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Brain-targeted water soluble drug carrier as well as preparation method and application thereof

A water-soluble drug and brain-targeted technology, which can be used in drug combinations and neurological diseases, etc., can solve the problems of low protein yield, destruction of LDL structure, and cumbersome procedures

Inactive Publication Date: 2014-12-17
吴正治 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this "recombination method" is that the process is cumbersome, the protein yield is not high, and the whole process may destroy the structure of LDL, and it requires hydrophobic modification of hydrophilic drugs

Method used

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  • Brain-targeted water soluble drug carrier as well as preparation method and application thereof
  • Brain-targeted water soluble drug carrier as well as preparation method and application thereof
  • Brain-targeted water soluble drug carrier as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] 1. Synthesis of formaldehyde chitosan (CS-CHO)

[0049] As a natural polysaccharide, chitosan has the characteristics of good biocompatibility and biodegradability, and is especially suitable for drug carriers. However, the main problem limiting its application is poor water solubility, which needs to be dissolved in acidic medium. Therefore, in this project, firstly, chitosan was oxidized with periodate to obtain chitosan with different molecular weights and chitosan chains containing o-dialdehyde functional groups, which greatly improved its water solubility. The synthetic route is as follows:

[0050]

[0051] Wherein, the range of x is 2-30; the range of y is 10-50, the range of y' is 2-20; the range of z is 8-30, wherein y=y'+z.

[0052] Under the protection of nitrogen, add N-hydroxysuccinimide to the aqueous solution of propiolic acid, dissolve it and drop it into the aqueous solution of aldo-chitosan CS-CHO, stir well, then add 1-ethyl-(3- Dimethylaminopro...

Embodiment 2

[0066] The synthesis of embodiment 2 azide probes

[0067]Palmitic acid with hexadecyl group can fix the "probe" in the phospholipid layer of LDL. In order to prevent the functional group - azide end group from being completely buried in LDL and lose its reactivity, we introduced a single azide The ethylene glycol unit is used as a "spacer" to synthesize N-(2-(2-azidoethoxy)ethyl)palmitamide (NAEP). Concrete synthetic route is as follows:

[0068]

[0069] Among them, a, 2-(2-aminoethoxy)ethanol, 1N HBTU and HOBt, reacted in DMF solution at room temperature for 24 hours; b, TsCl, pyridine; c, 1.2N sodium nitride, pyridine.

[0070] (1)C 15 h 31 CONHCH 2 CH 2 OCH 2 CH 2 Synthesis of OH(NHEP)

[0071] Dissolve 1 mol of palmitic acid, 1 mol of 2-(2-aminoethoxy)ethanol and 3 mol of triethylamine in a nitrogen atmosphere, add 3 mol of dimethylformamide (DMF) and stir to dissolve, place in an ice bath, cool and then add Mix 2 mol of benzotriazole-N, N, N', N'-tetramethyl...

Embodiment 3

[0082] Example 3 Probe labeling of LDL

[0083] LDL was extracted from human plasma by density gradient method (reference: Lundberg, B. Preparation of drug-low density lipoprotein complexes for delivery of antitumoral drugs via the low density lipoprotein pathway. Cancer Res. 1987, 47, 4105). NAEP and LDL are mixed in a co-solvent, and the LDL with an azide probe on the surface is obtained through a self-assembly reaction (NAEP-LDL, denoted as N 3 -LDL).

[0084] The particle size distribution and zeta potential between NAEP-LDL and native LDL after compounding are shown in Table 1 below:

[0085] Table 1 Composition, average particle size and zeta potential of pristine LDL and NAEP-LDL

[0086]

[0087] According to Table 1, it can be found that the particle size distribution and zeta potential difference between the compounded NAEP-LDL and the original LDL are not much different, indicating that the hydrophobic probe modification does not change much the mobility of LDL...

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Abstract

The invention provides a brain-targeted water soluble drug carrier as well as a preparation method and application thereof. An LDL (low density lipoprotein) receptor of an endothelial cell of blood-brain barrier is selected as a transmission water soluble drug to treat a target spot of central nervous system diseases, and chitosan with very good biocompatibility is taken as a drug carrier material to research a low-toxicity efficient water soluble drug nano brain-targeted preparation. The brain-targeted water soluble drug carrier can be used for strengthening brain targeting of water soluble drugs, strengthening the curative effect, lowering the toxic and side effect, and improving the bioavailability.

Description

technical field [0001] The invention belongs to the technical field of targeting carrier drugs, and in particular relates to a brain-targeting water-soluble drug loading and its preparation method and application. Background technique [0002] With the aging of the population, the number of people suffering from central nervous system (central nervous system, CNS) diseases is increasing day by day. The treatment of many nervous system diseases requires the penetration of therapeutic drugs into the entire central nervous system. [0003] The blood-brain barrier (BBB) ​​is a dynamic interface between blood, brain and spinal cord, with low permeability and selective passage ability. The existence of the blood-brain barrier can effectively protect the brain tissue from harmful substances (such as toxins and viruses), but it also prevents many therapeutic drugs from entering the brain lesion, such as anticancer drugs, antibiotics and macromolecular substances (peptides). )Wait....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/36C08B37/08A61P25/28
Inventor 吴正治段丽红
Owner 吴正治
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