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Novel biodegradable controlled-release preparation of Pin1 inhibitor ATRA, and preparing method and application thereof

A technology of biodegradable and controlled-release preparations, applied in anti-inflammatory agents, pharmaceutical formulations, microcapsules, etc., can solve the problems of costing money, destroying the carrier structure, and time-consuming, and achieve high encapsulation efficiency and yield, and biocompatibility Good sex, enhanced inhibitory effect

Inactive Publication Date: 2018-04-20
FUJIAN MEDICAL UNIV +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, people have tried to prepare ATRA sustained-release agents such as ATRA-loaded liposomes by various methods, but there is no ATRA sustained-release agent used in clinical practice, especially for the treatment of solid tumors.
Although commercialized ATRA sustained-release tablets can effectively inhibit tumor growth, the sustained-release tablets can only be used in animals
In addition, the encapsulation efficiency, stability and sustained-release performance of the reported ATRA sustained-release agents are still relatively poor
Moreover, the existing sustained-release preparation methods are complicated, time-consuming, and costly. The preparation conditions are severe, and additional steps are required for organic solvent removal and product drying. These treatments may destroy the structure of the carrier and affect the activity of the loaded drug.

Method used

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  • Novel biodegradable controlled-release preparation of Pin1 inhibitor ATRA, and preparing method and application thereof
  • Novel biodegradable controlled-release preparation of Pin1 inhibitor ATRA, and preparing method and application thereof
  • Novel biodegradable controlled-release preparation of Pin1 inhibitor ATRA, and preparing method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Add ATRA and PLLA to the organic solvent dichloromethane, and obtain a homogeneous oil phase by stirring, wherein the concentration of PLLA is 1% (% is mass volume percentage, % in the embodiments of the present invention refers to kg / L), ATRA and PLLA The mass ratio is 3%; the oil phase is pumped (flow rate is 1.0 mL / min) into the reactor, under the condition of supercritical carbon dioxide (pressure is 7.6 MPa; temperature is 45°C, carbon dioxide flow rate is 40 g / min ), to obtain ATRA-loaded PLLA microspheres, and then continue to dry the microspheres with supercritical carbon dioxide for 30 min to fully remove dichloromethane. Blank PLLA microspheres and FITC-loaded PLLA microspheres were prepared under the same experimental conditions. Scanning electron microscopy (SEM) results showed that ATRA-PLLA microspheres had good sphericity and uniform particle size. Transmission electron microscopy (TEM) results showed that ATRA-PLLA microspheres were solid microspheres. ...

Embodiment 2

[0051] Weigh 4 mg of ATRA-PLLA microspheres, add them into 4 mL of dichloromethane, and dissolve them fully with magnetic stirring, and measure the absorbance of the solution at 360 nm with a microplate reader. The blank PLLA microspheres were dissolved in dichloromethane as a background control. The ATRA standard curve was established with the ATRA standard substance, and the concentration of ATRA in the dichloromethane solution was calculated. In addition, 4 mg of ATRA-PLLA microspheres were weighed and added to 4 mL of 75% ethanol to elute the loosely adsorbed or bound ATRA on the surface of the microspheres, and then filtered with a 0.22 μm filter membrane and read at 360 nm with a microplate reader. Measure the absorbance of the ethanol solution. The concentration of ATRA in the ethanol solution was calculated according to the ATRA standard curve. The drug loading, encapsulation efficiency and yield were calculated according to the formula. Drug loading (%) = (weight o...

Embodiment 3

[0053] Weigh 2 mg of ATRA-PLLA microspheres, disperse them in 1 mL of PBS (pH7.4), PBS containing 5% serum, MEM medium, or MEM medium containing 5% serum, and place at 37°C , 100 rpm shaker, at different time points (2 h, 6 h, 12 h, 1 d, 2 d, 3 d, 4 d, 5 d, 6 d, 7 d, 8 d, 9 d, 10 d , 11 d, 12 d), take out the experimental samples, centrifuge at 10,000 rpm for 5 min, collect the supernatant, then resuspend the microspheres with the fresh above-mentioned release medium, and put them back in the shaker to continue the experiment. The concentration of ATRA in each supernatant was measured, and the cumulative release rate of ATRA was calculated. As a result, ATRA-PLLA microspheres could release ATRA for 12 days even in serum-containing MME medium; in serum-free medium solution, there was no burst release phenomenon of ATRA-PLLA microspheres. That is, ATRA-PLLA microspheres can effectively release ATRA in vitro.

[0054] figure 2 It is the in vitro release profile of ATRA-PLLA m...

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Abstract

The invention discloses a novel biodegradable controlled-release preparation of a Pin1 inhibitor ATRA, and a preparing method and an application thereof; the preparing method includes the following steps: a, dissolving ATRA and PLLA in an organic solvent, and preparing ATRA-loaded PLLA microspheres under a condition of supercritical carbon dioxide; and b, with liver cancer as a model, researchingthe anti-cancer efficacy and action mechanism of the ATRA-PLLA microspheres in vivo and in vitro. Under mild conditions, the ATRA-PLLA microspheres are obtained by the one-step method; the microspheres have uniform particle size, high encapsulation efficiency and high yield, can effectively slowly release ATRA, and have a main pharmacokinetic index better than that of commercialized ATRA slow-release tablets (the slow-release tablets can be used only for animals). The ATRA-PLLA microspheres have good biocompatibility and can selectively enhance the ATRA inhibition on tumor growth, and have theanti-cancer efficacy better than that of the ATRA slow-release tablets. ATRA plays an anti-cancer role by degrading Pin1 and inhibiting multiple Pin1-regulated oncogenic signaling pathways and cell cycle progression. The ATRA-PLLA microspheres are expected to be used in clinic treatment of Pin1-related diseases such as tumor, inflammation, arthritis, lupus erythematosus and asthma.

Description

technical field [0001] The invention relates to a novel controlled-release preparation of Pin1 inhibitor ATRA and its application in the treatment of Pin1-related diseases. Background technique [0002] Molecular targeted drugs play an important role in the treatment of cancer and other diseases, but are less effective in the long-term treatment of solid tumors. The main reason is that the current molecular targeted drugs mostly target a single signaling pathway for tumor treatment, while multiple oncogenic signaling pathways are often activated simultaneously in malignant tumors, especially for liver cancer with high heterogeneity and complex etiology. In order to improve the therapeutic effect on tumors such as liver cancer, it is urgent to develop new molecularly targeted drugs that can simultaneously block multiple cancer signaling pathways without harm. [0003] In cell proliferation and transformation signaling pathways, the main common mechanism is proline-directed p...

Claims

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Application Information

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IPC IPC(8): A61K9/52A61K31/203A61K47/34A61P35/00A61P29/00A61P19/02A61P11/06A61P37/02
CPCA61K9/5031A61K9/5089A61K31/203
Inventor 杨达云卢坤平周小珍王士斌
Owner FUJIAN MEDICAL UNIV
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