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Hydroxycamptothecine linoleate micromolecular prodrug and construction of self-assembled nanoparticles

A technology of hydroxycamptothecin linoleate and self-assembled nanoparticles, which is applied in the direction of drug combination, medical preparations with no active ingredients, medical preparations containing active ingredients, etc., can solve the problem of no obvious advantages and poor clinical results Ideal and other problems, to achieve the effect of simple and easy preparation method, simple and easy synthesis method, and high-efficiency entrapment

Inactive Publication Date: 2020-08-04
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the paclitaxel-docosahexaenoic acid prodrug has entered the clinical phase III, and its clinical results in phase III are not satisfactory. Since the parent drug is difficult to release quickly from the prodrug, it is comparable to the first-line drug in inhibiting the growth of melanoma. Compared with the anticancer drug dacarbazine, there is no obvious advantage

Method used

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  • Hydroxycamptothecine linoleate micromolecular prodrug and construction of self-assembled nanoparticles
  • Hydroxycamptothecine linoleate micromolecular prodrug and construction of self-assembled nanoparticles
  • Hydroxycamptothecine linoleate micromolecular prodrug and construction of self-assembled nanoparticles

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1: Synthesis of hydroxycamptothecin linoleate small molecule prodrug (HCPT-SS-LA)

[0042] Add linoleic acid to the toluene solution in which p-toluenesulfonic acid and 2,2'-dithiodiethanol have been dissolved, and the reaction system is in N 2 The temperature was raised to 110°C under protection. After the reaction was detected by TLC, the reaction was carried out with saturated NaHCO 3 solution extraction, followed by anhydrous Na 2 SO 4 The excess water was removed and the intermediate product was finally isolated by column chromatography. The intermediate product was dissolved in dichloromethane, DIPEA and p-nitrobenzoic chloroformate were added under ice-bath conditions, and stirred overnight at room temperature. Remove the solvent by rotary evaporation under reduced pressure, redissolve the system with DMF, cool it to 0°C in ice bath, slowly add the hydroxycamptothecin solution dissolved in DMF, add anhydrous triethylamine, react at room temperature...

Embodiment 2

[0045] Example 2: Preparation of small molecule prodrug self-assembled nanoparticles

[0046] Precise weighing of TPGS 2k Appropriate amount (8% is 0.35 mg, 20% is 1 mg, 30% is 1.7 mg) and 4 mg of prodrug, dissolved in 1 mL of THF, slowly added the THF solution dropwise to 4 mL of deionized water under stirring, spontaneously formed Uniform nanoparticles (HCPT-SS-LA nanoparticles, HCPT-SS-LA / 8% PEG nanoparticles, HCPT-SS-LA / 20% PEG nanoparticles, HCPT-SS-LA / 30% PEG nanoparticles). Under the condition of 35°C, the organic solvent in the nano-preparation was removed by rotary evaporation under reduced pressure.

[0047] Table 1. Drug loading of hydroxycamptothecin linoleate prodrug

[0048]

[0049] The formulations in Table 1 can produce prodrug self-assembled nanoparticles, but the particle size of 30% PEGylated nanoparticles is not reproducible in different batches, fluctuating around 130-160nm, while 8% and 20% PEGylated There is almost no difference in particle size b...

Embodiment 3

[0054] Example 3: Cytotoxicity of PEG-modified small molecule prodrug self-assembled nanoparticles

[0055] The cytotoxicity of PEG-modified small molecule prodrug self-assembled nanoparticles on mouse breast cancer (4T1) cells was investigated by MTT assay. Digest the cells in good condition, dilute them with culture medium to a cell density of 1000cells / mL, blow evenly, add 200 μL of cell suspension to each well of a 96-well plate, and incubate in an incubator for 24 hours to make them adhere to the wall. After the cells adhere to the wall, add hydroxycamptothecin or the prodrug nanoparticles prepared in Example 2. In the experiment, the preparation and dilution of the drug solution and the nanoparticle preparation were all made with 1640 culture solution, and sterile filtered with a 0.22 μm filter membrane. 200 μL of the test solution was added to each well, and 3 parallel wells were prepared for each concentration. For the control group, without adding the drug solution ...

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Abstract

The invention belongs to the technical field of medicines. The invention relates to a hydroxycamptothecine linoleate micromolecular prodrug and construction of self-assembled nanoparticles. Accordingto the invention, the disulfide bond bridged hydroxycamptothecine linoleate prodrug is designed and synthesized, and the prodrug is self-assembled into the nanoparticles by adopting a one-step nano precipitation method, so that an efficient and low-toxicity drug delivery system which is good in stability, high in drug loading capacity, low in toxic and side effects, accumulated in tumor parts, capable of selectively releasing drugs and high in anti-tumor activity is obtained, the preparation process is simple, and industrialization is easy. Meanwhile, a hydroxycamptothecine solution is used asa contrast, and morphological characterization of the prodrug self-assembled nanoparticles and in-vitro and in-vivo anti-tumor effects are investigated. More choices are provided for designing camptothecin drug nano-preparations with high drug loading capacity, a new strategy is provided for developing an efficient and low-toxicity drug delivery system, the clinical service life of first-line chemotherapeutic drugs is prolonged, and the urgent requirement for high-end cancer chemotherapeutic preparations in clinic is met.

Description

technical field [0001] The invention belongs to the field of new auxiliary materials and new dosage forms for pharmaceutical preparations, and includes the construction of hydroxycamptothecin linoleate small molecule prodrugs and self-assembled nanoparticles, and their application in drug delivery. Background technique [0002] Cancer threatens the health of all human beings. According to the World Health Organization (WHO), more than 8 million people worldwide die of cancer every year. Chemotherapy is an important tool in cancer treatment, especially for those tumors that cannot be removed by surgery and metastatic spread. Camptothecins can act as good antitumor drugs by inhibiting DNA topoisomerase I. In the exploration of camptothecin and its derivatives, it was found that the 10-position hydroxylation of camptothecin can greatly enhance the antitumor activity of camptothecin, so 10-hydroxycamptothecin (referred to as hydroxycamptothecin) and 7 -Ethyl-10-hydroxycamptoth...

Claims

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Application Information

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IPC IPC(8): C07D491/22A61K31/4745A61K9/51A61K47/22A61K47/24A61K47/34A61P35/00
CPCA61K9/5146A61K31/4745A61P35/00C07D491/22
Inventor 孙进何仲贵李冠廷郑顺哲徐璐
Owner SHENYANG PHARMA UNIVERSITY
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