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Deep-penetrating nano drug delivery system having tumor microenvironment responsiveness

A nano-drug delivery system and hyaluronic acid technology, applied in the field of pharmaceutical preparations, can solve the problems of hindering the delivery of nano-drug delivery systems, poor penetration effects, and unsatisfactory therapeutic effects.

Inactive Publication Date: 2017-11-03
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, it is far from enough to accumulate nano-drugs to the tumor site. The high pressure of the tumor interstitium generated by the dense tumor stroma and abnormal tumor blood vessels hinders the delivery of the nano-drug delivery system to the core of the tumor, making the therapeutic effect less effective. not ideal
Experiments show that nanoparticles with smaller particle size have better penetration effect, but smaller particle size is easily cleared by the body in blood circulation; nanoparticles with larger particle size have better retention effect but their penetration effect Poor, so the nano drug delivery system with variable particle size appears to be of high research value

Method used

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  • Deep-penetrating nano drug delivery system having tumor microenvironment responsiveness
  • Deep-penetrating nano drug delivery system having tumor microenvironment responsiveness
  • Deep-penetrating nano drug delivery system having tumor microenvironment responsiveness

Examples

Experimental program
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Effect test

Embodiment 1

[0019] The preparation of embodiment 1, DOX-DGL-HA

[0020] (1) Take 3.7 mg doxorubicin hydrochloride (DOX•HCl) in a reaction bottle, add N,N-dimethylformamide (DMF) and stir for 30 minutes to dissolve;

[0021] (2) Add triethylamine in an equimolar amount to DOX•HCL and stir overnight in the dark;

[0022] (3) Take 10 mg DGL, dissolve it in DMF and add it to the above reaction system, and continue to react for 36 h;

[0023] (4) Dialysis in the phosphate buffer system to remove organic solvents and unreacted chemotherapeutic drugs;

[0024] (5) The DOX-encapsulated dendritic polymer core was obtained by filtration with a 0.22 μm microporous membrane. The particle size was measured to be 20-50 nm, and the potential was + 50 mV to + 55 mV.

[0025] (6) Dissolve 2.9 mg HA in 100 μL of deionized water, and add it dropwise to the above reaction system under vortex. The mass ratio of DGL to HA is 1:5~1:50, preferably, the mass ratio is 1:16 After the dropwise addition, continue ...

Embodiment 2

[0026] The preparation of embodiment 2, PTX-DGL-HA

[0027] (1) Take 5.4 mg paclitaxel (PTX) in a reaction bottle, add N,N-dimethylformamide (DMF) and stir for 30 min to dissolve;

[0028] (2) Take 10 mg DGL, dissolve it in DMF, add it to the above reaction system, and continue the reaction for 36 h;

[0029] (3) Phosphate buffer system China dialysis to remove organic solvents and unreacted drugs;

[0030] (4) Filtration through a 0.22 μm microporous membrane to obtain the core of the dendrimer material loaded with PTX;

[0031] (5) Dissolve 2.9 mg HA in 100 μL of pure water, and add it dropwise to the above reaction system under vortex. The mass ratio of DGL to HA is 1:5~1:50, preferably, the mass ratio is 1:16 , and continued to vortex for 30 s after the dropwise addition was completed.

Embodiment 3

[0032] The preparation of embodiment 3, GC-PAMAM-HA

[0033] (1) Take 1.9 mg of gemcitabine hydrochloride (GC·HCl) in a reaction flask, add dimethyl sulfoxide (DMSO) and stir for 30 min to dissolve;

[0034] (2) Add triethylamine in an equimolar amount to GC·HCl and stir overnight in the dark;

[0035] (3) Take 12.4 mg PAMAM (G 4.0), add DMF to dissolve it, add it to the above reaction system, and continue to react for 36 h;

[0036] (4) Dialysis in a phosphate buffer system to remove organic solvents and unreacted chemotherapeutic drugs;

[0037] (5) Filtration through a 0.22 μm microporous membrane to obtain the core of the dendrimer material loaded with GC;

[0038] (6) Dissolve 2.9 mg HA in 100 μL of deionized water, and add it dropwise to the above reaction system under vortex. The mass ratio of PAMAM to HA is 1:5~1:50, preferably, the mass ratio is 1:16 , and continued to vortex for 30 s after the dropwise addition was completed.

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Abstract

The invention belongs to the field of medicinal preparations and relates to a nano drug delivery system having tumor microenvironment responsiveness and a preparation method and application thereof. The nano drug delivery system consists of biodegradable hyaluronic acid, dendritic polymer and a chemotherapeutic drug. A framework is the hyaluronic acid (HA), and a small-particle-diameter dendritic polymer material is a chemotherapeutic drug carrier. The preparation method of the system comprises the steps of preparation of a dendritic polymer kernel and preparation of responsive tumor-targeted nanoparticles. The HA in the system can achieve tumor targeting, and the toxic and side effects of the drug delivery system on the normal tissues are reduced. In addition, the HA produces responsive particle size degradation under the effect of high-expressed hyaluronidase in a tumor microenvironment, the small-particle-diameter drug delivery nanoparticles are released, deep tumor penetration is achieved, retention and accumulation of drugs at tumor parts are increased, and accordingly the treating effect is improved.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and relates to a nano drug delivery system with tumor microenvironment responsiveness and a preparation method thereof. The invention is composed of degradable hyaluronic acid, dendritic macromolecule material and chemotherapeutic drugs. The backbone is hyaluronic acid (HA), which has targeting and tumor microenvironment-sensitive degradability. Using dendrimers with small particle size as chemotherapeutic drug carriers, and through electrostatic interaction and chemical bond interaction with HA, a nano drug delivery system with tumor targeting and tumor microenvironment responsive degradation is made. This system has superior tumor Retention and deep penetration capabilities. Background technique [0002] Malignant tumor is the second largest disease that seriously threatens human health and life, and it is difficult to treat and the overall survival rate is low. Chemotherapy and ra...

Claims

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Application Information

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IPC IPC(8): A61K47/64A61K47/59A61K47/61A61K31/704A61K31/337A61K31/7068A61K31/519A61K31/475A61P35/00
CPCA61K31/337A61K31/475A61K31/519A61K31/704A61K31/7068
Inventor 高会乐胡川
Owner SICHUAN UNIV
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