Programmed multi-target tree-shaped macromolecular assembled body medicine conveying system as well as preparation method and application thereof

A technology of dendritic macromolecules and delivery systems, which is applied in the field of biomedical materials and can solve the problems that nano-delivery systems have not been properly solved.

Inactive Publication Date: 2015-09-16
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In clinical treatment, there are still many problems in the nano-delivery system that have not been properly resolved, especially how to reduce the toxic and side effects of chemotherapy through the specific recognition of tumor tissues and cells.

Method used

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  • Programmed multi-target tree-shaped macromolecular assembled body medicine conveying system as well as preparation method and application thereof
  • Programmed multi-target tree-shaped macromolecular assembled body medicine conveying system as well as preparation method and application thereof
  • Programmed multi-target tree-shaped macromolecular assembled body medicine conveying system as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] Example 1: Preparation of self-assembling motif of amphiphilic dendrimer with programmed multiple targeting (synthetic route is as figure 1 )

[0076] The second generation lysine dendrimer (HO-Lys(G2)-Boc 4 )Synthesis

[0077] Weigh 4.0 g H-Lys-OMe·2HCl, 14.8 g Boc-Lys(Boc)-OH, 5.1 g HOBT and 13.2 g EDC·HCl in a 100 mL round-bottom flask with a branch tube, evacuate and fill with nitrogen, Add 30 mL of redistilled DCM, stir to dissolve, add 28.3 mL of DIEA in an ice bath to react for 0.5 h, and then react at room temperature for 48 h. The solvent was removed by rotary evaporation with a water pump, and the chloroform was dissolved, followed by 1 M HCl and saturated NaHCO 3 After washing with NaCl, use anhydrous MgSO 4 After drying overnight, filter, spin off the solvent, and separate by 200-300 mesh silica gel column chromatography (eluent DCM / EA = 1:1) to obtain white powder MeO-Lys(G2)-Boc 4 (Compound 1).

[0078] Demethylation protection, accurately weigh 4.0 g of MeO-Ly...

Embodiment 2

[0089] Example 2: Preparation of self-assembling motif two of amphiphilic dendrimer with programmed multiple targeting (the synthetic route is as image 3 )

[0090] Functionalized hydrophilic end (PEG 1500 -Biotin) synthesis

[0091] Accurately weigh 1.0 g of biotin, 1.6 g of EDC·HCl and 0.6 g of HOBT in a 250 mL round-bottom flask with a branch tube, evacuate, fill with nitrogen, and add 20 mL of DMSO to dissolve. After biotin was activated for 2 h, add 12.2 g PEG 1500 And 3.4 mL DIEA in DCM, continue to react at room temperature for 24 h. After the oil pump spins off the solvent, the residue is dissolved in chloroform, and then saturated NaHCO 3 After washing with NaCl, use anhydrous MgSO 4 After drying overnight, filter, spin off the solvent, and separate by 200-300 mesh silica gel column chromatography to obtain white solid PEG 1500 -Biotin (Compound 11).

[0092] Synthesis of Oleic acid-Lys-OH hydrophobic end

[0093] Accurately weigh out 5.0 g of H-Lys-OMe·2HCl, 16.5 g of EDC·...

Embodiment 3

[0097] Example 3: Determination of Critical Aggregation Concentration of Amphiphilic Dendrimer Self-Assembly Element

[0098] The first preparation concentration is 6.02 × 10 -7 mol / L pyrene aqueous solution, and then dilute the amphiphilic dendrimer prepared in Example 1 with the pyrene water prepared above to 1.0 mg / mL to 1.0×10 -7 mg / mL solutions of different concentrations. The fixed emission wavelength is 395 nm, the excitation wavelength in the range of 300 nm-380 nm is measured with a fluorescence spectrophotometer, and the fluorescence values ​​at 338 nm and 334 nm are recorded. Take I 338 / I 334 The ratio of is the ordinate, and the concentration is the abscissa. The result is as Figure 5 Shown. The measured critical aggregation concentration is 4.85 μg / mL. A smaller critical aggregation concentration value indicates that the assembly has good potential stability and prevents disassembly due to large dilution by blood during in vivo delivery.

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Abstract

The invention discloses a programmed multi-target tree-shaped macromolecular assembled body medicine conveying system as well as a preparation method and application thereof and belongs to the field of biomedical materials. The medicine conveying system taking an amphipathic tree-shaped macromolecular assembled body as a carrier is used for realizing programmed multi-target through responding a tumor micro-environment, so that main biological obstacles met in a process of transferring the medicine carrier in a body are overcome, and finally, medicines are conveyed to the destination. The obtained self-assembled body has a multi-target effect through the functionalization effect of a plurality of types of terminal groups. On one hand, tree-shaped molecules are used as the medicine carrier and have the advantages of good stability, high mechanical strength, multivalent terminal groups, hyper-branched structures, and intracellular conveying of echoviruses; on the other hand, a multi-element cooperated self-assembling policy is integrated with the advantages of all functional groups on a tree-shaped macromolecular self-assembled unit, so that the assembled body can be conveyed by the multifunctional and efficient medicine system. The system is particularly suitable for conveying anti-tumor medicines.

Description

technical field [0001] The invention belongs to the field of biomedical materials, in particular to a programmed multi-target drug carrier. technical background [0002] At present, malignant tumors are a serious threat to human health and development, and are one of the common problems faced by all mankind. Chemotherapy, as one of the most commonly used treatment methods, has achieved a certain degree of tumor inhibition; however, current chemotherapy drugs face problems such as poor water solubility, unsatisfactory metabolism and distribution in the body, and large toxic and side effects that need to be resolved urgently. Nano-delivery systems have significant advantages in increasing drug solubility, improving drug metabolism, and reducing side effects. After research and development in recent years, some nano-drug delivery systems have been successfully used in clinical treatment (such as nano-liposomes loaded with doxorubicin Doxil ? , Nanomicelle Genexol-PM loaded wi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/51A61K47/42A61K47/34A61K47/36A61K47/26A61K47/22A61K47/48A61P35/00A61K31/704A61K31/337A61K31/4745
Inventor 顾忠伟徐翔晖张志军张晓李亚超李芸焜钟单
Owner SICHUAN UNIV
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