CN109568579A - A kind of composite Nano diagnosis and treatment agent and the preparation method and application thereof - Google Patents
A kind of composite Nano diagnosis and treatment agent and the preparation method and application thereof Download PDFInfo
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- 238000003745 diagnosis Methods 0.000 title claims abstract description 81
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
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- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
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Classifications
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/221—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by the targeting agent or modifying agent linked to the acoustically-active agent
-
- 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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- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Radiology & Medical Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Physics & Mathematics (AREA)
- Organic Chemistry (AREA)
- Acoustics & Sound (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Ultra Sonic Daignosis Equipment (AREA)
Abstract
The present invention discloses a kind of composite Nano diagnosis and treatment agent and the preparation method and application thereof, wherein composite Nano diagnosis and treatment agent includes black phosphorus quantum dot and the protective agent for being incorporated in the black phosphorus quantum dot surface, and the protective agent is poly-dopamine or melanin.The present invention prepares the composite Nano diagnosis and treatment agent using poly-dopamine or melanin as the protective agent of black phosphorus quantum dot; the biocompatibility and stability of black phosphorus quantum dot can not only be significantly improved; and the absorbing properties and photothermal conversion efficiency of black phosphorus quantum dot can also be enhanced, to improve its light treatment effect and can be used for tumour photoacoustic imaging.The preparation process of composite Nano diagnosis and treatment agent of the present invention is simple and convenient to operate, the equipment for not needing complex and expensive, it is easy to accomplish industrialized production.
Description
Technical field
The present invention relates to medical nano material field more particularly to a kind of composite Nano diagnosis and treatment agent and preparation method thereof with answer
With.
Background technique
Black phosphorus has good electrical and optical performance, has been widely used as a kind of emerging two-dimensional layer material
Research in fields such as biomedicines, including photoacoustic imaging, photo-thermal therapy, optical dynamic therapy and drug delivery etc..Wherein, ruler
The very little black phosphorus quantum dot between 1-10 nm shows good optoacoustic because having strong near infrared absorption and high photothermal conversion efficiency
Imaging and photo-thermal therapy effect, it has also become the hot spot of Recent study.Photo-thermal therapy (Photothermal therapy, PTT)
A kind of emerging technology of cancer treatment, by optical-thermal conversion material by luminous energy Efficient Conversion be thermal energy, rise local organization quickly
Temperature kills cancer cell.The treatment technology have the advantages that Noninvasive, fixed point ablation and it is easy to operate, be expected to replace operation cut
It removes to realize tumour ablation.In addition, successfully photo-thermal therapy is also needed by means of suitable imaging technique.Photoacoustic imaging
(Photoacoustic Imaging, PAI) is a kind of non-invasively imaged skill that current field of biomedicine is emerging and quickly grows
Art, using after material absorbing luminous energy generate sound wave principle, in conjunction with the advantages of two kinds of light, sound imaging techniques, thus improve at
While as depth, high contrast and high-resolution image are realized.
However, being very easy to oxidative deformation since black phosphorus quantum dot is extremely unstable in air and water, greatly limiting
Its further biomedical applications.Therefore, stability of the black phosphorus in air and physiological environment can be enhanced by developing one kind,
It is able to maintain that its performance is constant or even the surface modification method of synergy is particularly important again.
Summary of the invention
In view of above-mentioned deficiencies of the prior art, the purpose of the present invention is to provide one kind can enhance black phosphorus stability, together
Shi Tigao black phosphorus photo-thermal, the composite Nano diagnosis and treatment agent of optoacoustic performance and the preparation method and application thereof.
Technical scheme is as follows:
A kind of composite Nano diagnosis and treatment agent, wherein including black phosphorus quantum dot and be incorporated in the protection of the black phosphorus quantum dot surface
Agent, the protective agent are poly-dopamine or melanin.
The composite Nano diagnosis and treatment agent, wherein the composite Nano diagnosis and treatment agent includes 5-15%'s by weight percentage
The protective agent of black phosphorus quantum dot and 85-95%.
The composite Nano diagnosis and treatment agent, wherein the shape of the composite Nano diagnosis and treatment agent is spherical shape.
The composite Nano diagnosis and treatment agent, wherein the partial size of the spherical composite nano diagnosis and treatment agent is 20-200nm.
A kind of preparation method of composite Nano diagnosis and treatment agent, wherein comprising steps of
Block black phosphorus is dispersed in N-Methyl pyrrolidone, the block black phosphorus is prepared by black phosphorus amount using liquid phase stripping method
Sub- point；
Black phosphorus quantum dot and dopamine hydrochloride or melanin are added in alkaline aqueous solution by predetermined weight ratio, make to give birth to after mixing
At poly-dopamine or melanin be incorporated in the black phosphorus quantum dot surface, obtain composite Nano diagnosis and treatment agent.
The preparation method of composite Nano diagnosis and treatment agent, wherein it is described that block black phosphorus is dispersed in N-Methyl pyrrolidone, it adopts
The step of block black phosphorus is prepared into black phosphorus quantum dot with liquid phase stripping method specifically includes:
Block black phosphorus is dispersed in N-Methyl pyrrolidone, control temperature is lower than 15 DEG C, in the alkalinity that power is 300-600 W
It is ultrasonically treated 5-10 days under aqueous environment；
Supernatant is taken after the product of the ultrasonic treatment is centrifuged 60-120 min with 6000-12000 rpm, by the supernatant
Precipitating is taken after being centrifuged 60-120 min with 15000-18000 rpm；
By it is described precipitating be dispersed in aqueous solvent, use power for the ultrasonic echography 5-30 min of 300-600 W, then with retain
The super filter tube that molecular weight is 10-300 kDa filters twice, obtains black phosphorus quantum dot.
The preparation method of the composite Nano diagnosis and treatment agent, wherein it is described by black phosphorus quantum dot and dopamine hydrochloride or
Melanin is added in alkaline aqueous solution by predetermined weight ratio, is incorporated in the poly-dopamine generated or melanin after mixing described black
Phosphorus quantum dot surface, the step of obtaining composite Nano diagnosis and treatment agent, specifically include:
Black phosphorus quantum dot and dopamine hydrochloride or melanin are added to according to predetermined weight ratio by ethyl alcohol, ammonium hydroxide and deionization
In the alkaline solution of water composition, after stirring 24 at room temperature, filtered several times with the super filter tube that molecular cut off is 10-300 kDa
Until filtrate pH is neutrality, using the composite Nano diagnosis and treatment agent is made after the non-velum filteration that aperture is 220nm, using ICP
Test the BP content of the composite Nano diagnosis and treatment agent.
The preparation method of the composite Nano diagnosis and treatment agent, wherein the black phosphorus quantum dot and dopamine hydrochloride black
The predetermined weight ratio of element is 1:1-1:10 or the predetermined weight ratio of the black phosphorus quantum dot and melanin is 1:1-1:10.
A kind of application of composite Nano diagnosis and treatment agent, wherein the composite Nano diagnosis and treatment agent is used for tumour photoacoustic imaging
And/or tumor thermal therapy.
The utility model has the advantages that composite Nano diagnosis and treatment agent provided by the invention includes black phosphorus quantum dot and is incorporated in the black phosphorus amount
Son selects the protective agent on surface, and the protective agent is poly-dopamine or melanin.The present invention using poly-dopamine or melanin as
The protective agent of black phosphorus quantum dot prepares the composite Nano diagnosis and treatment agent, can not only significantly improve the bio-compatible of black phosphorus quantum dot
Property and stability, and the absorbing properties and photothermal conversion efficiency of black phosphorus quantum dot can also be enhanced, to improve its light treatment
Effect simultaneously can be used for tumour photoacoustic imaging.The preparation process of composite Nano diagnosis and treatment agent of the present invention is simple and convenient to operate, and is not needed multiple
The equipment of miscellaneous valuableness, it is easy to accomplish industrialized production.
Detailed description of the invention
Fig. 1 is the route map that the present invention prepares black phosphorus quantum dot.
Fig. 2 is the route map that the present invention prepares black phosphorus quantum dot@poly-dopamine composite Nano diagnosis and treatment agent.
Fig. 3 is the transmission electron microscope picture of black phosphorus quantum dot of the present invention.
Fig. 4 is the transmission electron microscope picture of black phosphorus quantum dot@poly-dopamine of the present invention.
Fig. 5 is poly-dopamine of the present invention (PDA), black phosphorus quantum dot (BP) and black phosphorus quantum dot@poly-dopamine (BP@PDA)
X-ray photoelectron spectroscopic analysis figure.
Fig. 6 is the Raman spectrogram of BP of the present invention.
Fig. 7 is the Raman spectrogram of BP@PDA of the present invention.
Fig. 8 is the map that the UV absorption of BP and BP@PDA of the present invention changes over time.
Fig. 9 is that BP and BP@PDA solution of the present invention temperature under 808 nm laser irradiations changes over time situation map.
Figure 10 is that the external photoacoustce signal intensity of the BP and BP@PDA solution of various concentration of the present invention is quantitatively schemed.
Figure 11 is toxicity test result of the BP and BP@PDA of the present invention to A375 tumour cell.
Figure 12 is photo-thermal therapy effect picture of the BP and BP@PDA of the present invention to A375 tumour cell.
Figure 13 is photoacoustic imaging figure of the BP and BP@PDA of the present invention in A375 tumor-bearing mice tumor region different time points.
Figure 14 is what BP and BP@PDA of the present invention was changed over time in the photoacoustic signal value of A375 tumor-bearing mice tumor region
Figure.
Figure 15 is the figure of changing of different treatment group tumors volumes (relative volume) (Day) at any time.
Figure 16 is the figure of changing of the life cycle (survival) (Day) at any time of different treatment group mouse.
Specific embodiment
The present invention provides a kind of composite Nano diagnosis and treatment agent and the preparation method and application thereof, to make the purpose of the present invention, skill
Art scheme and effect are clearer, clear, and the present invention is described in more detail below.It should be appreciated that tool described herein
Body embodiment only to explain the present invention, is not intended to limit the present invention.
Black phosphorus is a kind of direct band-gap semicondictor, and band gap is adjustable with the number of plies, has unique electricity, optical characteristics and good
Good biocompatibility.The research discovery black phosphorus quantum dot aqueous dispersions of field of biomedicine are in 808 nm laser irradiation of near-infrared
It is lower that apparent temperature raising is presented, and there is significant fragmentation effect to cancer cell, therefore have in tumor thermal therapy field
Great application potential.But black phosphorus quantum dot stability is poor, and it is dispersed low in aqueous solution, it has been seriously affected from basis
Study the conversion of clinical application.So the stability how research improves black phosphorus quantum dot is very important, and the field
Research there is not yet report.
Based on this, the present invention provides a kind of composite Nano diagnosis and treatment agent, wherein the composite Nano diagnosis and treatment agent includes black phosphorus amount
The protective agent of the black phosphorus quantum dot surface is selected and be incorporated in son, and the protective agent is poly-dopamine or melanin.The present invention
It, not only can be with by preparing the composite Nano diagnosis and treatment agent using poly-dopamine or melanin as the protective agent of black phosphorus quantum dot
The biocompatibility and stability of black phosphorus quantum dot are significantly improved, and the absorbing properties and light of black phosphorus quantum dot can also be enhanced
Thermal conversion efficiency, to improve its light treatment effect and can be used for tumour photoacoustic imaging.
Specifically, melanin is as a kind of large biological molecule being distributed widely in plant, animal even protist
Pigment, itself has good biocompatibility.The main component of melanin is poly-dopamine, and poly-dopamine has phenol abundant
Hydroxyl and amino can be a kind of good by a variety of effects such as complexing, coordination, hydrogen bond, pi-pi accumulation in conjunction with other substances
Coating material.Poly-dopamine has stronger near-infrared absorption and higher photothermal conversion performance, can be used for tumour light
Acoustic imaging and photo-thermal therapy.At the same time, poly-dopamine also has good antioxidation, can efficiently remove free radical, because
This prepares one kind based on poly-dopamine or melanin package black phosphorus using melanin or poly-dopamine as anti-oxidant protective agent
The composite Nano diagnosis and treatment agent of quantum dot, can not only significantly improve the stability and biocompatibility of black phosphorus quantum dot, moreover it is possible to increase
Its strong light absorpting ability, photothermal conversion efficiency and photoacoustic signal contrast etc. are expected to realize tumour enhancing photoacoustic imaging guidance
Efficient photo-thermal therapy.
As a wherein embodiment, the composite Nano diagnosis and treatment agent includes the black phosphorus amount of 5-15% by weight percentage
The melanin or poly-dopamine of son point and 85-95%.In the proportional region, the black phosphorus quantum dot surface and melanin or
Poly-dopamine sufficiently combines, and can enhance to greatest benefit the biocompatibility and stability of black phosphorus quantum dot, and improves compound receive
The photothermal conversion efficiency of rice diagnosis and treatment agent.
Preferably, the shape of the composite Nano diagnosis and treatment agent is spherical, and the partial size of the spherical composite nano diagnosis and treatment agent
For 20-200nm.When the partial size of the composite Nano diagnosis and treatment agent is greater than 200nm, quilt is easy in photo-thermal therapy cancer disease process
It is trapped in liver or lung, side effect is larger；When the partial size of the composite Nano diagnosis and treatment agent is less than 20nm, then it is controlled in photo-thermal
It treats and is easy directly to be discharged by kidney in cancer disease process, do not have the effect for the treatment of cancer.The present invention is experimentally confirmed, at this
Within the scope of preferable particle size, the composite Nano diagnosis and treatment agent can either the maximum effect for playing photo-thermal therapy cancer, having can be effective
It excretes, reduces side effect.
Further, the present invention also provides a kind of preparation methods of composite Nano diagnosis and treatment agent, wherein comprising steps of
S10, block black phosphorus is dispersed in N-Methyl pyrrolidone, is prepared into the block black phosphorus using liquid phase stripping method black
Phosphorus quantum dot；
S20, black phosphorus quantum dot and poly-dopamine or melanin are added in alkaline aqueous solution by predetermined weight ratio, make to gather after mixing
Dopamine or melanin are incorporated in the black phosphorus quantum dot surface, obtain composite Nano diagnosis and treatment agent.
As a wherein embodiment, the step S10, block black phosphorus is dispersed in N-Methyl pyrrolidone, is used
The block black phosphorus is prepared into black phosphorus quantum dot and specifically included by liquid phase stripping method:
Block black phosphorus is dispersed in N-Methyl pyrrolidone, to prevent the excessively high oxidation for accelerating black phosphorus of temperature, control temperature is low
In 15 DEG C；Further, it is ultrasonically treated in the case where power is the alkaline aqueous solution environment of 300-600 W 5-10 days, it then will be described
The product of ultrasonic treatment takes supernatant after being centrifuged 60-120 min with 6000-12000 rpm, by the supernatant with 15000-
Precipitating is taken after 18000 rpm centrifugation 60-120 min；Finally the precipitating is dispersed in aqueous solvent, uses power for 300-
The ultrasonic echography 5-30 min of 600 W, then filtered twice with the super filter tube that molecular cut off is 10-300 kDa, obtain black phosphorus
Quantum dot.
Specifically, the partial size of the black phosphorus quantum dot prepared by present embodiment is 1-5nm, black in the particle size range
Phosphorus quantum dot is difficult by being collected by centrifugation, and therefore, present embodiment uses molecular cut off to come for the super filter tube of 10-300 kDa
Black phosphorus quantum dot is collected by filtration, within the scope of the molecular cut off, can guarantee that black phosphorus quantum dot will not lose as far as possible.
As wherein another embodiment, the step S20, by black phosphorus quantum dot and poly-dopamine or melanin by predetermined
Weight ratio is added in alkaline aqueous solution, so that melanin is incorporated in the black phosphorus quantum dot surface after mixing, obtains composite Nano and examine
Agent is treated to specifically include:
It is preferred that black phosphorus quantum dot and dopamine hydrochloride or melanin are dispersed in alkaline solution according to the weight ratio of 1:1-1:10
In, mixed solution is obtained after stirring 24 hours at room temperature.When black phosphorus quantum dot and dopamine hydrochloride or melanin
When weight ratio is less than 1:10, the black phosphorus quantum dot content in composite Nano diagnosis and treatment agent is too low, and light light and heat power effect cannot fill
Distribution is waved；And when the weight ratio of black phosphorus quantum dot and dopamine hydrochloride or melanin is greater than 1:1, in composite Nano diagnosis and treatment agent
Poly-dopamine content it is too low, cannot sufficiently coat black phosphorus quantum dot, cause its photothermal conversion efficiency lower.In the present embodiment
In the proportional region of offer, finally obtained composite Nano diagnosis and treatment agent specifically very high photothermal conversion efficiency and have enhancing light
Acoustic imaging function.
Further, since the composite Nano diagnosis and treatment agent of generation is easily dissolved in the alkaline solution, by simple
Centrifugation can not effectively collect composite Nano diagnosis and treatment agent, therefore the present embodiment is 10-300 with molecular cut off
The super filter tube of kDa filters obtained solution several times, until pH value of solution is neutrality, obtains the composite Nano diagnosis and treatment agent.
Specifically, the alkaline solution in the present embodiment is made of ammonium hydroxide, ethyl alcohol and deionized water, wherein DOPA amine salt
The mass ratio of the material of hydrochlorate and ammonium hydroxide is 1:16.
As a wherein specific embodiment, the preparation of the black phosphorus quantum dot comprising steps of
0.1-0.5 g block black phosphorus is weighed, the anhydrous NMP of 50 mL is added, with 300 W supersonic wave cleaning machine water bath sonicator one week
(temperature is controlled at 10 °C) left and right, obtains dispersion liquid；
Above-mentioned gained dispersion liquid is centrifuged 60 min with 9000 rpm, takes supernatant, by supernatant with 15000 rpm centrifugation 60
Min takes precipitating, as black phosphorus quantum dot；
Suitable quantity of water is added into black phosphorus quantum dot, twice of (the super filter tube filter of super filter tube ultrafiltration for being 10k-300k with cutoff
Liquid is without black phosphorus), add water after testing ICP, concentration is adjusted to 0.2-1 mg/mL；
The preparation step of the composite Nano diagnosis and treatment agent (black phosphorus quantum dot Compound Black pigment) includes:
According to m(BP): m(melanin)=1:1-1:10 be added certain mass melanin powder, water bath sonicator 10-30min, drop
Enriching ammonium hydroxide, until pH is 9-11, super filter tube ultrafiltration several times for being 10k-300k with cutoff, until pH ~ 7.5(ultrafiltration
Pipe filtrate is almost without melanin).After the non-velum filteration for being 220 nm using aperture, ICP test b P content is utilized.
Based on above-mentioned composite Nano diagnosis and treatment agent, the present invention also provides a kind of applications of composite Nano diagnosis and treatment agent, will be described
Composite Nano diagnosis and treatment agent is used for tumour photoacoustic imaging and/or tumor thermal therapy.
Composite Nano diagnosis and treatment agent prepared by the present invention is tested for the property below by specific embodiment:
Embodiment 1
Prepare black phosphorus quantum dot@poly-dopamine composite nano materials:
To in the present invention black phosphorus quantum dot and composite Nano diagnosis and treatment agent carry out form and property test:
Fig. 1 is the route map for preparing black phosphorus quantum dot, and Fig. 2 is to prepare black phosphorus quantum dot@poly-dopamine composite Nano diagnosis and treatment agent
Route map, Fig. 3 are the transmission electron microscope picture (TEM) of black phosphorus quantum dot, and Fig. 4 is that the TEM of black phosphorus quantum dot@poly-dopamine schemes, from figure
In it can be seen that the diameter of the black phosphorus quanta point material is 1-5 nm, the diameter of the composite Nano diagnosis and treatment agent is 20-200
nm。
Embodiment 2
Test is compared to the stability of composite Nano diagnosis and treatment agent of the present invention:
Detect P elements (P) concentration and the identical black phosphorus quantum dot of volume and black phosphorus quantum dot@poly-dopamine solution at normal temperature
Save the stability in 7 days.Fig. 5 is poly-dopamine (PDA), black phosphorus quantum dot (BP) and black phosphorus quantum dot@poly-dopamine (BP@
PDA there is PO in x-ray photoelectron spectroscopy figure), the black phosphorus quantum dot being as can be seen from the figure directly dispersing in waterxOxidation
Signal peak, and the black phosphorus quantum dot for being compounded with poly-dopamine does not occur PO thenxAoxidize signal peak, it was demonstrated that the height of BP@PDA is steady
It is qualitative.Fig. 6 and Fig. 7 is respectively the Raman spectrogram that BP and BP@PDA saves 7 days front and backs, and the Raman signal of BP decreased significantly,
And the Raman signal of BP@PDA is then basically unchanged, and further demonstrates the high stability of BP@PDA.Fig. 8 is the purple of BP and BP@PDA
It is outer to absorb the map that changes with time, while demonstrating the high stability of BP@PDA and comparing the stronger absorbing properties of BP.
Embodiment 3
Test is compared to the photo-thermal of composite Nano diagnosis and treatment agent of the present invention, optoacoustic performance:
P concentration and the identical BP and BP@PDA solution of volume are detected in 1 W/cm2, temperature in 3 min under 808 nm laser irradiations
Situation is changed over time, it can be seen in figure 9 that the photothermal conversion efficiency of BP is 22.6%, black phosphorus amount under identical P concentration conditions
The photothermal conversion efficiency of sub- point@poly-dopamine is 64.2%, and photothermal conversion efficiency improves 2.84 times.Figure 10 is various concentration
The external photoacoustce signal intensity of BP and BP@PDA solution, it was demonstrated that BP@PDA has stronger photoacoustic signal compared to BP.
Embodiment 4
The photo-thermal effect pair of composite Nano diagnosis and treatment agent in the present invention is evaluated using the CCK-8 cell Proliferation toxicity detection method of standard
The influence of A375 tumor cell survival:
A375 cell is inoculated into 96 orifice plates with the cell density in 5000/hole, is placed in 37 DEG C, 5% CO2Under the conditions of train
Educate 24 h.Then, the old culture medium in 96 orifice plates is sucked out, is separately added into the BP@containing 20,10,5,2.5,1,0 μ g/mL BP
The DMEM culture medium solution of PDA.It wherein, the use of wavelength is 808 nm after treatment group's cell culture 4-6 h, power is 1 W/
cm2 Laser to 5 min of cell irradiation in each hole, and continue cultivate 20 h.Dark toxicity group cell continues to cultivate 24 h
Afterwards, the old culture medium in 96 orifice plates is sucked out, the culture medium solution that 100 μ L contain 10% CCK8 is added in each hole, continues
Cultivate 4 h.
The OD value (Detection wavelength is 450 nm) that each hole is detected in BioTek SYNERGY-H1 type microplate reader, with such as
Lower formula calculates cell survival rate.Cell survival rate (cell viability) (%)=(OD450 value/blank OD450 of sample
Value) × 100%, as is illustrated by figs. 11 and 12, composite Nano diagnosis and treatment agent and cell co-cultivation do not apply laser to experimental result for 24 hours and
In the case where irradiation, cell survival rate is greater than 90%, it was demonstrated that the BP@PDA has good biocompatibility, and swashs applying
In the photo-thermal therapy group of light irradiation, BP PDA is significantly better than BP to the fragmentation effect of cell to the fragmentation effect of cell.
Embodiment 5
The animal that all experimental implementations are passed through according to Shenzhen University's clinical center animal health and using the committee use and
Health care system.It selects female athymic nude mice (six weeks, 20-25 g), by being subcutaneously injected 5 × 10 in nude mice back leg6 Quantity
The PBS solution of A375 tumour cell establish tumor model.When gross tumor volume reaches 60 mm3When, it is by 150 μ L concentration
The PBS solution of the BP@PDA of 10 mg/mL is injected in mouse body by way of tail vein injection, utilizes toy photoacoustic imaging
" PA " mode in system (VisualSonics Vevo LAZR system) examines the variation of tumor region photoacoustic signal
It surveys.Experimental result is shown in Figure 13,14.
Such as Figure 13, shown in 14, in 4 h to 12 h, the photoacoustic signal (PA of the tumour of BP@PDA has been injected
Amplitude) significantly increased than the photoacoustic signal of the tumour of having injected BP, and after injecting BP@PDA in 12 h tumour optoacoustic
Signal significantly increases, while the photoacoustic signal of tumor region significantly reduces after injecting 24 h, it may be possible to which BP@PDA is sent out in vivo
Katabolism is given birth to.
Embodiment 6
Female athymic nude mice (six weeks, 20-25 g), by being subcutaneously injected 5 × 10 in nude mice back leg6 The A375 of quantity is swollen
The PBS solution of oncocyte establishes tumor model.When gross tumor volume reaches 60 mm3When, carry out photo-thermal therapy experiment.A375 lotus
Tumor mouse is randomly divided into five groups: (1) blank group (Control)；(2) laser radiation group (PBS+Laser)；(3) BP@is injected
PDA group；(4) laser irradiation group (BP@PDA+Laser) after injection 12 h of BP@PDA.Every other day use vernier caliper measurement tumour
Volume, and according to formula V=AB2/ 2 calculate gross tumor volume (relative volume), and wherein A is the major diameter (mm) of tumour,
B is the minor axis (mm) of tumour.Each measurement result is normalized using the starting tumor volume before treatment, and is observed every
The life cycle (survival) of group animal.Experimental result is shown in Figure 15 and 16.
Figure 15 indicates the variation feelings of the animal tumor volume (relative volume) of different treatment groups (Day) at any time
Condition.As shown in figure 15, the experimental group for applying laser irradiation after injecting 12 h of BP@PDA shows significant Tumor growth inhibition
Effect, and the basic unrestraint effect of the growth of the tumour of other control groups；Figure 16 indicates the existence week of animal in different treatment groups
The situation of change of phase (survival) (Day) at any time applies laser irradiation after injecting 12 h of BP@PDA as shown in figure 16
Significantly extend the life cycle of mouse.
In conclusion composite Nano diagnosis and treatment agent provided by the invention includes black phosphorus quantum dot and is incorporated in the black phosphorus amount
Son selects the protective agent on surface, and the protective agent is poly-dopamine or melanin.The present invention using poly-dopamine or melanin as
The protective agent of black phosphorus quantum dot prepares the composite Nano diagnosis and treatment agent, can not only significantly improve the bio-compatible of black phosphorus quantum dot
Property and stability, and the absorbing properties and photothermal conversion efficiency of black phosphorus quantum dot can also be enhanced, to improve its light treatment
Effect simultaneously can be used for tumour photoacoustic imaging.The preparation process of composite Nano diagnosis and treatment agent of the present invention is simple and convenient to operate, and is not needed multiple
The equipment of miscellaneous valuableness, it is easy to accomplish industrialized production.
It should be understood that the application of the present invention is not limited to the above for those of ordinary skills can
With improvement or transformation based on the above description, all these modifications and variations all should belong to the guarantor of appended claims of the present invention
Protect range.
Claims (9)
1. a kind of composite Nano diagnosis and treatment agent, which is characterized in that including black phosphorus quantum dot and be incorporated in the black phosphorus quantum dot table
The protective agent in face, the protective agent are poly-dopamine or melanin.
2. composite Nano diagnosis and treatment agent according to claim 1, which is characterized in that the composite Nano diagnosis and treatment agent by weight hundred
Divide the protective agent of the black phosphorus quantum dot and 85-95% than meter including 5-15%.
3. composite Nano diagnosis and treatment agent according to claim 1 to 2, which is characterized in that the composite Nano diagnosis and treatment agent
Shape is spherical shape.
4. composite Nano diagnosis and treatment agent according to claim 3, which is characterized in that the grain of the spherical composite nano diagnosis and treatment agent
Diameter is 20-200nm.
5. a kind of preparation method of composite Nano diagnosis and treatment agent, which is characterized in that comprising steps of
Block black phosphorus is dispersed in N-Methyl pyrrolidone, the block black phosphorus is prepared by black phosphorus amount using liquid phase stripping method
Sub- point；
Black phosphorus quantum dot and dopamine hydrochloride or melanin are added in alkaline aqueous solution by predetermined weight ratio, make to give birth to after mixing
At poly-dopamine or melanin be incorporated in the black phosphorus quantum dot surface, obtain composite Nano diagnosis and treatment agent.
6. the preparation method of composite Nano diagnosis and treatment agent according to claim 5, which is characterized in that described by block black phosphorus point
The step of being dispersed in N-Methyl pyrrolidone, the block black phosphorus is prepared into black phosphorus quantum dot using liquid phase stripping method is specifically wrapped
It includes:
Block black phosphorus is dispersed in N-Methyl pyrrolidone, control temperature is lower than 15 DEG C, in the alkalinity that power is 300-600 W
It is ultrasonically treated 5-10 days under aqueous environment；
Supernatant is taken after the product of the ultrasonic treatment is centrifuged 60-120 min with 6000-12000 rpm, by the supernatant
Precipitating is taken after being centrifuged 60-120 min with 15000-18000 rpm；
By it is described precipitating be dispersed in aqueous solvent, use power for the ultrasonic echography 5-30 min of 300-600 W, then with retain
The super filter tube that molecular weight is 10-300 kDa filters twice, obtains black phosphorus quantum dot.
7. the preparation method of composite Nano diagnosis and treatment agent according to claim 5, which is characterized in that described by black phosphorus quantum dot
It is added in alkaline aqueous solution with dopamine hydrochloride or melanin by predetermined weight ratio, the poly-dopamine or black generated is made after mixing
The step of pigment is incorporated in the black phosphorus quantum dot surface, obtains composite Nano diagnosis and treatment agent specifically includes:
Black phosphorus quantum dot and dopamine hydrochloride or melanin are added to according to predetermined weight ratio by ethyl alcohol, ammonium hydroxide and deionization
In the alkaline solution of water composition, after stirring 24 at room temperature, filtered several times with the super filter tube that molecular cut off is 10-300 kDa
Until filtrate pH is neutrality, using the composite Nano diagnosis and treatment agent is made after the non-velum filteration that aperture is 220nm, using ICP
Test the BP content of the composite Nano diagnosis and treatment agent.
8. the preparation method of composite Nano diagnosis and treatment agent according to claim 7, which is characterized in that the black phosphorus quantum dot with
The predetermined weight ratio of dopamine hydrochloride melanin is the predetermined weight of 1:1-1:10 or the black phosphorus quantum dot and melanin
Than for 1:1-1:10.
9. a kind of application of composite Nano diagnosis and treatment agent, which is characterized in that by any composite Nano diagnosis and treatment of claim 1-4
Agent is used for tumour photoacoustic imaging and/or tumor thermal therapy.
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