CN103463642A - Preparation and application of human serum albumin-ruthenium inorganic medicine compound - Google Patents
Preparation and application of human serum albumin-ruthenium inorganic medicine compound Download PDFInfo
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- CN103463642A CN103463642A CN2013103711462A CN201310371146A CN103463642A CN 103463642 A CN103463642 A CN 103463642A CN 2013103711462 A CN2013103711462 A CN 2013103711462A CN 201310371146 A CN201310371146 A CN 201310371146A CN 103463642 A CN103463642 A CN 103463642A
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Abstract
The invention discloses preparation and application of a human serum albumin-NAMI-A ruthenium inorganic medicine compound. NAMI-A and the human serum albumin are incubated, the mixture is concentrated, the concentrated mixture is repeatedly washed by secondary deionized water till the DMSO content is smaller than 0.01 percent, then concentration is performed to obtain the human serum albumin-NAMI-A ruthenium inorganic medicine compound, and the compound is prepared into an injection, tablets, pills, capsules, a suspending agent or an emulsion to treat breast cancer, stomach cancer, lung cancer, colon cancer or liver cancer. The compound has high vascular permeability and retention rate, the medicine selectivity gathers in tumor cells while not influencing normal cells, the targeting of the ruthenium inorganic medicine is remarkably improved and the toxicity is greatly lowered.
Description
Technical field
The present invention relates to antitumor drug, specifically human serum albumin-the preparation of NAMI-A ruthenium inorganic drug complex and the application in anti-tumor disease thereof.
Background technology
In recent years, ruthenium complex is studied by people widely as the new type anticancer medicine.Ruthenium complex, owing to having unique physics and chemistry character, generally believes that ruthenium complex belongs to hypotoxicity in the world, easily absorbs and excretion very soon in vivo.At present existing hundreds of ruthenium complex is synthesized out, and NAMI-A completed the I clinical trial phase, is entering the research of II phase clinical stage.Yet we have to face a reality: the antitumor inorganic drug remains a double-edged sword, in the treatment disease, inevitably produces many side effect, although NAMI-A has completed clinical first phase, but still has very large toxic and side effects.Obviously, how to improve the real difficult problem of capturing of being badly in need of of the intelligent people of being of antitumor drug.With normal structure, compare, rich blood vessel, the structure of tumor tissues are special, and an important performance is exactly that the blood vessel endothelium gap is larger, and this is the reason that in the pathological changes situation, macromole can see through the tumor tissues blood vessel wall.Albumin meets macromolecular substances to be strengthened and is detained (enhancedpermeability and retention, EPR) effect at the permeability of tumor tissues, so albumin has been tested to play the part of as pharmaceutical carrier clinically, the role who becomes more and more important is arranged.
Summary of the invention
The purpose of this invention is to provide the preparation method of human serum albumin-NAMI-A ruthenium inorganic drug complex and this complex in the drug effect that improves tumour medicine and the application aspect targeting.
The technical scheme that realizes the object of the invention is:
Human serum albumin-NAMI-A ruthenium inorganic drug complex, it is the ruthenium inorganic drug target biology carrier using the human serum albumin as NAMI-A, its preparation comprises the steps:
(1) NAMI-A and human serum albumin are hatched;
(2) concentrated;
(3) wash cyclic washing by secondary deionized water, make human serum albumin-NAMI-A ruthenium inorganic drug complex.
The structural formula of NAMI-A ruthenium inorganic drug of the present invention is:
The described process of hatching is as follows: taking the medicine prepared, with DMSO, be configured to solution, is that 1:1 mix with the aqueous solution of HSA by amount of substance by the DMSO solution of medicine, and the content of DMSO is no more than 5%, 4 ℃ standing, both are reacted 24 hours.
The overall structure of inventor's serum albumin-NAMI-A ruthenium inorganic drug complex is heart type, six fatty acid molecules and two asymmetric running through wherein of ruthenium inorganic drug molecule.At human serum albumin's IB subdomain, NAMI-A ruthenium inorganic drug is exposed in water environment fully, with histidine-146 coordination, is combined.At the IIA subdomain, NAMI-A ruthenium inorganic drug is combined in large hydrophobic pocket, and the oxygen atom in NAMI-A and histidine-242 forms hydrogen bond.
The application of inventor's serum albumin-NAMI-A ruthenium inorganic drug complex, that human serum albumin-NAMI-A ruthenium inorganic drug complex is made to injection, tablet, pill, capsule, suspending agent or Emulsion, be used for the treatment of the diseases such as breast carcinoma, gastric cancer, pulmonary carcinoma, colon cancer, hepatocarcinoma, its dosage is: 60-100 μ M/L.
By In vitro cell experiment, prove that human serum albumin of the present invention-NAMI-A ruthenium inorganic drug complex is inhibited to tumor cell, and suppression ratio compares the ruthenium inorganic drug and be significantly improved, and Normocellular suppression ratio is obviously descended.Albumin-ruthenium inorganic drug complex has obvious facilitation to apoptosis and the period ratio ruthenium inorganic drug of tumor cell.
Advantage of the present invention is: the target biology carrier of the present invention using the human serum albumin as NAMI-A ruthenium inorganic drug, make human serum albumin-NAMI-A ruthenium inorganic drug complex, make this complex there is high vascular permeability and rejection, drug selectivity is gathered in tumor cell, on normal cell without any impact, obviously improve the targeting of ruthenium inorganic drug, greatly reduced toxicity.
The accompanying drawing explanation
The cloud density figure that Fig. 1 is human serum albumin-NAMI-A ruthenium inorganic drug complex.
The overall structure figure that Fig. 2 is human serum albumin-NAMI-A ruthenium inorganic drug complex.
Fig. 3 be the ruthenium inorganic drug albumin and binding site and in conjunction with chamber. A and D:IB subdomain; B and C:IIA subdomain.
The specific embodiment
The invention will be further described by the following examples.
Embodiment 1: the preparation of human serum albumin-NAMI-A ruthenium inorganic drug complex
Prepared according to document by NAMI-A: 1g RuCl
3join in the ethanol of 30ml, reflux and obtain dirty-green solution in 3 hours, filter, be concentrated into 1/10th initial volume, then add in the DMSO of 1ml concentrated hydrochloric acid and 2ml, keep 15 minutes in 80 ℃, obtain bright orange solution.Cooling solution, to room temperature, adds 10ml acetone, obtains orange red crystal, adds several of ether, accelerates its crystallization, filters and collects.With cold acetone 20ml washing, then with ether, wash 10ml, vacuum drying, obtain 1.5g, productive rate 72%.The above-mentioned product of 1.0g is suspended in 20ml acetone, adds the 0.49g imidazoles, stir 4 hours, color becomes brick-redly by orange, and with the washing of 10ml acetone and 10ml ether, product is 60 ℃ of dryings.
Taking the NAMI-A medicine prepared, be configured to the solution of 400mM with DMSO, is that 1:1 mix with the aqueous solution of HSA by amount of substance by the DMSO solution of NAMI-A, and the content of DMSO is no more than 5%, at 4 ℃, hatches 24 hours.The mixture of concentrated HSA and the inorganic cancer therapy drug of ruthenium, with the secondary deionized water washing, make the content of DMSO be no more than 0.01% repeatedly, and reconcentration, to volume required, obtains orange human serum albumin-NAMI-A ruthenium inorganic drug complex.
Embodiment 2: the structure determination of human serum albumin-NAMI-A ruthenium inorganic drug complex
By HSA (1.5mM, 100 μ L), saturated 16 fatty acids (2.5mM, 960 μ L), medicine (100mM, 1.5 μ L) mix, hatch 24 hours, centrifugal removal precipitation, then concentrated, and use the secondary deionized water cyclic washing, finally be concentrated into 100 μ L, in sit dripping plate, by gas phase diffusion method (PEG3350 of 26-30%, 5% glycerol, 5% 2-methyl isophthalic acid, ammediol), cultivate albumin-fatty acid of being applicable to X-ray diffraction-Metal Drugs compound crystal.Utilize the Shanghai synchrotron radiation light source to collect crystal data.After with HKL2000, data being processed, adopt the molrep program of ccp4, using in Protein Data Bank with the strong albumen of this Argine Monohydrochloride sequence homology as template, the template that the searching of fast rotational and translation function is applicable, and integrated.If do not have the albumen that homology is strong as template, will adopt the method for soaking heavy atom to determine the experiment phase angle, thereby set up structural model in existing Protein Data Bank.After electron gain density map and suitable coordinate file, will use Coot, 0 supervisor is revised structure.After obtaining applicable model, adopt Refmac, Phenix, the CNS supervisor carries out refine to structure.
The overall structure of human serum albumin-NAMI-A ruthenium inorganic drug complex is heart type, six fatty acid molecules and two asymmetric run through wherein (Fig. 2) of ruthenium inorganic drug molecule.At human serum albumin's IB subdomain, NAMI-A ruthenium inorganic drug is exposed in water environment fully, with histidine-146 coordination, is combined.At the IIA subdomain, NAMI-A ruthenium inorganic drug is combined in large hydrophobic pocket, and the oxygen atom in NAMI-A and histidine-242 forms hydrogen bond (Fig. 1 and Fig. 3).
Claims (3)
1. the preparation method of human serum albumin-NAMI-A ruthenium inorganic drug complex, it is characterized in that: it is the target biology carrier using the human serum albumin as NAMI-A ruthenium inorganic drug, and its preparation method comprises the steps:
(1) NAMI-A and albumin are hatched: take NAMI-A ruthenium inorganic drug, be configured to solution with DMSO, by the DMSO solution of medicine, with the aqueous solution of HSA, by amount of substance, be that 1:1 mixes, the content of DMSO is no more than 5%, standing at 4 ℃, both are reacted 24 hours, obtain DMSO and HAS mixture;
(2) enriched mixture;
(3) wash cyclic washing to DMSO content<0.01% by secondary deionized water, make human serum albumin-NAMI-A ruthenium inorganic drug complex.
2. preparation method according to claim 1, it is characterized in that: described human serum albumin-NAMI-A ruthenium inorganic drug complex is heart-shaped structure, six fatty acid molecules and two asymmetric running through wherein of ruthenium inorganic drug molecule, at human serum albumin's IB subdomain, NAMI-A ruthenium inorganic drug is exposed in water environment fully, with histidine-146 coordination, be combined, at the IIA subdomain, NAMI-A ruthenium inorganic drug is combined in large hydrophobic pocket, and the oxygen atom in NAMI-A and histidine-242 forms hydrogen bond.
3. the application of human serum albumin claimed in claim 1-NAMI-A ruthenium inorganic drug complex, it is characterized in that: human serum albumin-NAMI-A ruthenium inorganic drug complex is made to injection, tablet, pill, capsule, suspending agent or Emulsion, be used for the treatment of breast carcinoma, gastric cancer, pulmonary carcinoma, colon cancer, liver cancer diseases, its dosage is: 60 ~ 100 μ M/L.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113248547A (en) * | 2021-04-27 | 2021-08-13 | 山西大学 | Nitrosyl ruthenium complex, nitrosyl ruthenium complex and serum protein complex, and preparation method and application thereof |
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2013
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Non-Patent Citations (1)
| Title |
|---|
| MICHAEL I,ET AL: "Control of ligand-exchange processes and the oxidation state of the antimetastatic Ru(III) complex NAMI-A by interactions with human serum albumin", 《DALTON TRANS》, vol. 40, 31 December 2011 (2011-12-31), pages 1322 - 1231 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113248547A (en) * | 2021-04-27 | 2021-08-13 | 山西大学 | Nitrosyl ruthenium complex, nitrosyl ruthenium complex and serum protein complex, and preparation method and application thereof |
| CN113248547B (en) * | 2021-04-27 | 2022-03-18 | 山西大学 | Nitrosyl ruthenium complex, nitrosyl ruthenium complex and serum protein complex, and preparation method and application thereof |
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