CN109464672A - A kind of platinum medicine/black phosphorus compound and its preparation method and application - Google Patents
A kind of platinum medicine/black phosphorus compound and its preparation method and application Download PDFInfo
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- CN109464672A CN109464672A CN201811360336.3A CN201811360336A CN109464672A CN 109464672 A CN109464672 A CN 109464672A CN 201811360336 A CN201811360336 A CN 201811360336A CN 109464672 A CN109464672 A CN 109464672A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention discloses a kind of platinum medicine/black phosphorus compound and its preparation method and application, the platinum medicine/black phosphorus compound is the product obtained by two-dimentional black phosphorus and platinum medicine active constituent ligand complex；The present invention enhances the material stability of two-dimentional black phosphorus material using platinum medicine active constituent, and this method using drug homeostasis black phosphorus material is simple and efficient, and be capable of safe devoid of risk is applied to clinic；Platinum medicine/black phosphorus the compound can stablize photo-thermal and the chemotherapy combined treatment realized to tumour, and platinum medicine/black phosphorus compound is also used as stable black phosphorus carrier system, further loads other medicines, have a good application prospect in terms of preparing anti-tumor drug.
Description
Technical field
The invention belongs to technical field of biomedical materials.In particular it relates to a kind of platinum medicine/black phosphorus compound and its preparation
Methods and applications.
Background technique
Cancer is to endanger one of global major disease of human life and health.According to the number of World Cancer Research Foundation
According to cancer has become one of main inducing of human death, and world's cancer morbidity increases 3-5%, the 2008 years whole world every year
Newly-increased cancer patient 12,700,000, it is contemplated that the year two thousand thirty will increase 21,000,000 newly.Traditional strategy of cancer treatment mainly include operation excision,
The modes such as chemotherapy, radiotherapy and biological therapy.In recent years, near infrared light heat cure because of it efficiently and a variety of advantages such as Noninvasive,
To be widely believed that the substituted or supplemented traditional cancer treatment method of great potential.
Black phosphorus (BP) is controlled as near-infrared photothermal converting agent for cancer for nearly 2 years as a kind of new two-dimensional material
Treatment has become the research hotspot quickly broken out.The multilayered fold honeycomb structure that BP is made of single P element forms, and is in layer
P-P covalent bond, interlayer rely on Van der Waals weak interaction, black phosphorus nanometer sheet, black phosphorus can be prepared using liquid phase stripping method
Quantum dot and black phosphorus micron chip.As a kind of metal-free layered semiconductor, the energy gap of black phosphorus changes with the variation of the number of plies,
Increase to 2 eV of single layer phosphorus alkene from 0.3 eV of massive material, therefore its absorption region is extensive, has from ultraviolet to near-infrared
It absorbs.In addition to excellent optical property, black phosphorus material bio-medical field another very unique advantage is exactly that it has
Extraordinary biocompatibility and biodegradability.Studies have shown that black phosphorus material can react in turn in water with oxygen and water
Degradation, and its product for finally degrading is to be widely present in vivo and avirulent phosphate radical.Therefore, black phosphorus material is because its is excellent
Different photo-thermal effect and biocompatibility and the prospect of great clinical application.
However, black phosphorus material is easily reacted with oxygen and water in external environment, so as to cause material component degradation and light
Performance is learned to be remarkably decreased.Black phosphorus is a kind of honeycomb of fold, the three P atoms closed in its each P atom and layer
By being covalently keyed, and a pair of of lone pair electrons are exposed, this is very active to lone pair electrons, can generate with oxygen reaction
PxOy, and expose P0 again to continue to aoxidize, and then cause the degradation of black phosphorus.Therefore, try to stablize this to lone pair electrons
It is the potential strategy for inhibiting BP degradation, although have has using covalent modification, transition metal ions coordination or adsorption at present
The organic molecule of drawing electron group cures practical biology to stablize the report that the lone pair electrons of BP inhibit BP oxidation in turn
With selection is efficient and really has the BP antihunt means of clinical landscapes to be still the task of top priority.
Platinum series antineoplastic medicament is widely applied line anti-tumor drug in current clinic, wherein most representative to be
Cis-platinum (Cisplatin) and oxaliplatin (Oxaliplatin).They after entering cell the active constituent that hydrolyzes to form can and
DNA base forms cross-linking products in chain in a manner of complex bound, and then the duplication and transcription of blocking dna and cancer cell is caused to wither
It dies.It has not yet to see in relation to utilizing platinum class medicine enhancing BP stability and for antitumor report in external environment.
Summary of the invention
The technical problem to be solved by the present invention is to overcome the defect of the prior art and deficiency, by by platinum medicine active constituent with
A kind of platinum medicine/black phosphorus compound has been prepared in two-dimentional black phosphorus material ligand complex, is enhancing two dimension using platinum medicine active constituent
While the stability of black phosphorus material, realizes and clinically the photo-thermal of tumour and chemotherapy combined are treated, before there is biggish application
Scape.
The first purpose of the invention is to provide a kind of platinum medicine/black phosphorus compounds.
A second object of the present invention is to provide the preparation methods of above-mentioned platinum medicine/black phosphorus compound.
Third purpose of the present invention is to provide above-mentioned platinum medicine/black phosphorus compound and is preparing the application in black phosphorus carrier system.
4th purpose of the invention is to provide above-mentioned platinum medicine/black phosphorus compound application in preparation of anti-tumor drugs.
Above-mentioned purpose of the present invention is achieved through the following technical solutions:
A kind of platinum medicine/black phosphorus compound is the product obtained by two-dimentional black phosphorus and platinum medicine active constituent ligand complex.Specifically,
It is that the product that ligand complex obtains is occurred by the P of the lone pair electrons of two-dimentional black phosphorus and the Pt atom of platinum medicine active constituent electron deficient.
The Pt of electron deficient and the orphan of two-dimentional black phosphorus are right in the active constituent that platinum medicine/black phosphorus compound of the invention passes through platinum medicine
Ligand complex occurs for the P of electronics, by utilizing drug homeostasis black phosphorus material.Therefore, theoretically thus contain electron deficient
The active constituent of platinum medicine of Pt can enhance the stability of two-dimentional black phosphorus by ligand complex.
Preferably, the platinum medicine active constituent is that (1,2- cyclohexanediamine) closes platinum (DACHPt) and/or two ammino platinum [Pt
(NH3)2]。
Particularly preferably, the platinum medicine/black phosphorus compound is BP/DACHPt and/or BP/Pt (NH3)2。
Preferably, the two-dimentional black phosphorus is one of black phosphorus nanometer sheet, black phosphorus quantum dot or black phosphorus micron chip or a variety of.
Particularly preferably, the size of the black phosphorus nanometer sheet is 20~500 nm, with a thickness of 1~20 nm；Black phosphorus quantum dot
Size be 2~15 nm, with a thickness of 1~5 nm；Micron chip is having a size of 1~20 μm.
The preparation method of any of the above-described platinum medicine/black phosphorus compound, by platinum medicine active constituent with two-dimentional black phosphorus in organic
It mixes, 12~48 h of complex reaction, is centrifuged in solvent, precipitating is platinum medicine/black phosphorus compound.
Preferably, the mass ratio of the two-dimentional black phosphorus and platinum medicine active constituent is 1:(0.5~10).
It is further preferred that the mass ratio of the two dimension black phosphorus and platinum medicine active constituent is 1:(0.5~8).
More electedly, the mass ratio of the two-dimentional black phosphorus and platinum medicine active constituent is 1:(0.5~4).
Preferably, the additional amount of the two-dimentional black phosphorus is the 0.1%~1% of organic solvent quality.
Preferably, the organic solvent is in N-Methyl pyrrolidone, dioxane, acetonitrile or n,N-Dimethylformamide
It is one or more.
It is further preferred that the black phosphorus nanometer sheet the preparation method comprises the following steps: BP powder is dispersed in 0.1~1% organic molten
In agent, and adjusting probe amplifier is 25%, and switch periods are 5s/5s ultrasound 4~8 hours, by obtained dispersion liquid 3000~
It is centrifuged 8~12 min under 4000 rpm, removes the bulk BP that does not remove and precipitates and collect supernatant BP nanometer sheet, 6000~
8000 rpm centrifuged supernatant, 8~12 min obtains BP nanometer sheet.
It is further preferred that the black phosphorus quantum dot the preparation method comprises the following steps: BP powder is dispersed in 0.1~1% organic molten
In agent, and adjusting probe amplifier is 25%, switch periods 5s/5s ultrasound 6~10 hours, then 16 DEG C thermostatic ultrasonic 8 hours,
By obtained dispersion liquid in 6000~8000 rpm centrifuged supernatant, 8~12 min, the bulk BP precipitating that do not remove is removed simultaneously
Supernatant BP quantum dot is collected, 10 min of centrifuged supernatant obtains BP quantum dot at 20000 rpm.
It is further preferred that the black phosphorus micron chip the preparation method comprises the following steps: BP powder is dispersed in 0.1~1% organic molten
In agent, and ice-bath ultrasonic 4~6 hours under 40 kHz frequencies, 80% power condition；By obtained dispersion liquid 3000~4000
It is centrifuged 8~12 min under rpm, removes the bulk BP that does not remove and precipitates and collect supernatant BP micron chip, 6000~8000
8~12 min of rpm centrifuged supernatant obtains BP nanometer sheet.
Preferably, the organic solvent is in N-Methyl pyrrolidone, dioxane, acetonitrile or n,N-Dimethylformamide
It is one or more.
It is further preferred that the active constituent of the oxaliplatin DACHPt's the preparation method comprises the following steps: 0.5~5% dichloro
(1,2- cyclohexanediamine) closes platinum DACHPtCl2It is dissolved in the water, and is protected from light normal-temperature reaction 1 day with the silver nitrate of 2 equivalents；Centrifugation
Remove silver nitride precipitation, by supernatant by the filtering of 0.22 μm of filter, and be lyophilized to get.
It is further preferred that the active constituent Pt (NH of the cis-platinum3)2The preparation method comprises the following steps: by two ammino platinum of dichloro
(CDDP) it is dissolved in the water, and is protected from light normal-temperature reaction 1 day with the silver nitrate of 2 equivalents；It is centrifuged off silver nitride precipitation, by supernatant
Filtered by 0.22 μm of filter, and be lyophilized to get.
Platinum medicine active constituent passes through in platinum medicine/black phosphorus compound of the invention and the BP nanometer sheet containing lone pair electrons is complexed
And enhancing stability of the BP in external environment, this strategy for constructing stable BP carrier system certainly using drug can not only
Avoid potential clinical application risk, moreover it is possible to realize and treat to the photo-thermal and chemotherapy combined of tumour.
Therefore, the platinum medicine/black phosphorus compound is preparing the application in black phosphorus carrier system also in the scope of the present invention
It is interior.
Meanwhile the platinum medicine and black phosphorus compound have the anti-tumor drug of stable photo-thermal and chemotherapeutic toxicity in preparation
In application also in the scope of the present invention.
In addition, platinum medicine active constituent is improving the application in two-dimentional black phosphorus stability of material also in the scope of the present invention
It is interior.
Compared with prior art, the invention has the following advantages:
The present invention provides a kind of platinum medicine/black phosphorus compounds, enhance the stabilization of two-dimentional black phosphorus material using platinum medicine active constituent
Property, this method using drug homeostasis black phosphorus material is simple and efficient, and be capable of safe devoid of risk is applied to clinic；It is described
Platinum medicine/black phosphorus compound can stablize photo-thermal and the chemotherapy combined treatment realized to tumour, and platinum medicine/black phosphorus compound is also used as
Stable black phosphorus carrier system, further loads other medicines, has a good application prospect in terms of preparing anti-tumor drug.
Detailed description of the invention
Fig. 1 is the schematic diagram that black phosphorus material and platinum medicine active constituent DACHPt form compound BP/DACHPt.
Fig. 2 is the drugloading rate of the BP of different DACHPt/BP feed ratios.
Fig. 3 is that the transmission electron microscope TEM of BP/DACHPt nanometer sheet schemes.
Fig. 4 is that the transmission electron microscope TEM of BP/DACHPt quantum dot schemes.
The Raman scattering Raman that Fig. 5 is pure BP and BP/DACHPt schemes.
Fig. 6 is that the x-ray photoelectron spectroscopy XPS of pure BP, BP/DACHPt and DACHPt scheme.Wherein, A figure is P spectrum, and B figure is
Pt spectrum.
Fig. 7 is the UV, visible light near infrared absorption UV-Vis- that pure BP and BP/DACHPt are changed over time in external environment
NIR figure.
Fig. 8 is pure BP, BP/DACHPt and BP/DACHPtCl2The external near infrared light thermal transition heating changed over time
Figure.
Fig. 9 is BP/CDDP and BP/ Pt (NH3)2The external near infrared light thermal transition heating figure changed over time.
Figure 10 is the atomic force microscope form on pure BP and BP/DACHPt micron chip surface after 24 hours.
Figure 11 is various concentration photo-thermal killing after pure BP and BP/DACHPt is placed 0 and 72 hour in external environment
The microscope figure of HeLa tumour cell.
Figure 12 is various concentration photo-thermal and chemotherapy connection after pure BP and BP/DACHPt is placed 72 hours in external environment
Close killing HeLa tumour cell quantitative result.
Figure 13 is the living body photo-thermal and chemotherapy combined antitumous effect of BP/DACHPt；Wherein, G1 is physiological saline+NIR,
G2 is by pretreated black phosphorus+NIR, G3 BP/DACHPt, the G4 BP/DACHPt+NIR of 72 h.
Specific embodiment
The present invention is further illustrated below in conjunction with Figure of description and specific embodiment, but embodiment is not to the present invention
It limits in any form.Unless stated otherwise, the present invention uses reagent, method and apparatus routinely try for the art
Agent, method and apparatus.
Unless stated otherwise, following embodiment agents useful for same and material are commercially available.
The preparation of the two-dimentional black phosphorus material of 1 three kinds of different shapes of embodiment
1, method
The preparation method of black phosphorus nanometer sheet: being ground into BP powder for BP crystal in mortar, then by BP powder with 0.2% dispersion
In N-Methyl pyrrolidone, and adjusting probe amplifier is 25%, switch periods 5s/5s ultrasound 4 hours, the dispersion that will be obtained
Liquid is centrifuged 10 min at 3500 rpm, removes the bulk BP not removed and precipitates and collect supernatant BP nanometer sheet, 7000
10 min of centrifuged supernatant obtains BP nanometer sheet under rpm.
The preparation method of black phosphorus quantum dot: being ground into BP powder for BP crystal in mortar, then by BP powder with 0.2%
It is dispersed in N-Methyl pyrrolidone, and adjusting probe amplifier is 25%, switch periods 5s/5s ultrasound 8 hours, is then followed by
16 DEG C thermostatic ultrasonic 8 hours, obtained dispersion liquid is centrifuged 10 min at 7000 rpm, it is heavy to remove the bulk BP not removed
It forms sediment and collects supernatant BP quantum dot, 10 min of centrifuged supernatant obtains BP quantum dot at 20000 rpm.
The preparation method of black phosphorus micron chip: being ground into BP powder for BP crystal in mortar, then by BP powder with 0.2%
It is dispersed in N-Methyl pyrrolidone, and ice-bath ultrasonic 4 hours under 40 kHz frequencies, 80% power condition, the dispersion that will be obtained
Liquid is centrifuged 10 min at 3000 rpm, removes the bulk BP not removed and precipitates and collect supernatant BP micron chip, 7000
10 min of centrifuged supernatant obtains BP micron chip under rpm.
2, result
The black phosphorus nanometer sheet being prepared by the above method is having a size of 77 nm, with a thickness of 12 nm；Black phosphorus quantum dot size is
4.3 nm, with a thickness of 1.5 nm；Black phosphorus quantum dot size is 8 μm.
The preparation of the two-dimentional black phosphorus material of 2 three kinds of different shapes of embodiment
The present embodiment is substantially the same manner as Example 1, the difference is that, the two-dimentional black phosphorus material preparation process of three kinds of different shapes
Used in organic solvent N-Methyl pyrrolidone replaced respectively with dioxane, acetonitrile and n,N-Dimethylformamide, together
Black phosphorus nanometer sheet, black phosphorus quantum dot and the black phosphorus micron chip of same size scope can be prepared in sample.
The preparation of 3 platinum medicine active constituent of embodiment
1, the active constituent (1,2- cyclohexanediamine) of oxaliplatin closes the preparation of platinum (DACHPt)
0.5% dichloro (1,2- cyclohexanediamine) is closed into platinum DACHPtCl2It is dissolved in the water, and is protected from light with the silver nitrate of 2 equivalents
Normal-temperature reaction 1 day, be centrifuged off silver nitride precipitation, by supernatant by the filtering of 0.22 μm of filter, and be lyophilized to get.
The active constituent (1,2- cyclohexanediamine) that oxaliplatin has successfully been prepared by the above method closes platinum
(DACHPt), chemical structural formula is as follows:
。
2, the two ammino platinum [Pt (NH of active constituent of cis-platinum3)2] preparation
Two ammino platinum (CDDP) of dichloro is dissolved in the water, and is protected from light normal-temperature reaction 1 day with the silver nitrate of 2 equivalents；It is centrifuged off
Silver nitride precipitation, by supernatant by the filtering of 0.22 μm of filter, and be lyophilized to get.
The two ammino platinum [Pt (NH of active constituent of cis-platinum has successfully been prepared by the above method3)2], chemical structure
Formula is as follows:
。
4 platinum medicine of embodiment/black phosphorus compound preparation method
1, method
In N-Methyl pyrrolidone, with black phosphorus nanometer sheet, quantum dot or the micron chip of mass percent 0.1% respectively with (0.5,
1,2,3,4,5,6,7 and 8 times) platinum medicine active constituent DACHPt or the Pt (NH of black phosphorus quality3)2Mixing is overnight.Mixture exists later
It is centrifuged 20 min under 12000 rpm, collects precipitating and obtains BP/DACHPt and BP/ (NH3)2Compound.
2, result
(1) drugloading rate result is as shown in Fig. 2, BP carrying medicament reaches saturation, drugloading rate after being 4 in DACHPt/BP feed ratio
It is 2.And Pt (NH3)2/ BP also reaches saturation, drugloading rate 2.5 after being 5 in feed ratio.
(2) when DACHPt/BP feed ratio is 5, the transmission electron microscope TEM result for the BP/DACHPt compound being prepared
As shown in figs. 34, Fig. 3 can intuitively prove the appearance and size of BP/DACHPt nanometer sheet and answer with platinum medicine active constituent
It closes, is observed that its pattern is random sheet from Fig. 3 A, having a size of 50~100 nm, Fig. 3 B shows its lattice fringe spacing
For 0.223 nm, this is the properties of crystal lattice of BP, it was demonstrated that the structure of BP does not change after compound, and 3C shows P and Pt in compound
Distribution, it was demonstrated that the certain even compact of DACHPt and BP it is compound；The pattern ruler of BP/DACHPt quantum dot as can be seen from Figure 4
Very little platinum medicine active constituent it is compound, be regular circle particle, having a size of 2~6 nm.
(3) in addition, by carrying out Raman scattering detection to pure BP and BP/DACHPt to verify whether platinum medicine and black phosphorus succeed
It is compound；Experimental result as shown in figure 5, BP with drug it is compound after Raman scattering features peak there is red shift, illustrate BP and DACHPt
Coordination inhibit the vibration of surface P atom, reduce Raman scattering energy.
Further by carrying out x-ray photoelectron spectroscopy detection to pure BP and BP/DACHPt, result as shown in fig. 6, from
Fig. 6-A can be seen that the P element in BP/DACHPt significantly aoxidizes, this shows that significant coordination network occurs for BP and DACHPt
It closes；Fig. 6-B shows: relative to platinum medicine active constituent, the Pt combination of BP/DACHPt can be reduced, this is because containing lone pair electrons
P and the Pt atom of electron deficient occur to be coordinated and the reason of give electronics, result above all proves that BP and DACHPt occurs efficiently
It is compound to forming BP/DACHPt compound.
The preparation method of embodiment 5 platinum medicine and black phosphorus compound
The present embodiment and 3 the method for embodiment are essentially identical, the difference is that, organic solvent N-Methyl pyrrolidone used
It is substituted by any one of dioxane, acetonitrile and n,N-Dimethylformamide, also available similar drugloading rate is as a result, say
Bright solvent type influences drugloading rate little.
6 compound BP/DACHPt and BP/Pt (NH of embodiment3)2Stability test
1, method
Oxaliplatin raw medicine DACHPtCl is prepared according to the similar approach of embodiment 42, cis-platinum raw medicine CDDP and black phosphorus it is compound
Object, by 5 groups of black phosphorus preparations (pure BP, BP/DACHPt, BP/DACHPtCl2, BP/CDDP and BP/Pt (NH3)2It is pre-dispersed in sudden and violent
It is exposed in the water of air (50 μ g/mL) and stirs the different time (0,12 h, 24 h, 72 h and 168 h).In each time
Point measures ultraviolet-visible-near infrared absorption of pure BP and BP/DACHPt nm from 300 to 800.Each time point 5 is detected simultaneously
Group preparation is in 808 nm near infrared light (1.0 W/cm2) irradiation 10 min when photo and thermal stability.And pure BP and BP/DACHPt are micro-
The stability of rice piece is then to pass through its form of atomic force microscope observation after 24 h in being exposed to wet air.
2, result
(1) Fig. 7 is the variation for the UV, visible light near infrared absorption that pure BP and BP/DACHPt are changed over time in external environment,
It shows that black phosphorus absorbs increase with time in 7 days to reduce rapidly, illustrates that it can fast degradation in external environment.This result
The result of wide coverage is consistent before.And B figure show BP/DACHPt 7 days interior suctions incorporate it is low seldom, still reach just
The 90% of initial value, it was demonstrated that its stability significantly improves.This proves the compound stability that can greatly enhance BP of platinum medicine.
(2) Fig. 8 is pure BP, BP/DACHPt and BP/DACHPtCl2The external near infrared light thermal transition liter changed over time
Temp effect, the photothermal conversion heating ability of pure BP reduces rapidly at any time as the result is shown, can only be warming up to 32 degree after 1 day, and
It can not almost heat up after 7 days.And the heating ability of BP/DACHPt then it is stable very much, even if it still has after 7 days
Significant heating ability.This verifies the compound stability that can greatly enhance BP of platinum medicine again.In addition, BP and not pulling out chlorine
Raw medicine DACHPtCl2Mixture can not also enhance the stability of BP, this illustrates that only platinum medicine active constituent is just from another side
Energy and BP and complexing, and enhance the stability of BP.
(3) Fig. 9 is BP/CDDP and BP/Pt (NH3)2The photothermal conversion temperature rise effect changed over time.It is similar with DACHPt,
Active constituent Pt (the NH of cis-platinum3)2The stability of black phosphorus can be significantly increased, and cis-platinum CDDP can not enhance.These the result shows that
The property that platinum medicine active constituent enhances BP has universality, be all because platinum medicine active constituent can stablize the lone pair electrons of BP into
And inhibit its oxidative degradation.
(4) Figure 10 is the atomic force microscope form on pure BP and BP/DACHPt micron chip surface after 24 hours.Knot
Fruit shows that pure BP micron chip is significantly aoxidized, and surface generates very fine and close vacuole.And BP/DACHPt micron chip does not occur then
Variation.This also proves the compound stability that can significantly increase BP of platinum medicine again.
The external photo-thermal of 7 compound BP/DACHPt of embodiment and chemotherapeutic toxicity test
1, method
(1) photo-thermal: human cervical carcinoma cell HeLa is used to the photo-thermal and chemotherapeutic toxicity of research BP/DACHPt, by HeLa cell
It sets and is cultured in 6 orifice plates 24 h.Pure BP and BP/DACHPt is pre-dispersed in 0 or 72 h in the water for be exposed to air before testing.
The pure BP and BP/DACHPt (50 μ g/mL) that advanced processing is added in HeLa cell later cultivate 4 h and closely red with 808 nm
Outer 10 min of laser irradiation, later after 30 min culture, with calcein AM (calcium fluorescein acetoxymethyl) and PI
(propidium iodide) photo-thermal that staining cell assesses BP/DACHPt with fluorescence microscope in turn altogether kills cell effect.
(2) chemotherapeutic toxicity: BP/DACHPt quantifies the toxicity of HeLa cell also by MTT test.By HeLa cell
(1*104Cells/well) cure 96 orifice plates and overnight incubation.By the pure BP and BP/DACHPt (10,20,50 by 72 h processing
μ g/mL) it is added in HeLa cell, and be respectively placed in irradiation and do not irradiate under near infrared light (808 nm laser at, 1.0 W/
cm210 min of for).After near infrared light, cell is further cultured for 12 h, then tests quantitative cell survival using MTT
Degree.
2, result
(1) as shown in figure 11, it can be transferred through photo-thermal in 50 μ g/mL by the pretreated pure BP and BP/DACHPt of 0h almost to kill
All tumour cells, this is consistent with the external photo-thermal effect of front.And after 72 h pretreatment, pure BP can not kill swollen
Oncocyte, it is consistent with the result of front that this illustrates that it is substantially completely degraded.And killing when BP/DACHPt is still kept and 0 h
Ability, this intuitively proves the stability of its photo-thermal.
(2) as shown in figure 12, the cell irradiation of BP is added and does not irradiate near infrared light, cell survival degree is above 90%,
This is because BP loses photo-thermal ability after having degraded.And the cell of 20 μ g/mL BP/DACHPt is added after light irradiates
It is significantly killed, 50 μ g/mL BP/DACHPt, which are added, can almost kill all cells.This also demonstrates again that BP/DACHPt has
Extraordinary photo and thermal stability.In addition, after BP/DACHPt is added, even if not irradiating laser, under cell survival degree is still significant
Drop, this illustrates that BP/DACHPt also has chemotherapeutic toxicity, this is derived from platinum medicine active constituent DACHPt.
The test of 8 compound BP/DACHPt living body antitumous effect of embodiment
1, method
4~5 week old female SCID nude mices are purchased from Zhongshan University's Experimental Animal Center and in SPF(specific pathogen-
Free) grade animal house is raised.All zooperies are in accordance with zooscopy administration committee, Zhongshan University decree regulation premise
Lower progress.Subcutaneous injection 5 × 10 on the right side of every nude mice6HeLa cell, after gross tumor volume reaches the size that can be touched,
Mouse is randomly divided into 4 groups of carry out intratumor injection physiological saline, pretreated by 72 h by the pretreated black phosphorus of 72 h
0.5 mg/mL platinum medicine of BP/DACHPt and BP/DACHPt(20 μ L and corresponding BP dosage).Then the 1st, 3,4 group after being anesthetized
808 nm irradiations are carried out to tumor locus, during which every two days tumor sizes of weighing and measure calculate relative tumour volume, continue 14
It.
2, result
The living body photo-thermal and chemotherapy combined antitumous effect of BP/DACHPt is as shown in figure 13, it can be seen from the figure that by controlling
After treatment, G4 group can completely inhibit the growth of tumour, the even up to effect of tumour ablation；And G1 and G2 group is several to tumour growth
Absolutely not influence；G3 then has the effect of that part inhibits tumour growth, this is derived from the chemotherapy effect of DACHPt, these results
The photo and thermal stability and excellent photo-thermal and the antitumor effect of chemotherapy combined of BP/DACHPt are demonstrated in animal level.
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, other any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present invention,
It should be equivalent substitute mode, be included within the scope of the present invention.
Claims (10)
1. a kind of platinum medicine/black phosphorus compound, which is characterized in that obtained by two-dimentional black phosphorus and platinum medicine active constituent ligand complex
Product.
2. platinum medicine/black phosphorus compound according to claim 1, which is characterized in that the platinum medicine active constituent is (1,2-
Cyclohexanediamine) close platinum and/or two ammino platinum.
3. platinum medicine/black phosphorus compound according to claim 1, which is characterized in that it is described two dimension black phosphorus be black phosphorus nanometer sheet,
One of black phosphorus quantum dot or black phosphorus micron chip are a variety of.
4. the preparation method of any one of claims 1 to 3 platinum medicine/black phosphorus compound, which is characterized in that by platinum medicine activity at
Divide and mixed in organic solvent with two-dimentional black phosphorus, 12~48 h of complex reaction, centrifugation, precipitating is platinum medicine/black phosphorus compound.
5. the preparation method according to claim 4, which is characterized in that the quality of the two dimension black phosphorus and platinum medicine active constituent
Than for 1:(0.5~10).
6. the preparation method according to claim 4, which is characterized in that the additional amount of the two dimension black phosphorus is organic solvent matter
The 0.1%~1% of amount.
7. the preparation method according to claim 4, which is characterized in that the organic solvent is N-Methyl pyrrolidone, two
One of six ring of oxygen, acetonitrile or n,N-Dimethylformamide are a variety of.
8. any one of claims 1 to 3 platinum medicine/black phosphorus compound is preparing the application in black phosphorus carrier system.
9. any one of claims 1 to 3 platinum medicine and black phosphorus compound have stable photo-thermal and chemotherapeutic toxicity in preparation
Anti-tumor drug in application.
10. platinum medicine active constituent is improving the application in two-dimentional black phosphorus stability of material.
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