA-Hyd -DOX)-b-PEG-OCH using PAMAM as a macromolecule carrier 3 / F3, and carry out nuclear magnetic resonance on the reaction drug substance and the reaction product of each step ( 1 HNMR) characterization; (such as figure 1 ), 1 H NMR (400MHz, DMSO) δ 7.94 (s, 1H), 5.33 (s, 1H), hydrogen 3.44 (d, J = 59.2 Hz,20H), attributed to the peak 1.05 of PEG (d, J = 151.7 Hz, 1H). Hydrogen on PAMAM.

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Abstract

The invention discloses an environmental pH stimuli-responsive type tumor targeting and controlled drug release nano-carrier and a preparation method of the nano-carrier. Dendrimer macromolecular nano-polymer material PAMAM (polyamidoamine) is taken as a main body of a structure and connected with an amphiphilic block copolymer PEG (methoxy polyethylene glycol)-PLA (poly-l-aspartic acid), DOX (doxorubicin) is covalently conjugated to a hydrophobic fragment, namely, PLA, of an arm of the amphiphilic block copolymer and is connected though a pH sensitive hydrazone bond, so that a system has thecharacteristic of in-vivo smart drug release, and drug release can be controlled by in-vivo pH. The connection with a F3 polypeptide nucleolin targeting ligand is realized through a hydrophilic PEG chain segment, and tumor targeting of the system is realized in specific uptake of tumor and nuclear localization. The nano-carrier has potential clinical application value, and powerful technical support is provided for treatment of other types of malignant tumor cells.

Description

technical field [0001] The invention relates to a tumor-targeting and environmental pH stimulus-responsive drug controlled-release nanocarrier and a preparation method, which belong to the field of biopolymer materials and nanotechnology. Background technique [0002] The treatment of cancer has long been a difficult problem that the medical field is trying to overcome. The main disadvantages of cancer treatment methods are: drugs or treatment methods are not highly targeted to cancer cells, and cannot distinguish cancer cells from normal cells, especially chemotherapy and some protein drugs have high cytotoxicity, and are also harmful to Normal organisms do a lot of damage. However, the new gene therapy also has problems in practical application due to the fact that nucleic acids are easily decomposed by enzymes in the body or viral vectors are toxic. It is of great significance to develop more effective and safe tumor treatment methods. [0003] In recent years, with th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/69A61K47/59A61K47/60A61K47/64A61K31/704A61P35/00
Inventor 徐文瑨杨佳朱妍肖金玲宗琦段天顺冯锦川
Owner WUHAN UNIV OF TECH
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