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Material for thioketal bonding doxorubicin and polyphosphate, and preparation method and application thereof

A technology of polyphosphate ester and adriamycin, which is applied to medical preparations without active ingredients, wave energy or particle radiation treatment materials, and medical preparations containing active ingredients, etc. Regional drug release, drug leakage and other problems, to achieve the effect of improving utilization rate and therapeutic effect, increasing drug concentration, and significant clinical application significance

Active Publication Date: 2019-01-18
SOUTH CHINA UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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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  • Material for thioketal bonding doxorubicin and polyphosphate, and preparation method and application thereof
  • Material for thioketal bonding doxorubicin and polyphosphate, and preparation method and application thereof
  • Material for thioketal bonding doxorubicin and polyphosphate, and preparation method and application thereof

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 reactive oxygen species-responsive polyphosphate-bonded doxorubicin PPE-TK-DOX

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

[0072] Build an 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 anhydrous and oxygen-free in a glove box. In the flask, after fully stirring at 43 °C for 20 min, stannous octoate (12 mg, 0.03 mmol) was added, and the reaction was carried out at 43 °C for 60 h 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 ) (500 mg, 0.03 mmol), mercaptoethylamine (153 mg, 1.35 mmol) was dissolved in 4 mL of DMF, and 2,2-dimethoxy-2-phenylacetophenone (DMPA, 5.0 mg, 0.038 mmol) was added. , nitrogen purged for 20min, under stirring conditi...

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Abstract

The invention discloses a Material for thioketal bonding doxorubicin and polyphosphate and a preparation method and application thereof. The method comprises the following steps: (1) using benzyl alcohol as an initiator, ring-opening polymerization of PPEG and phosphate ester monomer to obtain P (PPEG co AEP). (2) P (PPEG-Co-AEP (Cya)) was obtained by clicking on P (PPEG-Co-AEP) with mercaptoethylamine. (3) adding activated dipropionic acid containing thioketal bond into adriamycin for amide reaction. (4) P (PPEG-Co-AEP (Cya)) was synthesized by amidation reaction to give the material containing thioketal bonded doxorubicin and polyphosphate. The nanoparticles were self-assembled with photosensitizer, and the drug was rapidly released under 660 nm near-infrared light, the drug concentration and active oxygen content in tumor site increased, and the therapeutic effect of chemotherapy and PDT was improved. The nanoparticles have potential clinical application value.

Description

technical field [0001] The invention relates to the field of polyphosphate materials, in particular to a material for bonding doxorubicin and polyphosphate by thioketone bonds, and a preparation method and application thereof. Background technique [0002] Currently, nanocarriers deliver chemotherapeutic drugs to tumor tissues 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 should not be released or released 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 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 to load small molecule chemotherapeutic drugs on...

Claims

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Application Information

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Patent Type & Authority Applications(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
Owner SOUTH CHINA UNIV OF TECH
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