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PH-sensitive mixed micelle as well as preparation method and application thereof

A mixed micellar and sensitive technology, applied in the direction of drug combination, pharmaceutical formulation, organic active ingredients, etc., can solve the problems of multidrug resistance, low bioavailability of chemotherapy drugs, etc., and achieve long drug circulation time and good size Effect of tissue retention, good biocompatibility

Active Publication Date: 2017-12-08
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The present invention is a pH-sensitive mixed micelle with co-delivery of multiple drugs, which realizes simultaneous delivery of multiple drugs by physical mixing to form mixed micelles, so as to play a combined anti-tumor effect to kill tumor cells, thereby solving the problem of chemotherapeutic drugs The problem of low bioavailability, while improving the efficiency of drug delivery, and overcoming the problem of multidrug resistance of tumor cells

Method used

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  • PH-sensitive mixed micelle as well as preparation method and application thereof
  • PH-sensitive mixed micelle as well as preparation method and application thereof
  • PH-sensitive mixed micelle as well as preparation method and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0045] figure 1 It is a schematic diagram of the pH-sensitive polymer prodrug of the embodiment of the present invention. from figure 1 It can be seen that the pH-sensitive mixed micelles of the present invention have a double-layer structure, the outer layer is PEG with good hydrophilicity, the inner layer is hydrophobic drug DOX, and TPGS is also connected to it by amphiphilicity.

[0046] (a) Preparation of pH-sensitive polymeric prodrugs

[0047] With 20 mL of anhydrous DCM (dichloromethane) as the solvent and 694 μL of TEA as the catalyst, 2.00 g of mPEG with a molecular weight of 2000 was dissolved and then added TEA dropwise, and 1.0078 g of chloroformic acid was dissolved in 10 mL of anhydrous DCM as the solvent. After the phenyl phenyl ester was dissolved, it was added dropwise at 0°C, and reacted at 30°C for 24 hours. The solution was rotary evaporated at 28°C to remove DCM, anhydrous ether was added, the precipitated white substance was collected, reprecipitated ...

Embodiment 2

[0054] The particle size distribution characterization of the polymer prodrug and a pH-sensitive mixed micelle, the specific steps are as follows:

[0055] The polymer prodrug was made into a solution with a concentration of 500 μg / mL, and the polymer prodrug and TPGS were mixed at a molar ratio of 3:1. Measurement. The results of polymer prodrug testing are as follows: image 3 Shown in A, the average particle diameter of this polymer prodrug micelle is 204 nm, and PDI is 0.232; The detection result of mixed micelle is as follows image 3 As shown in B, the particle size distribution is uniform, the average particle size is 144 nm, and the PDI is 0.187. The particle size distribution of this mixed micelle is narrow, and it is significantly different from the particle size of the polymer prodrug, which indicates that a new Micellar rather than physical mixing of polymeric prodrug and TPGS.

Embodiment 3

[0057] Morphological characterization of polymer prodrugs and a pH-sensitive mixed micelle, the specific steps are as follows:

[0058] The polymer prodrug and a pH-sensitive mixed micelle were formulated into a 100 μg / mL solution with distilled water, dropped onto the copper grid, and dried overnight (14 hours). The morphology was observed with a transmission electron microscope. From the results of transmission electron microscopy, we can see that the polymer prodrug presents a spherical morphology with good monodispersity ( Figure 4 A), pH-sensitive mixed micelles exhibit a spherical structure with good monodispersity ( Figure 4 B).

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Abstract

The invention relates to a preparation method and an application of a pH-sensitive mixed micelle. An anti-cancer drug, namely DOX, is in covalent linkage with mPEG by virtue of acid-sensitive Cbm, an obtained material, as a polymer prodrug, is mixed with TPGS, and self-assembling is conducted in a water solution, so that the mixed micelle, which is of a core-shell structure, is formed. The pH-sensitive mixed micelle provided by the invention can, in response to a special low-pH environment of tumor tissues, can achieve specific release of the DOX, so that the excretion of the drug can be effectively inhibited and the multi-drug resistance of tumor cells can be reversed; and the mixed micelle is good in biocompatibility and long in drug circulating time, and the preparation method is convenient for operation and popularization and has a good development prospect.

Description

technical field [0001] The invention relates to a pH-sensitive mixed micelle, a preparation method and application thereof. The anticancer drug doxorubicin (DOX) is covalently linked to polyethylene glycol monomethyl ether (mPEG) via an acid-sensitive carbamate bond (Cbm) as a polymer prodrug, and D-α-tocopheryl polyethylene glycol Diol 1000 succinate (TPGS) was mixed and self-assembled in aqueous solution to form nanomicelles with nuclei structure. Background technique [0002] At present, there are about 14 million new cases of cancer each year in the world, of which more than 8 million people die. One of the most important treatments against cancer remains chemotherapy, but it has been challenged by the emergence of multidrug resistance, which greatly reduces the efficacy of chemotherapy. For example, P-glycoprotein located in the cell membrane is closely related to multidrug resistance. It can excrete drugs from cancer cells to reduce the concentration of drugs in cell...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/107A61K47/22A61K47/60A61K31/704A61P35/00
CPCA61K9/1075A61K31/704A61K47/22
Inventor 王永健于奡王鑫楠孙丹丹吕学明
Owner NANKAI UNIV
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