CN109549954A - A kind of phosphorous-based materials preparation and its preparation method and application - Google Patents
A kind of phosphorous-based materials preparation and its preparation method and application Download PDFInfo
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- CN109549954A CN109549954A CN201811524441.6A CN201811524441A CN109549954A CN 109549954 A CN109549954 A CN 109549954A CN 201811524441 A CN201811524441 A CN 201811524441A CN 109549954 A CN109549954 A CN 109549954A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/42—Phosphorus; Compounds thereof
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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
- A61K47/52—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 inorganic compound, e.g. an inorganic ion that is complexed with the active ingredient
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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
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
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- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B25/00—Phosphorus; Compounds thereof
- C01B25/02—Preparation of phosphorus
Abstract
The invention discloses a kind of phosphorous-based materials preparations and its preparation method and application, wherein phosphorous-based materials preparation includes phosphorous-based materials and modification in the calcium hydroxy phosphate on phosphorous-based materials surface, and phosphorous-based materials are that the material for generating phosphate anion can be converted under acidic environment.The phosphorous-based materials preparation is high in neutral physiological environment stability inferior, its drug that can be applied to preparation treatment tumour, the amplification and transfer of tumour cell can be effectively suppressed, to more effectively prevent the transfer of cancer cell and the recurrence of tumour, tumor effect is treated to improve, and during the entire course for the treatment of, phosphorous-based materials preparation normal tissue and impact cell are smaller, securely and reliably.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of phosphorous-based materials preparation and its preparation method and application.
Background technique
Malignant tumour (also referred to as cancer) seriously endangers human health, and oncotherapy has become Medical research neck
The significant challenge that domain is faced.Clinically the treatment method of tumour mainly includes operative treatment, radiotherapy and change at present
Learn the methods for the treatment of.Although these treatment methods achieve certain effect in tumor therapeutic procedure, they still remain office
Sex-limited and single treatment method cannot achieve good oncotherapy effect.Traditional therapeutic modality is difficult to realize tumour
The fully erased and specific killing of cell leads to Nasopharyngeal neoplasms, recurrence and since the damage to normal cell produces
Raw side effect.
Patent " a kind of composite material and preparation method and application of black phosphorus nanometer sheet-antitumoral compounds " (application number
CN106267204A), a kind of black phosphorus nanometer sheet and antitumor composite material and its system with primary amino group and/or phenolic hydroxyl group are disclosed
Preparation Method and application construct two-dimentional black phosphorus and load anti-tumor drug, realize Synergistic anti-cancer effect.Black phosphorus is received in the composite material
What rice piece played the role of is anti-cancer medicament carrier, and black phosphorus itself is not as a kind of anticancer drug, and drug is without targeting and spy
It is anisotropic.
Summary of the invention
In order to solve the above technical problem, the present invention provides a kind of phosphorous-based materials preparations and its preparation method and application, should
Phosphorous-based materials preparation is high in neutral physiological environment stability inferior, can be applied to the drug of preparation treatment tumour, can be effectively suppressed
The amplification and transfer of tumour cell, to prevent the transfer of cancer cell and the recurrence of tumour, more effectively to improve treatment tumour
Effect, and during the entire course for the treatment of, phosphorous-based materials preparation normal tissue and impact cell are smaller, securely and reliably.
The technical scheme adopted by the invention is that: the present invention provides a kind of phosphorous-based materials preparation, the phosphorous-based materials preparations
Comprising phosphorous-based materials and modification in the calcium hydroxy phosphate on the phosphorous-based materials surface, the phosphorous-based materials are can under acidic environment
Conversion generates the material of phosphate anion.
Preferably, the phosphorous-based materials are that can convert to generate the elemental phosphorous of phosphate anion and/or contain under acidic environment
Phosphorus compound.Phosphorus-containing compound include containing phosphorous oxides, halide and other can be converted under acidic environment generate phosphate radical from
The phosphorus-containing compound (such as phosphate) of son.Phosphorous-based materials are specifically including but not limited to the phosphorus list such as black phosphorus, red phosphorus, white phosphorus, violet phosphorus
Matter, the phosphorous oxides such as phosphorus trioxide, five phosphorous oxides, the phosphorus halides such as phosphorus pentahalides, phosphorus trihalide, four phosphorus Halides, and be based on
One in the phosphate compounds such as orthophosphoric acid, metaphosphoric acid, phosphorous acid, pyrophosphoric acid, triphosphoric acid, hypophosphorous acid, hypophosphoric acid, polyphosphoric acid
Kind is a variety of.
Preferably, the surface of the phosphorous-based materials can be oxidized, hydrolyze or ionize generation phosphate anion in situ, local volume
Phosphorus acid ion concentration is much larger than solution overall density in product, is conducive to phosphate anion and exists with calcium source, hydroxide ion donor
The progress of phosphorous-based materials surface in situ deposition reaction, thus in the surface modification calcium hydroxy phosphate of phosphorous-based materials.
Preferably, the phosphorous-based materials are phosphorus base micro-nano material, the material including nanometer and micron level.Wherein, nanometer
Grade material is conducive to intravenously administrable, reduces organ aggregate toxicity；Micron level material can be used for administration in situ, have stronger life
Object effect.In addition, nano material can target medicine by surface modification folic acid, antibody etc. while realizing drug carrier
Object obtains tumour cell targeting, modifies fluorescent molecule or realizes tumour cell imaging by the optical effect of itself, realizes
The diagnosis and treatment integrated therapeutic of tumour.In addition, the features such as the huge specific surface area of nano material and longer physiology cycle period,
It ensure that drug carrier and operational efficiency, help to realize the high-efficiency continuous killing of cancer cell.
Preferably, the phosphorous-based materials include in black phosphorus nanometer sheet, black phosphorus quantum dot and its face finish material at least
One kind, the surface of the face finish material, which can be oxidized, hydrolyzes or ionize, generates phosphate anion.It is, black phosphorus nanometer
Piece and/or black phosphorus quantum dot may also pass through surface modification, such as modify rare earth ion, titanium ligand or other substances, as long as through
The black phosphorus nanometer sheet and/or black phosphorus quantum dot surface of surface modification, which can be oxidized, hydrolyze or ionize, generates phosphate anion, this kind of
The black phosphorus nanometer sheet and/or black phosphorus quantum dot of surface modification also can be used as phosphorous-based materials.In the above phosphorous-based materials, black phosphorus
Catabolite be phosphate radical etc., it is required for human life activity, with good element biocompatibility.Its huge ratio
Surface area is conducive to surface modification and drug carrier.In addition, black phosphorus is fast under the microenvironment of subacidity and high pressure inside and outside cancer cell
Prompt drop solution generates a large amount of phosphate anions and reactive intermediates (such as: active oxygen ROS), itself has antitumaous effect effect.
Preferably, the phosphorous-based materials preparation is by surface modification for enhancing targeting.It is described to be targeted for enhancing
Property surface modification include but is not limited to utilize the peptide matters such as the compound-modified, cell-penetrating peptide such as folic acid modify and targeting cancer
The modification of aptamers, the antibody of cell etc..Targeting sex modification is carried out by the surface to phosphorous-based materials preparation, can more effectively be pressed down
The diffusion and transfer of cancer cell or tumour cell processed, to more efficiently prevent from the recurrence of cancer cell or tumour cell, with more into
One step improves therapeutic effect.
Black phosphorus sill through calcium hydroxy phosphate surface modification has loading functional molecule (such as target tumor marker point
Son, fluorescent tracing molecule, combination drug molecule, gene etc.) function, wherein the presence of hydroxyl has conducive to function in functional molecular
Group stablize grafting, therefore can by phosphorous-based materials surface constructing function platform, it can be achieved that cancer target grafting, fluorescent molecule
The functional modifications such as delivery, drug combination, delivery vehicles in gene.Thus, it is further preferred that being also loaded in the phosphorous-based materials preparation
Functional molecule, the functional molecular include fluorescent tracing molecule (such as Ce6, Cy5.5), target tumor marker molecules, medicine
Inorganic functionals molecule and the permutation and combination such as object molecule and bioactive macromolecule (such as cyclic DNA, RNA), ferroso-ferric oxide.Phosphorus
Sill formulation load functional molecular is concretely to adsorb and/or embed on the phosphorous-based materials of surface modification calcium hydroxy phosphate
Mode loading functional molecule.The functional molecular of load is released in calcium hydroxy phosphate degradation process, to realize material pref
Functionalization, the process be known as " responsiveness discharges (Responsive Co-release) altogether ".The above phosphorous-based materials preparation can answer
It is used to prepare the drug for the treatment of tumour；Target tumor marker, the phosphorus in tumor therapeutic procedure are loaded in phosphorous-based materials preparation
Sill preparation can be provided simultaneously with active targeting, passive target and selective killing and other effects；It is born in phosphorous-based materials preparation
Fluorescent tracing molecule is carried, high-efficiency low-toxicity killing tumour is can reach and fluorescent tracing diagnoses integrated purpose.This is with multiple
Biological function is known as " surface-functionalized bioactive P base diagnosis and treatment for tumor tissue specificity killing drug treatment
Method (Functionalized Bioactive Phosphorus-based Diagnose&Therapy) ", referred to as " functionalization
Phosphorus base diagnosis and treatment (FBPDT) ".
The present invention also provides the preparation methods of more than one phosphorous-based materials preparations, comprising the following steps:
S1, isolation air environment, will be scattered in solvent after phosphorus base grinding raw material, be made phosphorus base material it is molten
Liquid；Ultrasonic removing then is carried out to the phosphorus base material solution, obtains phosphorous-based materials stoste；
S2, the phosphorous-based materials stoste is centrifuged, takes supernatant；Calcium source is added into the supernatant, mixes
Hydroxide ion donor is added after even to be reacted, then is purified.
Preferably, the calcium source is calcium ions compound；The calcium source is preferably calcium gluconate, calcium chloride, lemon
At least one of sour calcium.It is further preferred that according to P:Ca molar concentration rate in solution after addition calcium source, (phosphorus and calcium mole are dense
Spend ratio) it is that 1:25~35 adds calcium source.
Preferably, the hydroxide ion donor is the alkali compounds that hydrolyzable or ionization generate hydroxide ion；Institute
Stating hydroxide ion donor is preferably at least one of concentrated ammonia liquor, sodium acetate, sodium hydroxide.It is further preferred that hydroxyl
The additive amount of ion donor account for be added calcium source after overall solution volume 5%~10%.
In addition, various solvents can be used in solvent in step S1, such as N-Methyl pyrrolidone (NMP), dimethylformamide
(DMF), dimethyl sulfoxide (DMSO), dehydrated alcohol, isopropanol etc..Ultrasound removing can be used Probe Ultrasonic Searching, water bath sonicator or
The mode that the two successively acts on, the effect that can be specifically removed by changing the adjustings such as the ultrasonic mode of action, supersonic frequency, can also
In conjunction with other lift-off technologies such as thermal Release Technology, ion insertion technology etc., the efficiency and yield of removing are improved.In addition, may be used also
Resulting phosphorous-based materials stoste is removed to ultrasound and carries out surface coordination or targeting modification, to enhance the stability and target of phosphorous-based materials
Tropism.
In step S2, after hydroxide ion donor is added, preferably adjusting pH value is 10~11, is placed in 45~60 DEG C of constant temperature
10~15h of heating in water bath for reaction.
In addition, the application the present invention also provides the above phosphorous-based materials preparation in the drug of preparation treatment tumour, described
Drug passes through the internal and external environment for changing the tumour cell, to inhibit tumor cell proliferation and/or inducing apoptosis of tumour cell.Tool
Body can be swallowed by phosphorous-based materials preparation therein by tumour cell, the calcium hydroxy phosphate degradation of phosphorous-based materials surface modification, phosphorus
Sill conversion generates phosphate anion, to change the internal and external environment of the tumour cell, and then inhibit tumor cell proliferation and/
Or inducing apoptosis of tumour cell.
Preferably, the phosphorous-based materials preparation can be used as single formulation；Or using the phosphorous-based materials preparation as activity
The drug that pharmaceutically acceptable auxiliary agent prepares treatment tumour together is added in ingredient；In addition, can also be added other anti-tumor activities at
Point, to reach synergistic effect.Specifically the dosage form of clinical receiving can be made according to common process, including tablet, capsule, pill,
Granule, sustained release preparation, controlled release preparation or ejection preparation etc. are applied to clinic.Wherein, phosphorous-based materials are shared in composition of medicine
Ratio because of concrete condition depending on, be based on pharmaceutical composition, the specific additive amounts of phosphorous-based materials can for 0.01wt%~
99.99wt%, preferably 20wt%~99.99wt%, further preferred 30wt%~80wt%.
By the above phosphorous-based materials formulation application in the drug of preparation treatment tumour, the administration mode of obtained drug can lead to
Cross the mode directly placed in intravenously administrable or tumour and around tumour.Preparation treatment is particularly used in originating from people and animal
Brain, blood, mammary gland, pancreas, uterus, endometrium, cervix, kidney, liver, gall-bladder, incidence, oral cavity, thyroid gland, skin
Skin, mucous membrane, body of gland, blood vessel, liver, lungs, oesophagus, ovary, prostate, bone tissue, lymph node, bladder, colon or rectum
The drug of primary or secondary cancer, sarcoma or carcinosarcoma.Specific dosage in therapeutic process can be according to institute's phosphorous-containigroups groups in drug
Situations such as type of material, targeted tumor type and application method, is determined.
The method have the benefit that: the present invention provides a kind of phosphorous-based materials preparation and preparation method thereof and answer
With phosphorous-based materials can be improved in neutral physiologic ring in the surface modifying calcium hydroxy phosphate of phosphorous-based materials in the phosphorous-based materials preparation
Stability under border；In addition, the surface roughness of phosphorous-based materials dramatically increases, and is conducive to cell after calcium hydroxy phosphate modification
Endocytosis improves endocytosis efficiency；And there is the decorative layer on phosphorous-based materials surface tumor microenvironment to respond degradation characteristic, when the material
When preparation acts on tumour cell, calcium hydroxy phosphate is degraded under the microenvironment of slant acidity inside and outside the tumour cell, exposure hydroxyl phosphorus
The activation site that sour calcium is reacted with phosphorous-based materials, accelerates the degradation rate of phosphorous-based materials, instantaneously generate a large amount of phosphate anions and
Other activated products destroy the ionic equilibrium of tumor microenvironment, and phosphorylation occurs for the albumen of induced tumor cell, to realize suppression
Tumor cell proliferation processed, the effect for inducing it dead.Specifically, phosphorous-based materials are due to the long retention effect of the Thief zone of tumor tissues
(enhanced permeability and retention effect, EPR) and/or due to originals such as the targetings on its surface
Because can be accumulated in tumor tissues microenvironment, and/or by tumour cell by endocytosis intake after, due in tumour cell and
Slant acidity microenvironment possessed by extracellular accelerates its conversion, and a large amount of phosphate anions are instantaneously generated in its rapid conversion process
And other activated products (i.e. unstable intermediate product, such as living radical, active oxygen), the process can be described as that " ion is fried
Bounce effect (Ionic Bomb Effect) ", and then the change of microenvironment inside and outside tumour cell can be further induced, and promote egg
The raw nonspecific phosphorylation effect of white hair inhibits tumor cell proliferation, and finally lure to upset the mitosis of tumour cell
Lead death of neoplastic cells.Since in phosphorous-based materials preparation of the present invention, there are hydroxyl, materials in the group of phosphorous-based materials surface modification
The electronegativity on surface enhances, and has more excellent functional molecular group (such as tumor target compared to unmodified phosphorous-based materials
To molecule, fluorescent tracing molecule etc.) binding ability and positive charge molecules adsorption capacity.In addition, phosphorus after calcium hydroxy phosphate degradation
Sill surface-active site can enhance " the ion bomb effect " of phosphorous-based materials, compared to unmodified phosphorous-based materials, energy
It is enough that more phosphate anion and other activated products are generated within the unit time, there is more excellent antitumor effect
Fruit.And for normal cell, due to the outer microenvironment intracellular of its slower mitotic activity and partial neutral, phosphorous-based materials system
Conversion degradation more slow, the phosphoric acid that in this mild conversion process is slowly released of the agent in normal tissue and cell
Radical ion has high biocompatibility, and therefore, the influence of normal tissue cell is very small.
To sum up, the solution of the present invention is simple, efficient, and phosphorous-based materials preparation of the invention can be applied to preparation treatment tumour
Drug has specificity and targeting in treatment neoplastic process.
Detailed description of the invention
For the clearer technical solution illustrated in the embodiment of the present invention, will make below to required in embodiment description
Attached drawing briefly describes.
Fig. 1 is the phenogram of calcium hydroxy phosphate modification front and back black phosphorus nanometer sheet Zeta potential situation of change in embodiment 1；
Fig. 2 is the black phosphorus nanometer sheet of the modification of calcium hydroxy phosphate obtained by embodiment 1 respectively in pH7.0 and pH4.0 ultrapure water
Neutralize the change curve of naked black phosphorus nanometer sheet ultraviolet absorptivity at 808nm in pH7.0 ultrapure water；
Fig. 3 is that the black phosphorus base nanometer sheet of calcium hydroxy phosphate surface modification obtained by embodiment 1 inhibits Cells Proliferation of Human Breast Cancer
Curve graph；
Fig. 4 is that the black phosphorus base nanometer sheet of calcium hydroxy phosphate surface modification obtained by embodiment 1 inhibits cervical cancer cell proliferation
Curve graph；
Fig. 5 is that the black phosphorus base nanometer sheet of calcium hydroxy phosphate surface modification obtained by embodiment 1 inhibits non-small lung cancers cell to increase
Grow curve graph；
Fig. 6 is that the black phosphorus base nanometer sheet of calcium hydroxy phosphate surface modification obtained by embodiment 1 inhibits normal cell proliferation bent
Line chart；
Fig. 7 is the black phosphorus base nanometer sheet inducing mammary cancer cell-apoptosis of calcium hydroxy phosphate surface modification obtained by embodiment 1
Figure；
Fig. 8 is the black phosphorus base nanometer sheet induction Hela Cell Apoptosis of calcium hydroxy phosphate surface modification obtained by embodiment 1
Figure；
Fig. 9 is that the black phosphorus base nanometer sheet induction non-small lung cancers cell of calcium hydroxy phosphate surface modification obtained by embodiment 1 withers
Die figure；
Figure 10 is the black phosphorus base nanometer sheet induction normal apoptosis of calcium hydroxy phosphate surface modification obtained by embodiment 1
Figure；
Figure 11 is the fluorescence delivery efficiency change pair of black phosphorus base nanometer sheet before and after calcium hydroxy phosphate surface modification in embodiment 1
Than figure；
Figure 12 is the qualitative observation of the black phosphorus base nanometer sheet delivery vehicles in gene of calcium hydroxy phosphate surface modification obtained by embodiment 1
Result figure.
Specific embodiment
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In addition, it should also be understood that, after reading the content taught by the present invention, those skilled in the art
Member can make various changes or modifications the present invention, and such equivalent forms equally fall within the application the appended claims and limited
Range.
Embodiment 1: the black phosphorus nanometer sheet of calcium hydroxy phosphate modification is prepared
It first passes through liquid phase stripping means and prepares biologically active black phosphorus nano flake.Specific steps include: to completely cut off
In the environment of air, it will be scattered in solvent N-methyl pyrilidone (NMP) and seal after the grinding of a certain amount of black phosphorus crystal；And
Afterwards in such a way that both Probe Ultrasonic Searching and water bath sonicator successively act on, ultrasonic removing is carried out to black phosphorus solution, is had with preparation
The black phosphorus thin slice stoste of bioactivity.The mode of independent Probe Ultrasonic Searching or water bath sonicator can also be used in ultrasound removing, and can lead to
The effect of the adjustings such as the mode of action, the supersonic frequency for changing ultrasound removing is crossed, also in combination with other lift-off technology such as thermal releases
Technology, ion insertion technology etc. improve the efficiency and yield of removing.Black phosphorus thin slice in obtained black phosphorus thin slice stoste has
It can be converted after being swallowed by tumour cell and generate a large amount of phosphate anions, change intraor extracellular environment, and then tumour cell is inhibited to increase
It grows and the bioactivity of inducing death of neoplastic cells.
Black phosphorus thin slice is made by such as liquid phase stripping means, can also carry out surface coordination or targeting to obtained black phosphorus thin slice
Modification, to enhance the stability and targeting of black phosphorus thin slice, obtained two-dimentional black phosphorus is (including exposed two-dimentional black phosphorus and through repairing
The two-dimentional black phosphorus of decorations) it is scattered in appropriate solvent, in order to the long-term preservation of material.
Appropriate black phosphorus stoste (solvent NMP) is taken, 10min is centrifuged at 7000rpm, supernatant black phosphorus concentration is measured, presses
Molar concentration rate according to P:Ca is that calcium gluconate is added in 1:30, and ultrasound 15min makes it be uniformly dispersed after shaking up.After ultrasound
Concentrated ammonia liquor is added according to account for liquor capacity 10% in solution, adjusting reaction pH is 10~11, is placed in 50 DEG C of waters bath with thermostatic control and adds
Hot 12h；The then centrifugal purification at 15000rpm, and twice with milli-Q water precipitating, surface modification is made after centrifugal purification
The black phosphorus nanometer sheet of calcium hydroxy phosphate.
Embodiment 2:Zeta potential measurement experiment
Zeta potential measurement experiment, gained are carried out to the black phosphorus nanometer sheet through calcium hydroxy phosphate modification front and back in embodiment 1
As a result as shown in Figure 1.As shown in Figure 1, before modifying through calcium hydroxy phosphate, the Zeta potential of black phosphorus nanometer sheet is -21.0mV, and is passed through
After calcium hydroxy phosphate modification, the Zeta potential of black phosphorus nanometer sheet is -29.7mV.This shows through the black of calcium hydroxy phosphate surface modification
It is enhanced for the relatively naked black phosphorus (black phosphorus i.e. without calcium hydroxy phosphate modification) of phosphorus nanometer sheet surface electronegativity.
Embodiment 3: the vitro stability of the black phosphorus nanometer sheet of surface modification calcium hydroxy phosphate is evaluated
By the black phosphorus nanometer sheet respectively to surface modification calcium hydroxy phosphate obtained by naked black phosphorus nanometer sheet and embodiment 1 into
Row external degradation experiment, to evaluate its vitro stability.It is specific as follows:
Take respectively the black phosphorus nanometer sheet of surface modification calcium hydroxy phosphate obtained by equivalent embodiment 1 be dissolved in pH 7.0 with
And in the ultrapure water of pH 4.0 (pH of ultrapure water is adjusted by dilute hydrochloric acid).It is ultraviolet every the 300~900nm for measuring each sample for 24 hours
Absorbance, according to the ratio calculation degradation rate of absorbance value and initial value, until black phosphorus is degradable.In addition, taking the naked of equivalent
Black phosphorus nanometer sheet is dissolved in the ultrapure water of pH 7.0, press more than method carry out external degradation experiment.
Specific experiment result is as shown in Figure 2.The result shows that the black phosphorus nanometer sheet of 4 days rear surface modification calcium hydroxy phosphates exists
Degradation rate in the ultrapure water of pH4.0 is 62.0%, hence it is evident that 31.0% corresponding degradation rate when higher than pH 7.0, it was demonstrated that the warp
The black phosphorus nanometer sheet of calcium hydroxy phosphate surface modification has certain pH responsiveness.
Compared with the naked black phosphorus nanometer sheet of control group, under 7.0 neutrallty condition of pH, the black phosphorus nanometer of calcium hydroxy phosphate modification
Tablet stability is apparently higher than naked black phosphorus nanometer sheet, shows that the surface modification of calcium hydroxy phosphate can be improved the stabilization of black phosphorus nanometer sheet
Property.
Embodiment 4: the black phosphorus nanometer sheet of surface modification calcium hydroxy phosphate evaluates the fragmentation effect of tumour cell
The black phosphorus nano flake of surface modification calcium hydroxy phosphate obtained by embodiment 1 is acted on into tumour cell and normal thin
Born of the same parents carry out cell Proliferation test experience and Apoptosis test experience.It is specific as follows:
(1) cell Proliferation test experience method
Different types of human cancer cell and normal cell are cultivated in advance, wherein human cancer cell includes cervical cancer cell
(Hela), breast cancer cell (MCF-7) and non-small lung cancers cell (A549), normal cell select human marrow mesenchymal stem cell
(Hmsc).Specifically, cell can be planted by the density in 5000/hole in 96 orifice plates, every group is done four multiple holes, every hole culture medium
It include the DMEM of 10%FBS for 100 μ L, cell is placed in 37 DEG C of incubators, 5%CO2, cultivate for 24 hours under the conditions of saturated humidity.
Then, culture medium is replaced with to the culture of the black phosphorus nano flake of the surface modification calcium hydroxy phosphate containing suitable size
Base, then in 37 DEG C of incubators, 5%CO2, 48h is cultivated under the conditions of saturated humidity.Wherein, the black phosphorus of surface modification calcium hydroxy phosphate
The size of nano flake can be thickness 2-20nm；Length and width dimensions 20-300nm, in favor of cell endocytic.In addition, in culture hole
The final concentration of the black phosphorus nano flake of surface modification calcium hydroxy phosphate is respectively 0,0.0625,0.125,0.25,0.5,1,2,4 and
8μg/mL.After culture, former culture medium is discarded, after 100 μ L CCK-8 working solutions incubation 1h is added, detects the absorbance at A450nm
(OD) value calculates cell survival rate by each hole OD value.
(2) Apoptosis test experience method
Different types of human cancer cell and normal cell are cultivated in advance, wherein human cancer cell includes cervical cancer cell
(Hela), breast cancer cell (MCF-7) and non-small lung cancers cell (A549), normal cell select human marrow mesenchymal stem cell
(Hmsc).Specifically, cell is pressed 5 × 104The density in a/hole is planted in 24 orifice plates, and every group is done three multiple holes, every hole culture medium
It include the DMEM of 10%FBS for 1mL, cell is placed in 37 DEG C of incubators, 5%CO2, cultivate for 24 hours under the conditions of saturated humidity.
Then, culture medium is replaced with to the culture of the black phosphorus nano flake of the surface modification calcium hydroxy phosphate containing suitable size
Base, then in 37 DEG C of incubators, 5%CO2, 48h is cultivated under the conditions of saturated humidity.Wherein, the black phosphorus of surface modification calcium hydroxy phosphate
The size of nano flake can be thickness 2-10nm；Length and width dimensions 20-300nm, in favor of cell endocytic.In addition, in culture hole
The final concentration of the black phosphorus nano flake of surface modification calcium hydroxy phosphate is respectively 0,0.25,0.5,1.0 and 2.0 μ g/mL.Culture knot
Shu Hou with trypsin treatment and collects cell, and 1000g is centrifuged 5min, abandons supernatant, collects cell, cell is gently resuspended with PBS
And it counts.The cell for taking 5-10 ten thousand to be resuspended, 1000g are centrifuged 5min, abandon supernatant, and 195 μ L Annexin V-FITC combination liquid are added
Cell is gently resuspended, adds 5 μ L Annexin V-FITC and 10 μ L propidium iodides (PI) mixes gently, room temperature is protected from light dyeing
15min, with machine testing on flow cytometer.
External application research as above, acquired results such as Fig. 3-are carried out to the black phosphorus nano flake of surface modification calcium hydroxy phosphate
Shown in 10.
Fig. 3 to Fig. 6 is please referred to, Fig. 3 is the black phosphorus nano flake suppression of surface modification calcium hydroxy phosphate in the embodiment of the present invention 1
Cells Proliferation of Human Breast Cancer curve graph processed, Fig. 4 are that the black phosphorus nano flake of surface modification calcium hydroxy phosphate inhibits cervical cancer cell to increase
Curve graph is grown, Fig. 5 is that the black phosphorus nano flake of surface modification calcium hydroxy phosphate inhibits non-small lung cancers cell Proliferation curve graph, Fig. 6
It is the black phosphorus nano flake inhibition human normal cell line growth curve figure of surface modification calcium hydroxy phosphate.In the above cell Proliferation curve
In figure, abscissa is the concentration of the black phosphorus nano flake of surface modification calcium hydroxy phosphate, and ordinate is cell survival rate.
As shown in Figures 3 to 6, in cell Proliferation test experience, the surface modification calcium hydroxy phosphate of a certain concentration gradient
Black phosphorus nano flake act on breast cancer cell (MCF-7), cervical cancer cell (Hela) and non-small lung cancers cell (A549) three
After kind cancer cell 48h, significant proliferation suppression is presented to three kinds of cancer cells in the black phosphorus nano flake of the surface modification calcium hydroxy phosphate
Production is used.Analysis as a result, it has been found that: culture 48h after, when calcium hydroxy phosphate modification black phosphorus nano flake concentration be 0.5 μ g/mL
When, the proliferation rate of breast cancer cell is inhibited by 50% or so (as shown in Figure 3)；When the black phosphorus nanometer thin of calcium hydroxy phosphate modification
When the concentration of piece is 0.5 μ g/mL or so, the proliferation inhibition rate of cervical cancer cell has reached 80% (as shown in Figure 4)；When hydroxyl phosphorus
When the black phosphorus nano flake concentration of sour calcium modification is 0.5 μ g/mL or so, non-small lung cancers cell proliferation inhibition rate reaches 90% or so
(as shown in Figure 5).And for normal cell human marrow mesenchymal stem cell, after cultivating 48h, each concentration calcium hydroxy phosphate modification
The processing of black phosphorus nano flake cell its cell survival rate in 40% or more (as shown in Figure 6).And by Fig. 3 to Fig. 6 it is found that
The black phosphorus nano flake of calcium hydroxy phosphate modification can significantly inhibit the proliferation of cancer cell under lower dosage；In same dose
Lower black phosphorus nano flake is far smaller than cancer cell to the inhibited proliferation of normal cell.
Fig. 7 to Figure 10 is please referred to, Fig. 7 is the black phosphorus nano flake of surface modification calcium hydroxy phosphate in the embodiment of the present invention 1
Inducing mammary cancer cell-apoptosis figure, Fig. 8 are the black phosphorus nano flake induction Hela Cell Apoptosis of surface modification calcium hydroxy phosphate
Figure, Fig. 9 are the black phosphorus nano flake induction non-small lung cancers Apoptosis figures of surface modification calcium hydroxy phosphate, and Figure 10 is surface modification
The black phosphorus nano flake of calcium hydroxy phosphate induces human normal cell line apoptosis figure.In the above Apoptosis figure, abscissa is
Annexin V fluorescence intensity；Ordinate is PI fluorescence intensity；The region Q4 is the normal cell of activity；Q3 is viable apoptotic cell；
Q2 is non-viable apoptotic cell；Q1 is non-viable non-apoptotic cell, be can be neglected.
As shown in Figure 7 to 10, in Apoptosis test experience, the apoptotic cell (Q2+Q3) of three kinds of cancer cells is found
Ratio significantly increases with the increase of concentration, and the black phosphorus nano flake of surface modification calcium hydroxy phosphate has one to three kinds of cancer cells
Fixed concentration dependent, i.e. the black phosphorus nano flake concentration of surface modification calcium hydroxy phosphate increase, to cell inhibition level phase
It should increase.And apoptotic cell (Q2+Q3) ratio of normal cell is smaller, and increases the increase of apoptotic cell ratio not with material concentration
Obviously.When the black phosphorus nanometer sheet concentration of calcium hydroxy phosphate modification is 1 μ g/mL or so, MCF-7, Hela and A549 of apoptosis are thin
Born of the same parents' proportion is respectively 50.05%, 34.4% and 37.02%, and in contrast, the Hmsc cell proportion of apoptosis is only
10.88%.This shows that the black phosphorus nanometer sheet of calcium hydroxy phosphate modification can be realized the differentiation to tumour cell and normal cell
Effect, i.e. selective killing tumour cell.
The result of Fig. 7 to Figure 10 further illustrates, relatively low-dose calcium hydroxy phosphate modify black phosphorus nanometer sheet just
Significantly inhibiting for cancer cell multiplication can be achieved, but significantly smaller to the inhibited proliferation of normal cell.
Result above proves that the black phosphorus nano flake of calcium hydroxy phosphate modification can significantly effectively inhibit the increasing of cancer cell
It grows, and induces its apoptosis, but cancer cell is much smaller than to the lethal effect of normal cell under same dose.
Embodiment 5: the black phosphorus nanometer sheet of surface modification calcium hydroxy phosphate evaluates small-molecule drug carrying capacity
Using fluorescent small molecule Ce6 as template, the small-molecule drug of the black phosphorus nanometer sheet of surface modification calcium hydroxy phosphate is detected
Carrying capacity.
According to the preparation method for the black phosphorus nanometer sheet that calcium hydroxy phosphate in embodiment 1 is modified, it is deposited in calcium hydroxy phosphate
Fluorescent small molecule Ce6 is added during black phosphorus nanometer sheet surface, is centrifuged Aspirate supernatant after reaction, supernatant after must delivering
Liquid；In addition, in a similar way, fluorescent small molecule is added during calcium hydroxy phosphate is deposited on black phosphorus nanometer sheet surface
Ce6, centrifuging and taking supernatant, must deliver preceding solution immediately.The fluorescence intensity of supernatant and the preceding solution of delivery after detection delivery respectively
Fluorescence intensity, acquired results are as shown in figure 11, according to drug carrier rate η=I/I0(I and I0Supernatant after respectively delivering
Solution fluorescence intensity before fluorescence intensity and delivery), delivery rate is calculated by Figure 11 result, obtains the carrying capacity of fluorescent small molecule about
It is 90.17%.
Embodiment 5: the black phosphorus nanometer sheet of surface modification calcium hydroxy phosphate comments bioactive macromolecule drug carrier ability
Valence
Delivery vehicles in gene experiment is carried out with fluorescent molecule Cy-5.5 label small, annular DNA, specifically according to hydroxyl in embodiment 1
The preparation method of the black phosphorus nanometer sheet of calcium phosphate modification, is added during calcium hydroxy phosphate is deposited on black phosphorus nanometer sheet surface
Cy-5.5 marks small, annular DNA, carries out the common location tracer of fluorescent molecule and DNA, is seen afterwards using fluorescence microscope for 24 hours
It examines, observation result is as shown in figure 12.Rear fluorescence area is consistent with cell outline for 24 hours as the result is shown in Figure 12, shows the hydroxyl
The black phosphorus nanometer sheet of calcium phosphate modification can passenger gene, and realize its release in the cell.
From the foregoing, it will be observed that the two-dimentional black phosphorus nanometer sheet of calcium hydroxy phosphate modification can be in the significant increasing for effectively inhibiting cancer cell
While growing, and induce its apoptosis, to normal cell, there are lower cytotoxicities.In addition, in calcium hydroxy phosphate forming process
Several functional molecules can be successfully delivered, realize the multifunction of anticancer drug.Therefore, which is highly suitable for
Exploitation as novel and multifunctionalization anticancer drug.
To sum up, the black phosphorus nano flake through calcium hydroxy phosphate surface modification has bioactivity and multi-functional modification potentiality,
Its mechanism of action mainly include the physically trapping of functional molecular and under environmental response molecule release, generate corresponding function and
Inside and outside tumour cell under slightly acidic environment, the black phosphorus binding site exposure of calcium hydroxy phosphate modification, black phosphorus surface is in the state of activation,
It is oxidized and generates a large amount of phosphate anions and other reactive intermediates (such as: ROS).Treatment of cancer, neoplasm tracing and
There are huge applications potentiality in terms of gene association treatment, drug carrier.
The surface of black phosphorus quantum dot can be oxidized generation phosphate anion as nanometer sheet, and with calcium ion, hydrogen-oxygen
Radical ion combination forms calcium hydroxy phosphate and is deposited on material surface, and then based on the black phosphorus nanometer sheet phase modified with calcium hydroxy phosphate
As mechanism, can be applied to prepare anti-tumor drug.It specifically can be by young in a small amount of N-Methyl pyrrolidone (NMP) by black phosphorus
Fine lapping adds appropriate N-Methyl pyrrolidone and uses cell crushing instrument Probe Ultrasonic Searching 3h, obtained dispersion liquid is again at powder
Black phosphorus quantum dot is prepared in the water bath sonicator 10h in ultrasonic cleaner；Again using similar above calcium hydroxy phosphate modification
The preparation method of black phosphorus nano flake black phosphorus quantum dot surface modification calcium hydroxy phosphate, to prepare surface modification di
The black phosphorus quantum dot of calcium.
Certainly, calcium hydroxy phosphate can also otherwise modify the surface in black phosphorus nanometer sheet or black phosphorus quantum dot, thus
The stability of black phosphorus nanometer sheet and black phosphorus quantum dot in a neutral environment can be enhanced, and be conducive to cell endocytic, improve endocytosis rate.
In addition, from the foregoing, it will be observed that black phosphorus nano flake has bioactivity can be thin by tumour after contacting with tumour cell
Endocytosis is bitten, and in tumour cell conversion generate phosphate anion, due in tumour cell and it is extracellular possessed by slant acidity it is micro-
Environment can accelerate its conversion, and a large amount of phosphate anions and other activated products are instantaneously generated in its rapid conversion process (i.e. not
Stable intermediate product), the change of microenvironment inside and outside tumour cell can be further induced, microenvironment inside and outside tumour cell is destroyed
Ionic equilibrium, and promote the albumen of tumour cell that nonspecific phosphorylation effect occurs, so that upsets tumour cell has silk point
It splits, inhibits tumor cell proliferation, and final inducing death of neoplastic cells.According to the above black phosphorus nano flake for tumour cell
The mechanism of action, other can convert the phosphorous-based materials for generating phosphate anion under acidic environment for deducibility, including other are elemental phosphorous
And/or phosphorus-containing compound, it can also be applied to the drug of preparation treatment tumour, it is swollen to be acted on by the mechanism of action like above
Oncocyte inhibits the proliferation and inducing death of neoplastic cells of tumour cell, realizes the treatment to tumour.And hydroxyl phosphorus can be passed through
The stability of the surface modification enhancing phosphorous-based materials of sour calcium in a neutral environment, and it is conducive to cell endocytic, improve endocytosis efficiency；
It can even be assigned in the pH response function of tumor microenvironment, accelerate the degradation under acidic environment, quickly and effectively inhibit tumour
The amplification and transfer of cell, to prevent the transfer of cancer cell and the recurrence of tumour, more effectively to improve treatment tumor effect.
Although specifically showing and describing the present invention in conjunction with preferred embodiment, those skilled in the art should be bright
It is white, it is not departing from the spirit and scope of the present invention defined by described claims, it in the form and details can be right
The present invention makes a variety of changes, and is protection scope of the present invention.
Claims (14)
1. a kind of phosphorous-based materials preparation, which is characterized in that the phosphorous-based materials preparation includes phosphorous-based materials and modification in the phosphorus
The calcium hydroxy phosphate on sill surface, the phosphorous-based materials are that the material for generating phosphate anion can be converted under acidic environment.
2. phosphorous-based materials preparation according to claim 1, which is characterized in that the phosphorous-based materials are can under acidic environment
Conversion generates the elemental phosphorous and/or phosphorus-containing compound of phosphate anion.
3. phosphorous-based materials preparation according to claim 1, which is characterized in that the surface of the phosphorous-based materials can be oxidized,
Hydrolysis or ionization generate phosphate anion.
4. phosphorous-based materials preparation according to any one of claim 1-3, which is characterized in that the phosphorous-based materials are phosphorus base
Micro-nano material；Preferably, the phosphorous-based materials include the black phosphorus nanometer of black phosphorus nanometer sheet, black phosphorus quantum dot and surface modification
At least one of piece and black phosphorus quantum dot, the black phosphorus nanometer sheet of the surface modification and the surface of black phosphorus quantum dot can be by oxygen
Change, hydrolysis or ionization generate phosphate anion.
5. phosphorous-based materials preparation according to any one of claim 1-3, which is characterized in that the phosphorous-based materials preparation warp
Surface modification is crossed for enhancing targeting；The surface modification for enhancing targeting includes peptide matters modification and targeting
At least one of the aptamers of cancer cell or antibody modification.
6. phosphorous-based materials preparation according to any one of claim 1-3, which is characterized in that in the phosphorous-based materials preparation
It is also loaded functional molecule, the functional molecular includes fluorescent tracing molecule, target tumor marker molecules, drug molecule and life
At least one of object active macromolecules.
7. a kind of preparation method of phosphorous-based materials preparation of any of claims 1-6, which is characterized in that including following
Step:
S1, isolation air environment, will be scattered in solvent after phosphorus base grinding raw material, be made phosphorus base material solution；And
Ultrasonic removing is carried out to the phosphorus base material solution afterwards, obtains phosphorous-based materials stoste；
S2, the phosphorous-based materials stoste is centrifuged, takes supernatant；Calcium source is added into the supernatant, after mixing
Hydroxide ion donor is added to be reacted, then is purified.
8. preparation method according to claim 7, which is characterized in that the calcium source is calcium ions compound.
9. preparation method according to claim 7, which is characterized in that the hydroxide ion donor is hydrolyzable or ionization
Generate the alkali compounds of hydroxide ion.
10. application of the phosphorous-based materials preparation of any of claims 1-6 in the drug of preparation treatment tumour, special
Sign is that the drug passes through the internal and external environment for changing the tumour cell, to inhibit tumor cell proliferation and/or induction tumour
Apoptosis.
11. application according to claim 10, which is characterized in that the drug based on the treatment tumour, the phosphorus substrate
The additive amount for expecting preparation is 1wt%~99.99wt%.
12. application according to claim 10, which is characterized in that the tumour includes people and animal brain, blood, cream
Gland, pancreas, uterus, endometrium, cervix, kidney, liver, gall-bladder, incidence, oral cavity, thyroid gland, skin, mucous membrane, body of gland,
Blood vessel, liver, lungs, oesophagus, ovary, prostate, bone tissue, lymph node, prostate, bladder, colon or rectum primary or
Secondary cancer, sarcoma or carcinosarcoma.
13. application according to claim 10, which is characterized in that the drug of the treatment tumour further includes pharmaceutically acceptable
Auxiliary agent.
14. application according to claim 13, which is characterized in that the drug of the treatment tumour is tablet, capsule, ball
Any one of agent, granule, sustained release preparation, controlled release preparation, ejection preparation.
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