7-ethyl-10-hydroxycamptothecin amphiphilic polymer prodrug as well as preparation method and nano-particles thereof

A technology of amphiphilic polymers and hydroxycamptothecin, which is applied in the field of nanoparticles, can solve the problems of cumbersome preparation methods and unclear drug structures, and achieve the effects of simple preparation methods, less use of carriers, and reduced side effects

Inactive Publication Date: 2013-08-21
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At the same time, the preparation method of the drug

Method used

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  • 7-ethyl-10-hydroxycamptothecin amphiphilic polymer prodrug as well as preparation method and nano-particles thereof
  • 7-ethyl-10-hydroxycamptothecin amphiphilic polymer prodrug as well as preparation method and nano-particles thereof
  • 7-ethyl-10-hydroxycamptothecin amphiphilic polymer prodrug as well as preparation method and nano-particles thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Example 1 Polyethylene glycol (Mn=5000) polymer prodrug (PEG 5000 -P(HEMASN38) 5000 )Synthesis

[0055] Synthesis of HEMASN38

[0056] Mono[2-[(2-methyl-acryloyl)oxy]ethyl] succinate (Mn=230, 4.6g) and 7-ethyl-10-hydroxycamptothecin (Mn=392, 3.92g ) were mixed in dichloromethane, N,N'-dicyclohexylcarbodiimide (Mn=206, 4.1g) and triethylamine were added, and stirred at room temperature for 24 hours. Then washed with acid water, dried, concentrated and purified by column, the 1H-NMR (400M, CDCl 3 ) for: 8.254(d), 7.829(s), 7.68(s), 7.53(d), 6.12(s), 5.75(d), 5.56(s), 5.27(d), 5.26(s), 4.39( m), 3.13(q), 2.97(t), 2.81(t), 1.89(m), 1.38(t), 1.02(t). It was shown that the compound HEMASN38 (4.8 g, yield 80%) of the structure shown above was obtained.

[0057] Add polyethylene glycol bromoisobutyrate (Mn=5000, 0.5g) and HEMASN38 (Mn=604, 0.5g) into 5mL of anisole, then add CuBr (Mn=141, 2.8mg) and bipyridine (Mn=156, 6.3mg) as a catalyst, heated to 60°C, and reacted fo...

Embodiment 2

[0063] Example 2 The polymer prodrug (PEG5000 -P(HEMASN38) 5000 )Synthesis

[0064] (1) Synthesis of SN38 tert-butyl carbonate (Boc-SN38)

[0065] Mix di-tert-butyl dicarbonate (Mn=186, 2g) and SN38 (392, 2g) in dichloromethane (150mL), add 10mL of pyridine as a catalyst, stir for 24 hours, wash with dilute hydrochloric acid, anhydrous sodium sulfate After drying, 3g product was obtained, and the product was characterized by NMR ( Figure 7 ), proved to be the product Boc-SN38, and the yield was close to 100%.

[0066] Add Boc-SN38 (Mn=493, 0.5g) and mono[2-[(2-methyl-acryloyl)oxy]ethyl] succinate (Mn=230, 0.46g) into dichloromethane, Add N,N'-dicyclohexylcarbodiimide (Mn=206, 0.41g) and triethylamine (0.5mL) and stir for 24 hours. Then it was washed with acid water and passed through the column to obtain the product Boc-HEMASN38. After detection, 1H-NMR10.238(s), 7.935(d), 7.35(d), 6.927(s), 5.89(s), 5.536(s), 5.409(s), 5.197(s), 4.262(d ), 4.135(d), 3.269(s), 3.011(d),...

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Abstract

The invention discloses a 7-ethyl-10-hydroxycamptothecin amphiphilic polymer prodrug comprising a segment of polyethylene glycols and a segment of poly(7-ethyl-10-hydroxycamptothecin); and the poly(7-ethyl-10-hydroxycamptothecin) is formed in the way that hydroxyls at the tenth position or/and twentieth position on 7-ethyl-10-hydroxycamptothecin are connected with a polymer framework through degradable chemical bonds. Polyethylene glycols with different lengths are introduced, so that the prodrug is self-assembled in water to form nano particles, and the solubility of the 7-ethyl-10-hydroxycamptothecin in water is greatly increased. The nanometer size of the polymer prodrug is adjustable so that the 7-ethyl-10-hydroxycamptothecin amphiphilic polymer prodrug can effectively meet the requirement for sizes under different tumor systems and target different intracorporeal organs, and cancers of different organs are possibly treated.

Description

technical field [0001] The present invention relates to the field of amphiphilic block prodrugs and its preparation, in particular to an amphiphilic polymer prodrug of 7-ethyl-10-hydroxycamptothecin, its preparation method and its self-assembled nanoparticles. Background technique [0002] 7-Ethyl-10-hydroxycamptothecin (SN38 for short), is one of the important derivatives of camptothecin drugs, its molecular formula is C22H20N2O0, molecular weight is 392.31, CAS.NO.86639-52-3, molecular structure as follows: [0003] [0004] SN38 is a high-efficiency camptothecin anti-tumor drug, and its anti-tumor activity is 100-1000 times that of the current clinical drug irinotecan, but its hydrophobicity prevents it from directly entering clinical application. Irinotecan and topotecan for clinical application contain hydrophilic functional groups, which improve the disadvantage of camptothecin drugs being insoluble in water, and thus can be used clinically. However, although the...

Claims

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Application Information

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IPC IPC(8): A61K31/4745A61K47/48A61K9/51A61P35/00
Inventor 申有青
Owner ZHEJIANG UNIV
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