CN109010836B - Platinum-derived drug self-delivery gene drug carrier and use method thereof - Google Patents
Platinum-derived drug self-delivery gene drug carrier and use method thereof Download PDFInfo
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- CN109010836B CN109010836B CN201810566749.0A CN201810566749A CN109010836B CN 109010836 B CN109010836 B CN 109010836B CN 201810566749 A CN201810566749 A CN 201810566749A CN 109010836 B CN109010836 B CN 109010836B
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Abstract
The invention discloses a self-delivery gene drug carrier of a platinum derivative drug, which consists of a polynuclear platinum complex, wherein the polynuclear platinum complex is formed by the reaction of the following substances: pt (NH)3)2(NO3)2And a pyridine or pyrazine ring. The self-assembled nanoparticles have certain synergistic inhibition on cell proliferation capacity, which is shown on the cell level of drug resistance and drug intolerance; and at the cellular and living level, the self-assembled nanoparticles can effectively deliver siRNA and platinum complexes to target tumor tissues and cancer cells.
Description
Technical Field
The invention relates to a drug carrier, in particular to a platinum derivative drug self-delivery gene drug carrier and a using method thereof.
Background
Cancer, as defined by the World Health Organization (WHO), is a malignant tumor caused by a failure of the mechanisms controlling cell division proliferation, and is characterized by a rapid and unlimited proliferation of abnormal cells, and these proliferating cells may invade surrounding normal tissues beyond their intrinsic range, and even metastasize to other parts of the body via the systemic circulatory system or lymphatic system. Cancer is a serious threat to human health and life worldwide, and is one of the major malignant diseases causing human death.
At present, the cancer treatment effect of the platinum compound is very obvious, but the toxic and side effect of the platinum medicine and the drug resistance of cancer cells to the platinum medicine greatly limit the further clinical application of the platinum medicine. In recent years, the nano material as a platinum compound drug carrier shows huge advantages and wide application prospects in the treatment of cancers, and has become one of the key research directions in the fields of nano science and technology and biological medicine health internationally. However, most of the nano materials are lack of therapeutic effect, and redundant nano material carriers form potential safety hazards. In particular, vectors that are not sufficiently metabolized and cleared from the body can lead to toxicity. Furthermore, large amounts of exogenous nanocarriers can activate the immune system, possibly leading to clearance of drugs and immunotoxicity. In addition, the cell will also reach the limit of the uptake capacity of the drug carrier, and the drug loading capacity of the carrier will be the major bottleneck in the treatment of cancer in the case that the cell reaches the limit of the carrier's endocytosis before an effective therapeutic drug concentration is achieved.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a zero-vector drug self-delivery system, which is a vector for realizing multi-target point synergistic treatment.
In order to achieve the purpose, the invention provides the following technical scheme:
a self-delivery gene drug carrier of platinum-derived drugs is composed of a polynuclear platinum complex, wherein the polynuclear platinum complex is formed by the reaction of the following substances:
Pt(NH3)2(NO3)2
and
a pyridine or pyrazine ring.
As a further improvement of the invention, the Pt (NH)3)2(NO3)2The structural formula of (A) is: .
As a further improvement of the invention, the Pt (NH)3)2(NO3)2Is prepared by the following method:
mixing Pt (NH)3)2Cl2By AgNO3Dechlorination to obtain Pt (NH)3)2(NO3)2。
As a further improvement of the invention, the Pt (NH)3)2(NO3)2In the preparation process, AgNO is selected3Reacting the aqueous solution at 50-70 ℃ for 12-30 hours to obtain Pt (NH)3)2(NO3)2An aqueous solution.
As a further improvement of the invention, the pyridine is 4, 4-bipyridine, and the structural formula of the pyridine is as follows:
as a further improvement of the invention, the structural formula of the polynuclear platinum complex is as follows:
as a further improvement of the method, the polynuclear platinum complex is reacted for 50-100 hours at the temperature of 80-100 ℃ to obtain a polynuclear platinum complex aqueous solution.
As another object of the present invention, there is provided a method for using a gene drug carrier comprising a drug as a carrier,
and mixing the polynuclear platinum complex water solution and the RNA solution, and stirring for 10 min.
As a further improvement of the invention, siRNA is selected as the RNA.
As a further improvement of the invention, the ratio of the polynuclear platinum complex to the siRNA is 1-20: 1.
The polynuclear platinum complex prepared by the method has a therapeutic effect, and can be used as a carrier to load gene drugs therein to play a dual role after entering a human body. Therefore, the carrier does not need to be specially prepared, the medicine is used as the carrier to prepare the medicine, and the concept of 'zero carrier' is realized.
Drawings
FIG. 1 is an agarose gel experiment: (A) optimization between the ratio of the polynuclear platinum complex and siRNA, (B) and (C) evaluation of the protective ability of the polynuclear platinum complex on siRNA in RNase and serum;
FIG. 2 is a self-delivery capability assessment of platinum complexes and siRNA self-assembled nanoparticles;
fig. 3 is an evaluation of the ability of polynuclear platinum complexes and siRNA self-assembled nanoparticles to inhibit tumor cells: (A) MDA-MB-231 tumor cell proliferation assay, (B) MDR MDA-MB-231 drug-resistant tumor cell proliferation assay.
Detailed Description
The invention will be further described in detail with reference to the following examples, which are given in the accompanying drawings.
As shown with reference to figure 1 of the drawings,
a gene drug carrier with multi-level response of tumor microenvironment is composed of a polynuclear platinum complex, wherein the polynuclear platinum complex is formed by the reaction of the following substances:
Pt(NH3)2(NO3)2
and
a pyridine or pyrazine ring.
As a specific embodiment of the improvement, the Pt (NH)3)2(NO3)2The structural formula of (A) is: .
As a specific embodiment of the improvement, the Pt (NH)3)2(NO3)2Is prepared by the following method:
mixing Pt (NH)3)2Cl2By AgNO3Dechlorination to obtain Pt (NH)3)2(NO3)2。
As the inventionIn a further improvement, the Pt (NH)3)2(NO3)2In the preparation process, AgNO is selected3Reacting the aqueous solution at 50-70 ℃ for 12-30 hours to obtain Pt (NH)3)2(NO3)2An aqueous solution.
As an improved specific embodiment, the pyridine is 4, 4-bipyridine, and the structural formula of the pyridine is as follows:
as an improved specific embodiment, the structural formula of the polynuclear platinum complex is:
as an improved specific implementation mode, the reaction condition of the polynuclear platinum complex is that the polynuclear platinum complex reacts for 50-100 hours at 80-100 ℃ to obtain a polynuclear platinum complex aqueous solution.
As an improved embodiment, a method for using a gene drug carrier,
and mixing the polynuclear platinum complex water solution and the RNA solution, and stirring for 10 min.
As a specific embodiment of the improvement, siRNA is selected as the RNA.
As a specific embodiment of improvement, the ratio of the polynuclear platinum complex to siRNA is 2-20: 1.
The specific reaction equation is as follows:
as shown in FIG. 1, the affinity of siRNA at different mass ratios (Pt/siRNA) was first studied by agarose gel experiments, and as shown in FIG. 1A, when Pt/siRNA > 1, the polynuclear platinum complex could effectively neutralize siRNA, and the agarose gel experiments of FIGS. 1B and C showed that the polynuclear platinum complex could effectively protect the degradation of siRNA placed in RNase or serum.
Alexa 555-labeled siRNA and Pt complex self-assembled nanoparticles, siRAN and Pt/siRNA alone were co-incubated in MDA-MB-231 triple negative breast cancer cells for 6, 24, 48, 72h, respectively, as shown in figure 2 below: laser confocal experimental results show that Pt/siRNA can be effectively counted into cytoplasm, and the Pt complex needs to be further verified in the position of subcellular cells where the Pt/siRNA is located. And the need to quantitatively analyze the delivery efficiency of siRNA by flow cytometry, and the ability of Pt complexes to enter cells by ICP-MS.
As shown in FIG. 3, the self-assembled nanoparticles can significantly inhibit cancer cell proliferation in MDA-MB-231 and MDR MDA-MB-231 cells, compared to the polynuclear platinum complex and siRNA drug alone.
The preliminary test results show that the self-assembled nanoparticles have certain capability of synergistically inhibiting cell proliferation on the levels of drug-resistant cells and drug-non-resistant cells; and at the cellular and living level, the self-assembled nanoparticles can effectively deliver siRNA and platinum complexes to target tumor tissues and cancer cells.
The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above examples, and all technical solutions belonging to the idea of the present invention belong to the protection scope of the present invention. It should be noted that modifications and embellishments within the scope of the invention may occur to those skilled in the art without departing from the principle of the invention, and such modifications and embellishments should also be considered as within the scope of the invention.
Claims (1)
1. The application of a platinum-derived drug self-delivery gene drug carrier in the preparation of drugs is characterized in that:
mixing the polynuclear platinum complex water solution and the siRNA solution, and stirring for 10min, wherein the mass ratio of the polynuclear platinum complex to the siRNA is 2-20: 1;
the polynuclear platinum complex aqueous solution is obtained by reacting a polynuclear platinum complex for 50-100 hours under the reaction condition of 80-100 ℃;
the polynuclear platinum complex consists of Pt (NH)3)2(NO3)2With a pyridine or pyrazine ring, said Pt (NH)3)2(NO3)2Has the structural formula
The Pt (NH)3)2(NO3)2From Pt (NH)3)2Cl2By AgNO3Dechlorination preparation by using AgNO3The aqueous solution of (A) is reacted for 12 to 30 hours at a temperature of between 50 and 70 ℃ to obtain the Pt (NH)3)2(NO3)2An aqueous solution;
the pyridine is 4, 4-bipyridine.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9901253D0 (en) * | 1999-01-20 | 1999-03-10 | Isis Innovation | Bis-terpyridine-platinum(II) complexes |
| CN107320736A (en) * | 2017-05-26 | 2017-11-07 | 首都医科大学 | The new Ru-polypyridine complex of cancer target carries siRNA preparation and evaluation |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9901253D0 (en) * | 1999-01-20 | 1999-03-10 | Isis Innovation | Bis-terpyridine-platinum(II) complexes |
| CN107320736A (en) * | 2017-05-26 | 2017-11-07 | 首都医科大学 | The new Ru-polypyridine complex of cancer target carries siRNA preparation and evaluation |
Non-Patent Citations (4)
| Title |
|---|
| DNA condensation induced by metal complexes;Li, Guan-Ying et al.;《COORDINATION CHEMISTRY REVIEWS》;20141228;第281卷;第106-109页5.34、6.1，Fig 8 * |
| Li, Guan-Ying et al..DNA condensation induced by metal complexes.《COORDINATION CHEMISTRY REVIEWS》.2014,第281卷 * |
| Pt(II) squares as selective and effective human telomeric G-quadruplex binders and potential cancer therapeutics;Zheng, Xiao-Hui et al;《DALTON TRANSACTIONS》;20121231;第41卷(第38期);Fig.1，第11808页Synthesis of Pt(II) squares * |
| Zheng, Xiao-Hui et al.Pt(II) squares as selective and effective human telomeric G-quadruplex binders and potential cancer therapeutics.《DALTON TRANSACTIONS》.2012,第41卷(第38期), * |
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