A kind of material of thioketal bonded doxorubicin and polyphosphate, its preparation method and application

A polyphosphate and doxorubicin technology is applied in the fields of wave energy or particle radiation treatment materials, medical preparations without active ingredients, and medical preparations containing active ingredients. Controlled local area drug release and other issues to achieve the effect of increasing drug concentration, improving utilization rate and therapeutic effect, good biocompatibility and degradability

Active Publication Date: 2021-05-14
SOUTH CHINA UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the current nanocarriers cannot meet these needs very well. It can be seen that it is of great significance to explore and develop nanocarriers with high specificity.
[0003] Among them, the main ways for nanocarriers to load small molecule chemotherapeutic drugs are physical encapsulation and chemical conjugation. However, drug leakage is inevitable during the delivery process of drug encapsulation, making it difficult to achieve highly controllable local area drug release.

Method used

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  • A kind of material of thioketal bonded doxorubicin and polyphosphate, its preparation method and application
  • A kind of material of thioketal bonded doxorubicin and polyphosphate, its preparation method and application
  • A kind of material of thioketal bonded doxorubicin and polyphosphate, its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Example 1. Synthesis and characterization of reactive oxygen species-responsive polyphosphate-bonded doxorubicin PPE-TK-DOX

[0052] 1. Synthesis of reactive oxygen species-responsive polyphosphate-bonded doxorubicin PPE-TK-DOX

[0053] PEGylated phosphate monomer (PPEG) and 2-(allyloxy)-2-oxo-1,3,2-di Polyphosphate P (PPEG-co-AEP) was obtained by ring-opening polymerization of oxaphospholane (2-(allyloxy)-1,3,2-dioxaphospholane 2-oxide, AEP). Then react with mercaptoethylamine to obtain polyphosphate P (PPEG n -co-AEP(Cya) m ). 3,3'-(propane-2,2-diylbis(sulfadiyl))dipropionic acid was added to doxorubicin (DOX) under activated conditions for amidation reaction, and then polyphosphate P( PPEG n -co-AEP(Cya) m ) further amidation reaction, after finishing the reaction, the material with thioketal bonded doxorubicin and polyphosphate is obtained. For the synthesis steps, see figure 1 .

[0054] 1. Polyphosphate P (PPEG 10 -co-AEP(Cya) 20 )Synthesis

[0055] Bu...

Embodiment 2

[0063] The material characterization result of embodiment 2 and embodiment 3 is similar to that of embodiment 1, can refer to the proton nuclear magnetic resonance spectrum of embodiment 1 ( 1 H NMR).

[0064] Example 2. Synthesis of active oxygen-responsive polyphosphate-bonded doxorubicin PPE-TK-DOX

[0065] 1. Polyphosphate P (PPEG 20 -co-AEP(Cya) 30 )Synthesis

[0066] Build a set of anhydrous reaction device to remove water vapor. In a glove box, AEP (0.62 g, 3.78 mmol), PPEG (1.65 g, 1.89 mmol), and benzyl alcohol (0.01 g, 0.092 mmol) and 8 mL of purified and dried tetrahydrofuran (THF) were added to an anhydrous, oxygen-free In the flask, after fully stirring at 45°C for 20 minutes, add stannous octoate (12 mg, 0.03 mmol) and react at 45°C for 2 d to complete the polymerization reaction. The product was precipitated twice in ether / methanol (4:1, v / v) to give P(PPEG n -co-AEP m ).

[0067] P(PPEG 20 -co-AEP 30 ) (500mg, 0.022mmol), mercaptoethylamine (225mg, 1....

Embodiment 3

[0070] Example 3, Synthesis of active oxygen-responsive polyphosphate-bonded doxorubicin PPE-TK-DOX

[0071] 1. Polyphosphate P (PPEG 15 -co-AEP(Cya) 25 )Synthesis

[0072] Build a set of anhydrous reaction device to remove water vapor. AEP (0.44 g, 2.7 mmol), PPEG (1.18 g, 1.35 mmol), and benzyl alcohol (0.01 g, 0.092 mmol) and 8 mL of purified and dried tetrahydrofuran (THF) were added to an anhydrous, oxygen-free In the flask, after fully stirring at 43°C for 20 minutes, add stannous octoate (12mg, 0.03mmol) and react at 43°C for 60h to complete the polymerization reaction. The product was precipitated twice in ether / methanol (4:1, v / v) to give P(PPEG 15 -co-AEP 25 ).

[0073] P(PPEG 15 -co-AEP 25 ) (500mg, 0.03mmol), mercaptoethylamine (153mg, 1.35mmol) was dissolved in 4mL of DMF, and 2,2-dimethoxy-2-phenylacetophenone (DMPA, 5.0mg, 0.038mmol) was added , purged with nitrogen for 20 min, and irradiated with ultraviolet light (λmax=365 nm) for 60 min under stirrin...

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Abstract

The invention discloses a material in which adriamycin and polyphosphate are bonded by a thioketal bond, a preparation method and an application thereof. The method comprises the following steps: (1) using benzyl alcohol as an initiator, ring-opening polymerization of PPEG and phosphate monomers to obtain P(PPEG-co-AEP). (2) Click mercaptoethylamine onto P(PPEG‑co‑AEP) to get P(PPEG‑co‑AEP(Cya)). (3) Add the activated dipropionic acid containing thioketal bond to doxorubicin for amide reaction. (4) P(PPEG‑co‑AEP(Cya)) was subjected to amidation reaction to obtain a material containing thioketal bonded doxorubicin and polyphosphate. The material self-assembles with the photosensitizer into nanoparticles, and under the irradiation of 660nm near-infrared light, the drug is released rapidly, the drug concentration and active oxygen content in the tumor site are increased, and the effect of chemotherapy and PDT treatment is improved, which has potential clinical application value.

Description

technical field [0001] The invention relates to the field of polyphosphate materials, in particular to a material in which doxorubicin and polyphosphate are bonded by a thioketal bond, and a preparation method and application thereof. Background technique [0002] At present, nanocarriers deliver chemotherapeutic drugs to tumor tissue mainly through the high permeability and retention effect (EPR effect) of solid tumors. An ideal nanocarrier should be able to circulate in the blood for a long time, and the drug will not be released or released in a small amount in healthy tissues, so as to reduce the toxicity of the drug to the body. When the nanocarrier reaches the tumor site, it can specifically release the drug, thereby causing apoptosis. However, the current nanocarriers cannot meet these requirements well, so it is of great significance to explore and develop nanocarriers with high specificity. [0003] The main ways to load small molecule chemotherapeutic drugs on na...

Claims

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Application Information

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Patent Type & AuthorityPatents(China)
IPC IPC(8): A61K9/51A61K47/34A61K47/59A61K41/00A61K31/704A61P35/00
CPCA61K9/5146A61K31/704A61K41/0071A61K47/605A61P35/00A61K2300/00
Inventor杨显珠张丽婷王均裴佩
OwnerSOUTH CHINA UNIV OF TECH