Preparation and characterization method of photosensitizer/antitumor drug self-assembled nano drug delivery system based on hyaluronic acid

A nano drug delivery system and anti-tumor drug technology, which is applied in the direction of anti-tumor drugs, drug combinations, medical preparations of non-active ingredients, etc., and can solve problems such as limited application, short half-life, and easy aggregation and photostability

Active Publication Date: 2017-05-31
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, due to the short half-life of indocyanine green, it is easy to non-specifically bind to lipoproteins in the body, easy to aggregate in solution, and has poor photostability, resulting in self-quenching of fluorescence, etc., which limits its application in the medical field.

Method used

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  • Preparation and characterization method of photosensitizer/antitumor drug self-assembled nano drug delivery system based on hyaluronic acid
  • Preparation and characterization method of photosensitizer/antitumor drug self-assembled nano drug delivery system based on hyaluronic acid
  • Preparation and characterization method of photosensitizer/antitumor drug self-assembled nano drug delivery system based on hyaluronic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Embodiment 1: the synthesis of hyaluronic acid-carboxylated indocyanine green (HA-ICG)

[0027] Weigh 46.4mg of carboxylated indocyanine green (ICG-COOH) and 126.4mg of N,N'-dihydroxyimidazole (CDI) and dissolve in 20ml of DMF solution, and stir at room temperature for 0.5h.

[0028] Weigh 100mg of sodium hyaluronate (HA-COONa) and 95.2mg of 4-dimethylaminopyridine (DMAP) and dissolve in 10ml of formamide solution, slowly add the activated carboxylated indocyanine green solution to the HA-COONa solution, N 2 Stir at room temperature under protection for 14h. The reactant was put into a dialysis bag (MWCO: 3500), dialyzed with 50% DMF solution for 24 hours, and then dialyzed with deionized water for 48 hours. Freeze-dry to obtain hyaluronic acid-carboxylated indocyanine green (HA-ICG) (see attached figure 1 ).

Embodiment 2

[0029] Example 2: Structural characterization of hyaluronic acid-carboxylated indocyanine green (HA-ICG)

[0030] (1) Infrared spectroscopy (FT-IR) characterization: Take appropriate amount of HA-COONa and HA-ICG, mix with KBr, grind into powder, and press into thin slices. Structural analysis was performed with Fourier transform infrared spectroscopy. FT-IR spectrum (attached figure 2 ) analysis results are as follows: The characteristic absorption peak of HA-COONa is 3391.6cm -1 (v NH ), 1642.3cm -1 (v C＝O , amide bond), 2898.6cm -1 (v S CH3 ); and in the HA-ICG spectrum, a new characteristic absorption peak appeared at 1629.2cm -1 (v C＝O , ester bond), 1529.3cm -1 、1509cm -1 (conjugated benzene ring), 929.8cm -1 (trans double bond), these are the characteristic peaks of ICG, indicating that ICG has been covalently linked to HA through ester bonds to form HA-ICG conjugates.

[0031] (2) NMR spectrum ( 1 (H-NMR) characterization: take appropriate amount of HA-C...

Embodiment 3

[0032] Embodiment 3: Synthesis of carboxylated indocyanine green-hyaluronic acid-paclitaxel (ICG-HA-PTX)

[0033] Weigh 75mg of HA-ICG and 49.95mg of N,N'-dihydroxyimidazole (CDI) and dissolve in 20ml of DMF solution, and stir at room temperature for 1h.

[0034] Another 14.06 mg of PTX and 37.5 mg of 4-dimethylaminopyridine (DMAP) were dissolved in 4 ml of DMF solution, and the above-mentioned activated HA-ICG solution was slowly added to the PTX solution, N 2 Stir at room temperature under protection for 24h. The reactant was put into a dialysis bag (MWCO: 3500), dialyzed with DMF solution for 24 hours, and then dialyzed with deionized water for 48 hours. Freeze-drying to obtain carboxylated indocyanine green-hyaluronic acid-paclitaxel (ICG-HA-PTX) (see attached figure 1 ).

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Abstract

The invention belongs to the field of organic synthesis or pharmaceutical preparations and relates to a synthesis method of a hyaluronic acid-photosensitizer/antitumor drug with synergistic anti-tumor efficacy and a preparation method of a nano drug delivery system. Conjugates are amphiphilic by connecting a photosensitizer and an indissolvable antitumor drug on a hyaluronic acid skeleton by ester bonds and are self-assembled in water to obtain a nanomicelle. The synthesis method and the preparation method are characterized by comprising the synthesis method of covalent linkage of hyaluronic acid and a photosensitizer/antitumor drug and a method for self-assembling the nano drug delivery system by the hyaluronic acid-photosensitizer/antitumor drug. The system is expected to have good biocompatibility and active targeting property of tumors in a body; the solubility of the indissolvable antitumor drug can be improved, the phagocytosis of a reticuloendothelial system is avoided, and the cycle time in the body is prolonged; after the system reaches a lesion location, the ester bonds of the system are fractured in a tumor microenvironment under the condition of a low pH value and releases the photosensitizer and the antitumor drug; the system is excited by near-infrared light to generate heat and fluorescence; on one hand, tumor cells are killed and wounded by a phototherapy and chemotherapy combined mode; on the other hand, distribution conditions of the tumor cells in the body can be characterized.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations and relates to the preparation of a hyaluronic acid-based photosensitizer / antitumor drug self-assembled nano drug delivery system. Background technique [0002] Cancer is one of the diseases that seriously threaten people's lives in the world, and its mortality rate is extremely high. It has been listed as the "second killer" (second only to cardiovascular diseases), causing about 13% of the global mortality rate. [0003] The commonly used anti-tumor method in clinical practice is chemotherapy. Most of the anti-tumor drugs are insoluble drugs, which have poor oral absorption, low bioavailability, fast metabolism, short half-life, and short residence time in the body. In order to maintain effective therapeutic concentration, it is necessary to Increase the dosage or increase the frequency of administration, but it will lead to greater toxic and side effects. Paclitaxel (PTX) belongs to ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/107A61K41/00A61K31/337A61K47/61A61P35/00
CPCA61K9/1075A61K31/337A61K41/0057A61K2300/00
Inventor 王伟周建平刘源王钝
Owner CHINA PHARM UNIV
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