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Acid environment sensitive nano predrug system with cellulose nanocrystal used as carrier and preparation method

An environment-sensitive, cellulose-based technology, applied in the field of biomedicine, can solve the problems of inability to release anti-tumor drugs in time, difficulty in maintaining the shape, and inability to achieve fixed-point release and treatment of drugs, achieve good tumor cell proliferation inhibition ability, and enhance intracellular Effects of swallowing, good passive targeting ability

Inactive Publication Date: 2018-07-20
EAST CHINA NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the shape of this type of carrier is difficult to maintain, and it is easy to rupture in the blood circulation, resulting in the early release of anti-tumor drugs, and it is impossible to achieve targeted drug release and treatment.
At the same time, this type of carrier also has defects such as insufficient sensitivity to the slightly acidic environment of tumor tissue, and cannot release anti-tumor drugs in time after reaching the tumor tissue, and the therapeutic effect is limited.

Method used

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  • Acid environment sensitive nano predrug system with cellulose nanocrystal used as carrier and preparation method
  • Acid environment sensitive nano predrug system with cellulose nanocrystal used as carrier and preparation method
  • Acid environment sensitive nano predrug system with cellulose nanocrystal used as carrier and preparation method

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preparation example Construction

[0044] The present invention simultaneously proposes a preparation method of an acidic environment-sensitive nano-prodrug system in which cellulose nanocrystals are used as a carrier: the method comprises the following steps: (1) preparing amino-modified cellulose nanocrystals; (2) drug A The intermediate product CAD was obtained by the reaction of mycin and cis-aconitic anhydride; (3) The nano-prodrug CNC-CAD was prepared by condensation reaction between CAD and aminated cellulose nanocrystals.

[0045] The specific implementation steps are as follows:

[0046] The first step: surface amination of cellulose nanocrystals (CNC-NH 2 )

[0047] Disperse cellulose nanocrystals in 1M NaOH solution, add epichlorohydrin drop by drop, control the temperature within the range of (55-65) ° C, stir, and dialyze until the pH value of the dialyzed liquid is around 12; use 50 % (w / v) NaOH solution to adjust the pH value of the solution in the dialysis bag, add concentrated ammonia water, ...

Embodiment 1

[0059] Embodiment 1 Drug reacts with cis-aconitic anhydride

[0060] 1.1 Drug Doxorubicin-3-NH 2 Preparation of CAD with cis-aconitic anhydride

[0061] Weigh 10 mg of doxorubicin hydrochloride, dissolve it in 3 ml of anhydrous dichloromethane (DCM), add 40 μl of triethylamine dropwise in the dark, protect it under nitrogen, and stir for 2 h. Weigh 10mg of cis-aconitic anhydride, dissolve in 3ml of anhydrous dichloromethane, and sonicate for 20min. The cis-aconitic anhydride solution was added dropwise to the DCM solution of doxorubicin, protected from light, under nitrogen protection, and stirred at room temperature for 8 h. The dichloromethane was distilled off under reduced pressure, separated by column chromatography, and the mobile phase was alcohol amine solution and dichloromethane. (The ratio of the mobile phase is methanolamine: dichloromethane=1:500), the purity detected by high performance liquid chromatography is 98%, and the dichloromethane is distilled off und...

Embodiment 2

[0068] Example 2 Amination of the surface of cellulose nanocrystals

[0069] Weigh cellulose nanocrystals (100-200) mg, disperse in 1M NaOH solution (100-200) ml / g cellulose nanocrystals, ultrasonically (30-60) min, add epichlorohydrin (6- 20) mmol / g cellulose nanocrystals, stirred at (55-65)°C for 2 hours, and dialyzed (MWCO=1000-3500) until the pH value of the dialyzed internal solution was lower than 12. Use 50% (w / v NaOH) solution to adjust the pH value of the solution in the dialysis bag to (11-13), add concentrated ammonia water, (5-10) ml / g cellulose, and stir at (55-65) °C (1-4) h, dialyze until the pH value of the dialysate is (7-7.4). Freeze dried. Refrigerate cold. (see the attached schematic diagram of the synthetic route figure 2 in the second step).

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Abstract

The invention discloses an acid environment sensitive nano predrug system with a cellulose nanocrystal used as a carrier and a preparation method. The predrug system comprises a rodlike cellulose nanocrystal, a connection unit and a drug, wherein the rodlike cellulose nanocrystal is the carrier, and the acid environment sensitive connection unit is connected with the drug; the system is of a structure shown in a formula I. A preparation process of the acid environment sensitive nano predrug system comprises the following steps: (1) preparing an aminated cellulose nanocrystal; (2) performing ring-opening reaction on the drug and cis-acotonic anhydride (CAA); (3) preparing the acid environment sensitive nano predrug system with the cellulose nanocrystal used as the carrier through heterogeneous reaction. The predrug system prepared through the preparation method disclosed by the invention realizes controlled release of the drug sensitive to a micro-acid environment at a nidus, and has relatively ideal capacities of endocytosis and tumor cell proliferation inhibition.

Description

technical field [0001] The invention belongs to the application field of biomedical technology, nanomedicine and renewable materials, and specifically relates to a nanoprodrug system, a preparation method and an application of a rod-shaped cellulose nanocrystal as a carrier and an acidic environment-sensitive chemical bond as a linking unit. As a carrier for constructing nanoprodrugs, cellulose nanocrystals, a renewable biomaterial, have the advantages of good biocompatibility and favorable cell endocytosis, and their rod-like shape is conducive to enhancing cell endocytosis. The introduction of sensitive and cleavable chemical bonds in the slightly acidic environment of the lesion can realize the controlled release of drugs at a specific point. Background technique [0002] As global environmental problems become increasingly prominent, human behaviors related to carcinogenicity increase, and the global incidence of tumors continues to increase. Chemotherapy is still one o...

Claims

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Application Information

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IPC IPC(8): A61K47/61A61K31/7024A61K38/08A61K31/7048A61K31/704A61K31/7068A61K49/00A61P35/00
CPCA61K31/7024A61K31/704A61K31/7048A61K31/7068A61K38/08A61K49/0017A61K2300/00
Inventor 余家会李娜张晗尤东磊
Owner EAST CHINA NORMAL UNIVERSITY
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