Small-molecular micelle drug-loaded nano-system, as well as preparation method and application thereof

A nano drug-loading and drug-loading system technology, which is applied in the direction of pharmaceutical formulations, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc., can solve the problems of poor stability and low loading rate of small molecule micelles

Active Publication Date: 2016-10-12
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This nano-carrier system not only uses the characteristics of simple synthesis and easy degradation of small molecule micelles, but also solves the problems of poor stability and low loading rate of small molecule micelles.

Method used

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  • Small-molecular micelle drug-loaded nano-system, as well as preparation method and application thereof
  • Small-molecular micelle drug-loaded nano-system, as well as preparation method and application thereof
  • Small-molecular micelle drug-loaded nano-system, as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Example 1 Preparation of cross-linked small molecule micelles nano-drug loading system.

[0071] a kind of like figure 2 In the small molecule micelle nano drug loading system, L1 is an amphiphilic molecule, the hydrophobic end is a cross-linkable alkyl chain, and the hydrophilic end is a hydrophilic drug. We use lipoic acid at the hydrophobic end, and jecitabine at the hydrophilic end. L1 self-assembles to form micelles through the amphiphilic principle, and then forms a stable cross-linked micellar drug-loading system through internal cross-linking.

[0072] (1) The following is the synthetic route of L1:

[0073]

[0074] resolve resolution:

[0075] The raw materials are Jecitabine, lipoic acid and organic base N,N - Diisopropylethylamine (DIPEA), condensing agent 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDCI), solvent DMF. Combine jesitabine and N,N -Diisopropylethylamine was dissolved in DMF, and then lipoic acid and 1-ethyl-(3-dimethylaminopropyl) ...

Embodiment 2

[0089] Example 2 Stability testing of small molecule cross-linked micellar nano-drug loading system.

[0090] Take 5 mL of water in 10 mL vials and mark them as No. 1 and No. 2 bottles respectively. Add 25 μL of L1 (0.1 mmol / ml ) solution respectively under the condition of vigorous stirring of water, and finally a micellar solution with a concentration of 0.5 mmol / L can be obtained. According to the previous method, the micelles in the No. 1 vial were cross-linked according to the method of Example 1 (4), and L1 cross-linked micelles and L1 uncross-linked micelles were finally prepared respectively. 4.5 mL of L1 crosslinked micelles and L1 uncrosslinked micelles were incubated with 0.5 mL of fetal bovine serum, and the DLS values ​​of the two micelles were measured at different time points. The result is as Figure 5 As shown in (a), after the L1 cross-linked micelles and L1 uncross-linked micelles were incubated in serum for 1 h, the particle size changes before and after ...

Embodiment 3

[0091] Example 3 In vitro release of cross-linked small-molecule micellar nano-drug delivery system (enzyme-sensitive detection)

[0092] In vitro release experiments of nanomicelles: L1 cross-linked micelles and L1 uncross-linked micelles were prepared at a concentration of 0.5 mmol / L, and the pH of the solution was adjusted to 5.5. Take 5 mL of materials respectively, place them in a water bath shaker at 37°C, add 40 μL of Cathepsin B (5 U / mL) or no Cathepsin B, shake and incubate, and sample 100 μL at the set time point, The samples taken out were detected by high performance liquid chromatography to detect the content of the drug jecitabine released in each sample, and finally the release curves of L1 cross-linked micelles and L1 uncross-linked micelles in the presence or absence of protease B were made , the result is as Figure 6 shown. It can be seen from the figure that the nanoparticles are hardly released in the absence of protease B (as a comparison, the present e...

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Abstract

The invention discloses a small-molecular micelle drug-loaded nano-system, and belongs to the field of biological materials. The drug-loaded system is a nano-micelle formed by self-assembly of amphiphilic molecules, wherein the amphiphilic molecule comprises a hydrophilic drug and a hydrophobic chain segment which are directly connected; the nano-micelle can obtain a stable structure through internal crosslinking, and the small-molecular micelle drug-loaded nano-system has high drug-loading capacity, and is simple in synthesis and easy to degrade. A hydrophilic drug and a cross-linkable hydrophobic alkyl chain are bonded through a sensitive bond to form an amphiphilic molecule, and the amphiphilic molecule is prepared into the small-molecular micelle, and the inside of the micelle is crosslinked to improve the stability of the micelle when circulating in a body; a targeted amphiphilic ligand is added into the small-molecular micelle, and can reach a tumor tissue through active and passive targets, and the sensitive bond is broken to release drug molecules and kill cancer cells; a ligand with a long-circulation function can be introduced into the small-molecular micelle to prolong the time of a nano-drug for circulating in the body; and ligands of different hydrophilic drugs can be introduced into the micelle to finally form multi-drug nano-particles, and the aim of multi-drug combination can be achieved.

Description

technical field [0001] The invention belongs to the field of biological materials, and in particular relates to a small-molecule micellar nanometer drug-carrying system and its preparation method and application. technical background [0002] Cancer is a common and frequently-occurring disease that seriously threatens human health. Overcoming cancer has always been a research hotspot in the world, and drug therapy is currently one of the most commonly used and most effective treatments. Small molecule drugs have obvious chemotherapeutic effects, but they cause great damage to normal tissues, have large toxic and side effects, and the drugs cannot be released in a controlled manner. [0003] Nano-loaded drug delivery system has significant advantages such as targeting, sustained release, and biodegradable carrier materials, so it has broad application prospects. The construction of nano-drug delivery system is inseparable from drug carriers with good performance. Among them,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K9/107A61K31/7068A61P35/00
Inventor 张仕勇廖春燕余孝其
Owner SICHUAN UNIV
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