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Preparation of tamibarotene-cytarabine conjugate and nano pharmacosomes and anti-tumor application of tamibarotene-cytarabine conjugate and nano pharmacosomes

A technology of cytarabine conjugates and tamibarotene, which is applied in the field of amphiphilic tamibarotene-cytarabine conjugates and their nano-pharmaceuticals, in vivo and in vitro evaluation, and can solve the problem of Drug-resistant bone marrow suppression and other issues

Inactive Publication Date: 2013-08-14
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is easily degraded by cytidine deaminase in the body and metabolized into inactive arabouridine (Ara-U). Continuous intravenous administration or frequent high-dose administration is often used clinically, which is prone to drug resistance and bone marrow suppression. reaction

Method used

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  • Preparation of tamibarotene-cytarabine conjugate and nano pharmacosomes and anti-tumor application of tamibarotene-cytarabine conjugate and nano pharmacosomes
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  • Preparation of tamibarotene-cytarabine conjugate and nano pharmacosomes and anti-tumor application of tamibarotene-cytarabine conjugate and nano pharmacosomes

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1 Preparation of Tamibarotene-Cytarabine Conjugate

[0029] Dissolve 0.702 g (2 mmol) Am80 (tamibarotene), 0.454 g (2.2 mmol) DCC (dicyclohexylcarbodiimide) and 0.270 g (2 mmol) HOBT (1-hydroxybenzotriazole) in Add appropriate amount of anhydrous pyridine solution, stir in ice bath for 60 minutes, add 0.558g (2mmol) Ara-C·HCl (cytarabine hydrochloride), stir in oil bath at 40°C for 2 days, TLC (chloroform / methanol, 6: 1) The points showing Am80 and Ara-C become shallower, spin the reaction solution to dryness under reduced pressure, and remove pyridine; add an appropriate amount of chloroform to dissolve, filter out DCU (dicyclohexyl urea), and spin the filtrate to dryness under reduced pressure. Grind and wash with ether overnight, drain the ether, dissolve the residue in chloroform, wash with 0.01N hydrochloric acid, saturated NaCl and saturated KHSO 4 Wash several times, concentrate the chloroform layer, wash with anhydrous Na 2 SO 4 Dry overnight, filter,...

Embodiment 2

[0032] Example 2 Preparation of Tamibarotene-Cytarabine Nano-pharmaceutical Body

[0033] Accurately weigh the tamibarotene-cytarabine conjugate and lecithin prepared in Example 1 with an appropriate mass ratio, dissolve in an appropriate amount of tetrahydrofuran; and take a certain volume of PBS (PH=7.4) For the buffer solution, slowly and uniformly inject the tetrahydrofuran solution (the needle is located under the liquid surface) into the PBS solution at an appropriate speed under constant stirring, after the addition is completed, continue to stir for a certain period of time, remove the tetrahydrofuran by rotary evaporation under reduced pressure at 37°C, and obtain the drug plastid. No precipitation by visual inspection, uniform dispersion system with light blue opalescence; spherical vesicle structure can be seen under optical microscope. As measured by a laser nanometer particle size analyzer, the particle size of the drug plasmid is 170-250nm, and the Zeta potentia...

Embodiment 3

[0034] Example 3 Inhibitory Effect of Tamibarotene-Cytarabine Conjugate on Proliferation of Human Leukemia Cell HL60

[0035] Test compound: Tamibarotene-cytarabine conjugate (Am80-Ara-C) prepared in Example 1;

[0036] Human leukemia cell line HL-60 was regularly subcultured with RPMI1640 medium (containing 15% extinguished fetal bovine serum, penicillin 100u / ml, streptomycin 100u / ml).

[0037] Drug preparation:

[0038]Positive control group: Weigh an appropriate amount of tamibarotene (Am80), cytarabine (Ara-C) and the physical mixture of tamibarotene and cytarabine (Am80+Ara-C), add DMSO medium, ultrasonically dissolved fully, and the final concentration was 10 -1 mol / L. Dissolve the test drug in DMSO to prepare a solution with the same amount and concentration as the positive control group. Before use, it was diluted step by step to make the final concentration 2×10 -3 mol / L, 4×10 -4 mol / L, 8×10 -5 mol / L, 1.6×10 -5 mol / L, 3.2×10 -6 mol / L, 6.4×10 -7 mol / L, 1.28×1...

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Abstract

The invention discloses preparation of tamibarotene-cytarabine conjugate, nano pharmacosomes and an anti-tumor application of the tamibarotene-cytarabine conjugate and nano pharmacosomes. The tamibarotene-cytarabine conjugate is prepared by coupling the carboxyl of tamibarotene with four locations of amino groups of cytarabine. The tamibarotene-cytarabine conjugate has a proper amphipathy, can form a nanoscale dispersive self-assembly transfer system in water and has good anti-tumor activity in vitro and vivo.

Description

field of invention [0001] The invention belongs to the fields of chemistry and biomedicine. In particular, it relates to an amphipathic tamibarotene-cytarabine conjugate and its nano-pharmaceutical body, and also involves the in vivo and in vitro evaluation of the conjugate and its nano-pharmaceutical body. Background technique [0002] The effect of drugs on the body depends on the concentration of drugs in the body, and absorption, distribution, metabolism and excretion have important influences on this. After drugs are administered through different routes, they need to pass through many biological membranes or cell membranes to reach the site of action, but drugs with strong water solubility are not easy to cross the membrane, and drugs with strong fat solubility are not easy to be transported. In order to improve the bioavailability of drugs, make them targeted, and achieve efficient and safe drug use, the absorption of water-soluble drugs and the distribution of fat-s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/09C07H1/00A61K31/7068A61K9/127A61P35/00
Inventor 崔国辉邢琳尧
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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