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Phosphate-based drug delivery system for intracerebral drug delivery

A delivery system and polyphosphate technology, applied in drug delivery, pharmaceutical formulations, etc., can solve problems such as inability to meet multi-functional modification and potential safety hazards, and achieve the effect of meeting the requirements of multi-functional modification and high safety

Inactive Publication Date: 2012-02-01
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently commonly used carrier materials include polyethylene glycol-polylactic acid block copolymer (PEG-PLA), polyisocyanoacrylic acid (PIBC), PEG-phospholipid, etc., and polyethylene glycol (PEG) is usually used as its hydrophilic chain, but because PEG is not biodegradable, there are certain safety hazards after entering the brain
In addition, PEG can only be functionalized at the end, so it cannot meet the requirements of multifunctional modification

Method used

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  • Phosphate-based drug delivery system for intracerebral drug delivery
  • Phosphate-based drug delivery system for intracerebral drug delivery
  • Phosphate-based drug delivery system for intracerebral drug delivery

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Example 1: Since the hydrophobic segment of the block copolymer only plays the role of encapsulating hydrophobic drugs and does not affect the surface properties of the finally formed nanomicelles, this example and the following examples are represented by PPE-PCL. The brain-targeting performance of polyphosphate-based amphiphilic block copolymers was investigated.

[0073] In order to prove that the micelles prepared by PPE-PCL can increase the distribution of drugs into the brain, nanomicelles loaded with fluorescent dye Coumarin-6 (purchased from Acros, USA) were prepared, and its toxicity and brain targeting were investigated. ability.

[0074] 1) Preparation of drug nanomicelles loaded with fluorescent dye coumarin-6

[0075] Using PCL-OH as a macroinitiator, the ring-opening polymerization of 2-ethoxy-1,3,2-dioxaphospholane was initiated in anhydrous THF, and purified by ether precipitation to obtain R 1 is ethyl, R 2 Hydrogen polymer PCL-PPE-OH. 40 mg of PCL-...

Embodiment 2

[0082] Example 2: In order to prove that functionalized nanomicelles modified by polyphosphate-based brain-targeting ligands can promote the distribution of drugs in the brain, the micelles were prepared and used for intracerebral administration. Because the connection mode of each targeting ligand and micelles has no effect on the targeting effect in the brain, and there is no significant difference in the essence of increasing drug distribution in the brain by different ligands, so this example uses maleimide groups and transgenic Taking the connection of ferritin as an example, the intracerebral drug delivery performance of functionalized nanomicelles modified with polyphosphate-based brain-targeting ligands was investigated.

[0083] 1) Thiolation of transferrin

[0084] Dissolve transferrin (Sigma) in HEPES buffer at pH 7.4 to obtain a 1 mg / mL solution, add 100 μl of 0.1 M hydroxylamine (Sigma) per mg of protein, thiolate transferrin for 2 h, and then carry out Purified ...

Embodiment 3

[0095] Example 3: Since the solubility of teniposide and paclitaxel are quite different, the preparation method of the nanomicelle according to the present invention is also slightly different. In order to illustrate the preparation method of brain-targeted nanomicelles loaded with teniposide, this example uses an anti-transferrin receptor antibody as an example to modify PCL-PPE-Mal with a brain-targeted ligand to illustrate its preparation method. The types of side chains of the hydrophobic segment and the hydrophilic segment do not affect its preparation method.

[0096] 1) Thiolation of anti-transferrin receptor antibody

[0097] Dissolve anti-transferrin receptor antibody (Wuhan Boster) in HEPES buffer at pH 7.4 to obtain a 1 mg / mL solution, add 100 μl of 0.1M hydroxylamine per mg of protein, add anti-transferrin receptor The antibody was thiolated for 2h, and then purified by ultrafiltration. The degree of sulfhydrylation of lactoferrin was determined by Ellman's reagent...

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Abstract

The invention relates to a novel drug delivery system with intracerebral drug delivery characteristics. The carrier material of the drug delivery system is an amphiphilic copolymer with polyphosphate as a hydrophilic chain, and is expected to self-assemble to form a nano micelle; and the surface of the nano micelle can be bonded with a brain-targeting ligand through covalent bonds. The drug delivery system has the characteristics that one or more of low-molecular-weight chemical drugs and diagnosis drugs can be delivered to penetrate through the blood-brain barrier and enter the brain, so as to exert the effects of prevention, treatment and diagnosis; the amount of the drug penetrating through the blood-brain barrier and the intracerebral distribution of the drug are increased, thereby improving treatment and diagnosis effects; the peripheral distribution of the drug is reduced, thereby reducing overall toxic and side effects; the carrier material can be biodegraded, thereby avoiding the toxicity of the carrier material; and the particle size, surface charge and ligand modification are controllable, thereby facilitating the optimization of the carrier material.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations and relates to a drug delivery system, in particular to a novel drug delivery system based on polyphosphate for delivering small molecule chemical drugs and diagnostic reagents into the brain. technical background [0002] The blood-brain barrier (BBB) ​​is a physiological barrier composed of brain capillary endothelial cells, basement membrane and glial cells, which can prevent most drugs from entering the brain. Therefore, if the drug is administered through a conventional non-invasive route, in order to achieve a therapeutic concentration of the drug in the brain, it is necessary to increase the dose, but the high concentration of the drug in the periphery can also cause serious side effects. However, if the invasive route of administration including hyperosmotic shock, carotid artery injection and direct intracerebroventricular injection is used, although the effect is better, it is ...

Claims

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Application Information

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IPC IPC(8): A61K47/34A61K9/00C08G79/04
Inventor 李亚平张鹏程张志文顾王文
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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