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Nanoparticles containing cis-platinum-linoleic acid and SN38-linoleic acid as well as preparation method and application of nanoparticles

A SN38-, nanoparticle technology, applied in medical preparations containing active ingredients, nanotechnology, nanotechnology, etc., can solve the problems of drug toxicity, drug resistance, lung cancer patient limitation, etc., and achieve biocompatibility High stability, inhibiting DNA repair protein Rad, and improving water solubility

Pending Publication Date: 2022-04-08
NINGBO FIRST HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, long-term use of cisplatin leads to the emergence of drug resistance in lung cancer, coupled with the toxic and side effects of the drug itself, and the treatment of lung cancer patients from cisplatin therapy is increasingly limited. Therefore, cisplatin resistance and cisplatin safety in lung cancer are still urgently needed key issues to solve
[0003] 7-Ethyl-10-hydroxycamptothecin is the active metabolite of irinotecan (CPT-11) in vivo, which mainly exerts anti-tumor activity by inhibiting DNA topoisomerase I, which leads to replication fork stagnation and eventually leads to DNA double-strand break, its way of killing tumors is different from that of cisplatin, and no research has reported the cross-resistance of cisplatin-resistant tumors to this drug, so it has the potential of anti-cisplatin resistance
However, SN38 itself has extremely poor water solubility and cannot be directly used in clinical practice to replace its water-soluble prodrug CPT-11.

Method used

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  • Nanoparticles containing cis-platinum-linoleic acid and SN38-linoleic acid as well as preparation method and application of nanoparticles
  • Nanoparticles containing cis-platinum-linoleic acid and SN38-linoleic acid as well as preparation method and application of nanoparticles
  • Nanoparticles containing cis-platinum-linoleic acid and SN38-linoleic acid as well as preparation method and application of nanoparticles

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] In this example, nanoparticles containing cisplatin-linoleic acid and SN38-linoleic acid were prepared by precipitation method, and the preparation schematic diagram is as follows figure 1 As shown, the specific steps are:

[0047] Weigh 2.86 mg of Pt-LA containing 1 mg of cisplatin with an electronic balance 2 and 1.67mg of SN38-LA containing 1mg of SN38 were dissolved in 500μL of dimethyl sulfoxide, and then weighed 0.45mg of DSPE-PEG 2k Dissolve in 500 μL of dimethyl sulfoxide, then dissolve and mix the above three kinds, and add dropwise to a beaker containing 9 mL of secondary ultrapure water placed in a water bath ultrasonically at 25 degrees Celsius. After the dropwise addition, evenly Stir steadily for 10 min. Subsequently, the excess dimethyl sulfoxide was removed through a dialysis bag (molecular weight cut-off 1kDa), concentrated with an ultrafiltration tube, and fixedly dissolved to 10mL to obtain an effective amount of 0.1mg / mL containing Pt-LA 2 The aqu...

Embodiment 2

[0049] In this example, nanoparticles comprising cisplatin-linoleic acid and SN38-linoleic acid were prepared by the following method:

[0050] Weigh 5.14 mg of Pt-LA containing 6 μmol cisplatin with an electronic balance 2 and 0.39 mg SN38-LA containing 0.6 μmol SN38 were dissolved in 500 μL dimethyl sulfoxide, and then weighed 0.5 mg DSPE-PEG 2k Dissolve in 500 μL of dimethyl sulfoxide, then dissolve and mix the above three kinds, and the subsequent steps are the same as in Example 1 to obtain a Pt-LA with a molar ratio of cisplatin and SN38 of 10:1. 2 and SN38-LA nanoparticles in aqueous solution.

Embodiment 3

[0052] In this example, nanoparticles comprising cisplatin-linoleic acid and SN38-linoleic acid were prepared by the following method:

[0053] Weigh 4.72 mg of Pt-LA containing 5.5 μmol cisplatin with an electronic balance 2 and 0.72 mg of SN38-LA containing 1.1 μmol SN38 were dissolved in 500 μL of dimethyl sulfoxide, and the subsequent steps were the same as in Example 2 to obtain a 5:1 molar ratio of cisplatin and SN38 containing Pt-LA 2 and SN38-LA nanoparticles in aqueous solution.

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Abstract

The invention belongs to the technical field of design of antitumor drugs, and particularly relates to a nanoparticle containing cis-platinum-linoleic acid and SN38-linoleic acid, the nanoparticle is formed by coating the cis-platinum-linoleic acid and the SN38-linoleic acid with an amphiphilic polymer, and the amphiphilic polymer is distearoyl phosphatidyl ethanolamine-polyethylene glycol. The amphiphilic polymer wraps the cis-platinum-linoleic acid and SN38-linoleic acid prodrug molecules, so that the water solubility of the drug molecules can be improved, in-vivo synchronous delivery and transportation of the prodrug molecules cis-platinum-linoleic acid and SN38-linoleic acid are realized, and a synergistic anti-tumor effect is realized. In mechanism, the invention proves that the SN38-linoleic acid prodrug in the co-coated nanoparticles not only can cause DNA (Deoxyribose Nucleic Acid) cis-injury, but also can inhibit DNA damage to repair protein Rad51, so that the drug effect of the cis-platinum-linoleic acid prodrug in drug-resistant tumors is enhanced, and the optimal tumor killing effect is achieved.

Description

technical field [0001] The invention belongs to the technical field of antineoplastic drug design, in particular to a cisplatin-linoleic acid (Pt-LA 2 ) and SN38-linoleic acid (SN38-LA) nanoparticles, preparation methods and applications. Background technique [0002] Lung cancer is a disease that seriously endangers human health, and its morbidity and mortality rank first among all kinds of cancers worldwide. Among them, 85% are non-small cell lung cancer (NSCLC), and its 5-year survival rate is only 15%. Although surgery is an important way to treat NSCLC patients, most patients are already in advanced stage and have metastases when they are diagnosed. Therefore, chemotherapy is still the main treatment. Cisplatin (also known as cis-dichlorodiamminoplatinum, abbreviated as Pt here) is currently the first choice drug for chemotherapy in patients with clinical NSCLC. It mainly kills tumor cells by forming DNA-cisplatin adducts, and its therapeutic effect is relatively low....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/51A61K47/24A61K33/243A61K31/4745A61K47/54A61P35/00B82Y5/00B82Y40/00
Inventor 李统宇王杭祥欧阳桂芳
Owner NINGBO FIRST HOSPITAL