CN104922671A - Indocyanine green composite nano-particles and preparation method and application thereof - Google Patents
Indocyanine green composite nano-particles and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides indocyanine green composite nanoparticles, which comprise indocyanine green, hydrophobic polymers, polyethylene glycol-derivatized phospholipids and cancer cell membranes, wherein the indocyanine green is surrounded by the hydrophobic polymers and forms a spheroid structure with the hydrophobic polymers, the polyethylene glycol-derivatized phospholipids are interpenetrated in the cancer cell membranes and form a vesicle structure with the cancer cell membranes, and the spheroid structure is coated in the vesicle structure. The invention also provides a preparation method and application of the indocyanine green composite nano-particles, and when the indocyanine green composite nano-particles are applied, the composite nano-particles have high-efficiency targeting property to tumors, and the indocyanine green is not easy to aggregate and has good stability.
Description
Technical field
The invention belongs to field of nanometer material technology, particularly a kind of indocyanine green composite nanometer particle and its preparation method and application.
Background technology
Indocyanine green (ICG) is a kind of three hydrocarbon class dyestuffs, its maximum absorption wavelength and maximum emission wavelength are at the near infrared region of 740nm and 800nm, fluorescence penetration power is strong, unique a kind of reagent for physianthropy imaging and diagnosis ratified by U.S. food Drug Administration (FDA), simultaneously it as a kind of photo-thermal formulation application in clinical thermotherapy.But indocyanine green can be assembled rapidly in polar solvent, less stable, and it can be removed fast in blood plasma, and circulation time is short in vivo, and indocyanine green also lacks tumor cell targeting specific, and these defects greatly limit the application of indocyanine green simultaneously.
Summary of the invention
For solving the problem, the invention provides a kind of indocyanine green composite nanometer particle and its preparation method and application.Well, preparation method technique is simple simultaneously for the stability of described indocyanine green composite nanometer particle and targets identification ability.
First aspect, the invention provides a kind of indocyanine green composite nanometer particle, described indocyanine green composite nanometer particle comprises indocyanine green, hydrophobic polymer, polyglycol derivatization phospholipid and cancer cell membrane, described indocyanine green by described hydrophobic polymer around and form class spherical structure with described hydrophobic polymer, described polyglycol derivatization phospholipid to be interspersed in described cancer cell membrane and to form imitated vesicle structure with described cancer cell membrane, described near-spherical structure is coated in described imitated vesicle structure, described indocyanine green, the mass ratio of hydrophobic polymer and polyglycol derivatization phospholipid is (0.25-1.5): 1:(0.09-0.27), described cancer cell membrane derives from cancerous cell, the number of described cancerous cell and the mass ratio of polyglycol derivatization phospholipid are (10
8-10
9): 180 μ g.
As described in the present invention, described imitated vesicle structure as the composite shell of described indocyanine green composite nanometer particle, for loading the class spherical structure that described indocyanine green and hydrophobic polymer are formed.
Preferably, described hydrophobic polymer is selected from one or more of Poly(D,L-lactide-co-glycolide (also known as poly (glycolide-co-lactide)), polylactic acid and polycaprolactone, but is not limited thereto.
Preferably, described hydrophobic polymer is Poly(D,L-lactide-co-glycolide (being abbreviated as PLGA), and the molecular weight of described hydrophilic polymer thing is 7000-17000, and the copolymerization ratio of monomer lactic acid and hydroxyacetic acid is 50:50.
Preferably, described polyglycol derivatization phospholipid to be connected with phospholipid substance by covalent bond by Polyethylene Glycol and to obtain.
Preferably, the molecular weight of described Polyethylene Glycol is 200 ~ 20000.
Preferably, that described phospholipid substance can be synthetic or that nature exists phospholipid, described phospholipid substance can be but be not limited to DSPE, DSPG or cholesterol.
Preferably, described polyglycol derivatization phospholipid is PEG-DSPE (DSPE-PEG).
As described in the present invention, described indocyanine green (ICG) is (0.25-1.5) with the mass ratio of described hydrophobic polymer: 1.
Preferably, the mass ratio of described indocyanine green and described hydrophobic polymer is (0.5-1.0): 1.
As described in the present invention, described cancer cell membrane derives from cancerous cell.
Preferably, described cancer cell membrane comprise in hepatoma carcinoma cell, breast cancer cell, lung carcinoma cell, cervical cancer cell one or more, but to be not limited thereto.
As described in the present invention, the mass ratio of described hydrophobic polymer and described polyglycol derivatization phospholipid is 1:(0.09-0.27).
Preferably, the mass ratio of described hydrophobic polymer and described polyglycol derivatization phospholipid is 1:(0.15-0.21).
Preferably, the particle diameter of described indocyanine green composite nanometer particle is 90-180nm.
As described in the present invention, described particle diameter adopts transmission electron microscope to record.
The described indocyanine green composite nanometer particle (being abbreviated as CCINPs) that first aspect present invention provides, described indocyanine green composite nanometer particle comprises indocyanine green, hydrophobic polymer, polyglycol derivatization phospholipid and cancer cell membrane, phospholipid in described polyglycol derivatization phospholipid is combined by the phospholipid molecule of physical action in described cancer cell membrane thus is interspersed in described cancer cell membrane, certain support is played to cancer cell membrane, fixation, and form imitated vesicle structure with described cancer cell membrane, described imitated vesicle structure has hydrophilic composite shell and hydrophobic cavity, described indocyanine green by described hydrophobic polymer around and form class spherical structure with described hydrophobic polymer, hydrophobic polymer wraps up hydrophilic indocyanine green, the hydrophobic cavity that described hydrophilic composite shell is formed, for loading ICG and hydrophobic polymer, can effectively avoid ICG to assemble.
Described indocyanine green composite nanometer particle provided by the invention, on the one hand, described cancer cell membrane is exposed to the outermost layer of described composite shell, owing to described cancer cell membrane containing the molecule with cancerous cell energy targets identification, as folacin receptor, alpha-fetoprotein, E-Cadherin, the multiple biological recognition ligand such as galectin-3, and mutually can identify based on homophilic adhesion effect with corresponding tumor cell, based on the synergism of multiple ligands, described indocyanine green composite nanometer particle can form specific binding with tumor cell, higher targeting is had to tumor cell, carrying indocyanine green well enters in cell, indocyanine green can be improved to tumor cell targeting specific, improve the oncotherapy effect of indocyanine green.On the other hand, PEG in described hydrophilic composite shell can effectively hinder immune system to the identification of described nano-particle, significant prolongation described nano-particle circulation time in vivo, and then be enriched in tumor tissues by enhancing infiltration retention effect (EPR effect), finally realize the passive target of tumor.Based on the passive target that active targeting and the PEG of above-mentioned cancer cell membrane cause, described indocyanine green composite nanometer particle has very strong affinity to tumor cell.
Homology absorption of the present invention, referring to the adhesion between phalangeal cell, be a kind of form that cell-tocell exchanges, and the solvable mediator of communication for information claims cell adhesion molecule (CAM).Cell adhesion molecule is the material that a class has independently molecular structure, can pass through the specific receptor of identification and its adhesion and mutual adhesion occur.Mutual identification between the allogenic cell adhesion molecule of two adjacent cell surfaces and combination, be homology absorption.
Therefore, indocyanine green composite nanometer particle provided by the invention can improve the stability of ICG, can effectively avoid removing in the decomposition of ICG and body, significantly can increase the targets identification effect to tumor simultaneously, can be advantageously applied to the thermotherapy of tumor.
Described indocyanine green composite nanometer particle has good biocompatibility, absorbed by biodegradation or excretes by normal physiological pathway, little to organism injury.
The mass ratio of described indocyanine green, hydrophobic polymer, polyglycol derivatization phospholipid and cancer cell membrane is (0.25-1.5): 1:(0.09-0.27), the number of described cancerous cell and the mass ratio of polyglycol derivatization phospholipid are 10
8-10
9: 180 μ g, under this mass ratio, nanoparticle structure can be formed well between each component, the particle size distribution stating indocyanine green composite nanometer particle is more even, mean diameter is 90-180nm, the gathering that pattern is more regular, favorable dispersibility avoids indocyanine green, improves stability and the targeting of indocyanine green.
Second aspect, the invention provides a kind of preparation method of indocyanine green composite nanometer particle, comprises the following steps:
(1) get cancerous cell, extract cancer cell membrane;
(2) imitated vesicle structure is prepared: compared for (10 with polyglycol derivatization phospholipid by the number of cancerous cell by the cancer cell membrane after extracting
8-10
9): 180 μ g weigh, and are dissolved in the first solvent, and ultrasonic 3-6min under ice bath, obtains the first mixed solution;
(3) class spherical inner core is prepared: indocyanine green is dissolved in the second solvent and obtains indocyanine green solution, hydrophobic polymer is dissolved in the 3rd solvent and obtains hydrophobic polymer solution, hydrophobic polymer dropwise is joined in indocyanine green solution, carry out ultrasonic 2-4min with ultrasound wave, obtain the second mixed solution;
(4) cancerous cell vesicle solution described in step (2) is joined in described second mixed solution of step (3), ultrasonic mixing 2-4min, obtain the 3rd mixed solution, described 3rd mixed solution is carried out centrifugal treating, collect supernatant and obtain indocyanine green composite nanometer particle, described indocyanine green composite nanometer particle comprises indocyanine green, hydrophobic polymer, polyglycol derivatization phospholipid and cancer cell membrane, described indocyanine green by described hydrophobic polymer around and form class spherical structure with described hydrophobic polymer, described polyglycol derivatization phospholipid to be interspersed in described cancer cell membrane and to form imitated vesicle structure with described cancer cell membrane, described near-spherical structure is coated in described imitated vesicle structure, wherein, described indocyanine green, the mass ratio of hydrophobic polymer and polyglycol derivatization phospholipid is (0.25-1.5): 1:(0.09-0.27).
Preferably, in step (1), described extraction cancer cell membrane is specially: get postdigestive cancerous cell, adds the Tris-HCl hypotonic buffer solution of pH=7.5, homogenizing is broken, low-speed centrifugal 5-10min, collect supernatant, high speed centrifugation 15-30min, regathers supernatant, again ultracentrifugation 40-60min is carried out to supernatant, collecting precipitation, and use buffer solution washing and precipitating, obtain the cancer cell membrane after purification.
Preferably, in step (1), the centrifugal force of described low-speed centrifugal is 3200g, and described ultracentrifugal centrifugal force is 20000g, and the centrifugal force of described ultracentrifugation is 100000g.
As described in the present invention, for different cancerous cell, the hypotonic buffer solution of different pH, variable concentrations, kind can be selected.
Described hypotonic buffer solution is conducive to being separated of cell membrane and cellular content, is convenient to extract cancer cell membrane.
Preferably, when described cancerous cell is human breast cancer cell, described hypotonic buffer solution also comprises KCl, MgCl
2, protease inhibitor, the concentration of KCl is 10mM, MgCl
2concentration be 2mM, the concentration of protease inhibitor is 0.06 ~ 2.0 μ g/ml.
As described in the present invention, in the process preparing composite nanometer particle, adopt low temperature ice bath, lower powered ultrasonication, the damage to albumen on cancer cell membrane can be reduced as far as possible, can certain ligand activity be retained.
Preferably, in step (2), described first solvent is one or more of ethanol, water and methanol.
Further preferably, in step (2), described first solvent to be mass fraction be 4% ethanol water.
Preferably, in step (3), described second solvent is one or more in ethanol, water and methanol.
Further preferably, in step (2), described first solvent to be mass fraction be 4% ethanol water.
Preferably, in step (3), described 3rd solvent is one or more in acetonitrile and acetone.
As described in the present invention, described 3rd solvent is the amphiphilic solvent of energy solubilizing hydrophobic polymer.
As described in the present invention, the mass ratio of described indocyanine green and described hydrophobic polymer is (0.25-1.5): 1.
Preferably, the mass ratio of described indocyanine green and described hydrophobic polymer is (0.5-1.0): 1.
As described in the present invention, the mass ratio of described hydrophobic polymer and described polyglycol derivatization phospholipid is 1:(0.09-0.27).
Preferably, the mass ratio of described hydrophobic polymer and described polyglycol derivatization phospholipid is 1:(0.15-0.21).
Preferably, in step (3), the mass concentration of described indocyanine green solution is 0.5mg/ml.
Preferably, in step (3), the concentration of described hydrophobic polymer solution is 1mg/ml.
Preferably, the volume ratio of described indocyanine green solution and described hydrophobic polymer solution is 1.5:1.
As described in the present invention, in step (4), joined by hydrophobic polymer dropwise in indocyanine green solution, to ensure that ultrasonic energy fully carries out, the dispersibility of the indocyanine green composite nanometer particle of final gained is better, particle diameter is less.
Preferably, in step (4), described centrifugal treating is ultrafiltration 2-3 time in the ultra-filtration centrifuge tube of 10kDa at molecular cut off.
Preferably, in step (4), described centrifugal treating is under centrifugal rotational speed 6000-7000rpm, centrifugal 1-3min.
As described in the present invention, centrifugal treating described in step (4), short time can avoid cancer cell membrane adherent, repeatedly fully can remove desolventizing, centrifugal speed is too high or too low, the form of capital to final nano-particle makes a big impact, and the application is centrifugal 1-3min under 6000-7000rpm, and repeats centrifugal treating 2-3 time.
Preferably, ultrasonic cell disruption instrument is adopted to carry out ultrasonic with the power of the frequency of 20kHz and 35W in step (2), (3), (4).
Preferably, the particle diameter of described indocyanine green composite nanometer particle is 90-180nm.
Preferably, described polyglycol derivatization phospholipid to be connected with phospholipid substance by covalent bond by Polyethylene Glycol and to obtain.
Preferably, the molecular weight of described Polyethylene Glycol is 200 ~ 20000.
Preferably, that described phospholipid substance can be synthetic or that nature exists phospholipid, described phospholipid substance can be but be not limited to DSPE, DSPG or cholesterol.
Preferably, described polyglycol derivatization phospholipid is PEG-DSPE (DSPE-PEG).
Preferably, described cancer cell membrane comprise in hepatoma carcinoma cell, breast cancer cell, lung carcinoma cell, cervical cancer cell one or more, but to be not limited thereto.Described cancer cell membrane is from the animal cancerous cell not containing cell wall.
According to the cancer cell membrane after purifying and the chemical property of polyglycol derivatization phospholipid, they are dissolved in hydrophilic solvent, according to the similar principle mixed, phospholipid in described polyglycol derivatization phospholipid is combined by the phospholipid molecule of physical action in described cancer cell membrane thus is interspersed in described cancer cell membrane, certain support, fixation are played to cancer cell membrane, and being assembled into imitated vesicle structure with described cancer cell membrane, described imitated vesicle structure has hydrophilic composite shell and hydrophobic cavity.
Described hydrophobic polymer is green around described small molecule indole cyanines by self assembly effect, is beneficial to the dispersion of ICG, and the hydrophobicity cavity in described imitated vesicle structure can be used for loading hydrophobic polymer and micromolecule ICG, can effectively avoid ICG to assemble.Described cancer cell membrane is the associated ligands that described indocyanine green composite nanometer particle provides that Polyethylene Glycol hydrophilic is outer and can be combined with tumor.
Described indocyanine green, hydrophobic polymer and cancer cell membrane and polyglycol derivatization phospholipid form described indocyanine green composite nanometer particle by self assembling process, and do not need to carry out chemical reaction, preparation process environment-protecting asepsis, preparation method is simple to operation.The indocyanine green composite nanometer particle obtained has the effect of optical diagnostics and Therapeutic cancer simultaneously.
The third aspect, the invention provides the application of a kind of indocyanine green composite nanometer particle in preparation tumor thermotherapy medicine.
Described indocyanine green composite nanometer particle adopts the preparation method described in second aspect present invention to obtain.
Preferably, the particle diameter of described indocyanine green composite nanometer particle is 90-180nm.
Indocyanine green composite nanometer particle provided by the invention can improve the targets identification to tumor, can improve the stability of ICG simultaneously, can effectively avoid removing in the decomposition of ICG and body, can apply the thermotherapy of tumor well.
To sum up, beneficial effect of the present invention comprises the following aspects:
(1) the indocyanine green composite nanometer particle that the present invention obtains effectively can improve the targeting of indocyanine green to tumor, can prevent the gathering of indocyanine green simultaneously, improves the stability of indocyanine green, extends its circulation time in vivo;
(2) preparation method of the composite nanometer particle of indocyanine green described in the present invention is simple, convenient operation;
(3) the described indocyanine green composite nanometer particle that the present invention obtains may be used for preparation tumor thermotherapy medicine.
Accompanying drawing explanation
Fig. 1 is the structural representation of indocyanine green composite nanometer particle prepared by embodiment 1;
Fig. 2 is the high-resolution-ration transmission electric-lens figure of indocyanine green composite nanometer particle prepared by embodiment 1;
Fig. 3 is the grain size distribution of indocyanine green composite nanometer particle prepared by embodiment 1;
Fig. 4 is the cell endocytic result figure of indocyanine green composite nanometer particle (CCINPs) prepared by embodiment 1, and first is classified as matched group, and second is classified as experimental group;
Fig. 5 is the design sketch that in Application Example, indocyanine green composite nanometer particle is tested for animal targeting.
Detailed description of the invention
The following stated is the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications are also considered as protection scope of the present invention.
Embodiment 1
A preparation method for indocyanine green composite nanometer particle, comprises the following steps:
(1) extract cancer cell membrane: get cancerous cell, add hypotonic buffer solution, homogenizing is broken, repeatedly centrifugal collecting precipitation, i.e. cancer cell membrane;
Human breast cancer cell (MCF-7) is inoculated in T-175 Tissue Culture Flask, cultivate by DMEM culture medium, and add 10%FBS, the penicillin of 1%, the streptomycin of 1%, after cell covers with, discard outmoded culture medium, with EDTA digestion, and centrifugal with PBS, wash 3 times, obtain targeted cancerous cells;
Add the Tris-HCl hypotonic buffer liquid of 20mM, pH=7.5 toward the MCF-7 cell after washing, described hypotonic buffer solution also comprises the MgCl of KCl, 2mM of 10mM
2, 1.0 μ g/ml protease inhibitor, with Douncehomogenizer homogenizer to cell homogenizing broken 20 times, low-speed centrifugal 5min under the centrifugal force of 3200g, preserve supernatant, and add hypotonic buffer liquid toward precipitation, then homogenizing is broken, low-speed centrifugal, collects twice supernatant; By above-mentioned supernatant high speed centrifugation 20min under the centrifugal force of 20000g, abandon precipitation, again supernatant is carried out ultracentrifugation 50min under the centrifugal force of 100000g, the Tris-HCL buffer (EDTA containing 1mM) of the pelletizing membrane material precipitation 10mM finally obtained, pH=7.5 cleans one time, obtains the cancer cell membrane after purification;
(2) imitated vesicle structure is prepared: the number of cancerous cell of originate the cancer cell membrane after extracting by it and the mass ratio of PEG-DSPE (DSPE-PEG) (wherein the molecular weight of PEG is 2000) are 6 × 10
8: 180 μ g weigh, and be dissolved in 0.5ml, 4% ethanol, under ice bath, adopt ultrasonic cell disruption instrument to carry out ultrasonic 5min with the power of the frequency of 20kHz and 35W, obtain the first mixed solution;
(3) class spherical inner core is prepared: indocyanine green (ICG) is dissolved in the ICG solution that ethanol obtains 0.5mg/ml, Poly(D,L-lactide-co-glycolide (PLGA) is dissolved in the PLGA solution that acetonitrile obtains 1mg/ml, get the ICG solution of 1.5ml, and carry out ultrasonic to it, while the PLGA dropwise of 1ml is joined in the ICG solution of 1.5ml, ultrasonic time is 2min, obtains the second mixed solution;
(4) the first mixed solution described in 0.5ml step (2) is joined in described second mixed solution of 2.5ml step (3), ultrasonic 2min is carried out with the power of the frequency of 20kHz and 35W with ultrasonic cell disruption instrument, obtain the 3rd mixed solution, described 3rd mixed solution is carried out centrifugal treating, described centrifugal be ultrafiltration 2-3 time in the ultra-filtration centrifuge tube of 10kDa at molecular cut off, centrifugal rotational speed is under 6000rpm, centrifugation time is 2min, collect supernatant and obtain indocyanine green composite nanometer particle (CCINPs), described indocyanine green composite nanometer particle comprises indocyanine green (ICG), hydrophobic polymer PLGA, polyglycol derivatization phospholipid DSPE-PEG and cancer cell membrane, described indocyanine green ICG by described hydrophobic polymer PLGA around and form class spherical structure with described hydrophobic polymer PLGA, described polyglycol derivatization phospholipid DSPE-PEG to be interspersed in described cancer cell membrane and to form imitated vesicle structure with described cancer cell membrane, described near-spherical structure is coated in described imitated vesicle structure.
Fig. 1 is the structural representation of indocyanine green composite nanometer particle (CCINPs) prepared by embodiment 1; In figure 11 be indocyanine green, 12 for hydrophobic polymer PLGA, 1 is the 11 and 12 class spherical structures formed; 21 is polyglycol derivatization phospholipid DSPE-PEG, 22 is cancer cell membrane, 2 is 21 and 22 imitated vesicle structures jointly formed, wherein 22 surfaces also have polysaccharide, cell adhesion molecule etc. (not drawing) here, in Fig. 1,11 represent with the rhombus of CCINPs inside, 12 represent with the curve of CCINPs inside, 11 represent ICG by 12 around and form class spherical structure 1 with 12,21 represent with the curve of CCINPs outside, 21 to be interspersed in described cancer cell membrane 22 and to form imitated vesicle structure with described cancer cell membrane 22, and described near-spherical structure is coated in described imitated vesicle structure.
Fig. 2 is the transmission electron microscope picture of the indocyanine green composite nanometer particle (CCINPs) that embodiment 1 obtains, as can be seen from Figure 2, the particle diameter of the indocyanine green composite nanometer particle (CCINPs) that the present embodiment is obtained is about 150nm, what Fig. 2 ectomesoderm color was darker is the imitated vesicle structure that cancer cell membrane and DSPE-PEG are formed, and what inner side colourity was more shallow is the class spherical structure that ICG and PLGA is formed.
Fig. 3 is the grain size distribution adopting dynamic light scattering to record the obtained indocyanine green composite nanometer particle (CCINPs) of embodiment 1, and as can be seen from Figure 3, the particle size distribution of the CCINPs that the present embodiment obtains is more even.
Embodiment 2
A preparation method for indocyanine green composite nanometer particle, comprises the following steps:
(1) cancer cell membrane is extracted: step is with embodiment 1;
(2) imitated vesicle structure is prepared: the number of cancerous cell of originate the cancer cell membrane after extracting by it and the ratio of DSPE-PEG (wherein the molecular weight of PEG is 400) are 3 × 10
8: 180 μ g weigh, and be dissolved in 1ml, 4% ethanol, under ice bath, adopt ultrasonic cell disruption instrument to carry out ultrasonic 5min with the power of the frequency of 20kHz and 35W, obtain the first mixed solution;
(3) class spherical inner core is prepared: indocyanine green (ICG) is dissolved in the ICG solution that ethanol obtains 0.5mg/ml, Poly(D,L-lactide-co-glycolide (PLGA) is dissolved in the PLGA solution that acetonitrile obtains 0.5mg/ml, get the ICG solution of 1.5ml, and carry out ultrasonic to it, while the PLGA dropwise of 1ml is joined in the ICG solution of 1.5ml, ultrasonic time is 2min, obtains the second mixed solution;
(4) the first mixed solution described in 0.75ml step (2) is joined in described second mixed solution of step (3), ultrasonic 2min is carried out with the power of the frequency of 20kHz and 35W with ultrasonic cell disruption instrument, obtain the 3rd mixed solution, described 3rd mixed solution is carried out centrifugal treating, described centrifugal be ultrafiltration 2-3 time in the ultra-filtration centrifuge tube of 10kDa at molecular cut off, centrifugal rotational speed is under 6500rpm, centrifugation time is 2min, collect supernatant and obtain indocyanine green composite nanometer particle (CCINPs), described indocyanine green composite nanometer particle comprises indocyanine green (ICG), hydrophobic polymer PLGA, polyglycol derivatization phospholipid DSPE-PEG and cancer cell membrane, described indocyanine green ICG by described hydrophobic polymer PLGA around and form class spherical structure with described hydrophobic polymer PLGA, described polyglycol derivatization phospholipid DSPE-PEG to be interspersed in described cancer cell membrane and to form imitated vesicle structure with described cancer cell membrane, described near-spherical structure is coated in described imitated vesicle structure.
Embodiment 3
A preparation method for indocyanine green composite nanometer particle, comprises the following steps:
(1) cancer cell membrane is extracted: step is with embodiment 1;
(2) imitated vesicle structure is prepared: the number of cancerous cell of originate the cancer cell membrane after extracting by it and the ratio of DSPE-PEG (wherein the molecular weight of PEG is 20000) are 9 × 10
8: 180 μ g weigh, and be dissolved in 1ml, 4% ethanol, under ice bath, adopt ultrasonic cell disruption instrument to carry out ultrasonic 5min with the power of the frequency of 20kHz and 35W, obtain the first mixed solution;
(3) class spherical inner core is prepared: indocyanine green (ICG) is dissolved in the ICG solution that ethanol obtains 0.5mg/ml, Poly(D,L-lactide-co-glycolide (PLGA) is dissolved in the PLGA solution that acetonitrile obtains 2mg/ml, get the ICG solution of 1.5ml, and carry out ultrasonic to it, while the PLGA dropwise of 1ml is joined in the ICG solution of 1.5ml, ultrasonic time is 2min, obtains the second mixed solution;
(4) the first mixed solution described in step (2) is joined in described second mixed solution of step (3), ultrasonic 2min is carried out with the power of the frequency of 20kHz and 35W with ultrasonic cell disruption instrument, obtain the 3rd mixed solution, described 3rd mixed solution is carried out centrifugal treating, described centrifugal be ultrafiltration 2-3 time in the ultra-filtration centrifuge tube of 10kDa at molecular cut off, centrifugal rotational speed is under 7000rpm, centrifugation time is 1min, collect supernatant and obtain indocyanine green composite nanometer particle (CCINPs), described indocyanine green composite nanometer particle comprises indocyanine green (ICG), hydrophobic polymer PLGA, polyglycol derivatization phospholipid DSPE-PEG and cancer cell membrane, described indocyanine green ICG by described hydrophobic polymer PLGA around and form class spherical structure with described hydrophobic polymer PLGA, described polyglycol derivatization phospholipid DSPE-PEG to be interspersed in described cancer cell membrane and to form imitated vesicle structure with described cancer cell membrane, described near-spherical structure is coated in described imitated vesicle structure.
Embodiment 4
A preparation method for indocyanine green composite nanometer particle, comprises the following steps:
(1) cancer cell membrane is extracted: step is with embodiment 1;
(2) imitated vesicle structure is prepared: the number of cancerous cell of originate the cancer cell membrane after extracting by it and the mass ratio of poly-DSPE-PEG (wherein the molecular weight of PEG is 7000) are 6 × 10
8: 180 μ g weigh, and be dissolved in 1ml, 4% ethanol, under ice bath, adopt ultrasonic cell disruption instrument to carry out ultrasonic 5min with the power of the frequency of 20kHz and 35W, obtain the first mixed solution;
(3) class spherical inner core is prepared: indocyanine green (ICG) is dissolved in the ICG solution that ethanol obtains 0.5mg/ml, Poly(D,L-lactide-co-glycolide (PLGA) is dissolved in the PLGA solution that acetonitrile obtains 1mg/ml, get the ICG solution of 1.5ml, and carry out ultrasonic to it, while the PLGA dropwise of 1ml is joined in the ICG solution of 1.5ml, ultrasonic time is 2min, obtains the second mixed solution;
(4) the first mixed solution described in 833 μ l steps (2) is joined in described second mixed solution of 2.5ml step (3), ultrasonic 2min is carried out with the power of the frequency of 20kHz and 35W with ultrasonic cell disruption instrument, obtain the 3rd mixed solution, described 3rd mixed solution is carried out centrifugal treating, described centrifugal be ultrafiltration 2-3 time in the ultra-filtration centrifuge tube of 10kDa at molecular cut off, centrifugal rotational speed is under 6000rpm, centrifugation time is 2min, collect supernatant and obtain indocyanine green composite nanometer particle (CCINPs), described indocyanine green composite nanometer particle comprises indocyanine green (ICG), hydrophobic polymer PLGA, polyglycol derivatization phospholipid DSPE-PEG and cancer cell membrane, described indocyanine green ICG by described hydrophobic polymer PLGA around and form class spherical structure with described hydrophobic polymer PLGA, described polyglycol derivatization phospholipid DSPE-PEG to be interspersed in described cancer cell membrane and to form imitated vesicle structure with described cancer cell membrane, described near-spherical structure is coated in described imitated vesicle structure.
Embodiment 5
A preparation method for indocyanine green composite nanometer particle, comprises the following steps:
(1) cancer cell membrane is extracted: step is with embodiment 1;
(2) imitated vesicle structure is prepared: the number of cancerous cell of originate the cancer cell membrane after extracting by it and the mass ratio of poly-DSPE-PEG (wherein the molecular weight of PEG is 7000) are 6 × 10
8: 180 μ g weigh, and be dissolved in 1ml, mass fraction is the ethanol of 4%, under ice bath, adopt ultrasonic cell disruption instrument to carry out ultrasonic 5min with the power of the frequency of 20kHz and 35W, obtain the first mixed solution;
(3) class spherical inner core is prepared: indocyanine green (ICG) is dissolved in the ICG solution that ethanol obtains 0.5mg/ml, Poly(D,L-lactide-co-glycolide (PLGA) is dissolved in the PLGA solution that acetonitrile obtains 0.5mg/ml, get the ICG solution of 1.5ml, and carry out ultrasonic to it, while the PLGA dropwise of 1ml is joined in the ICG solution of 1.5ml, ultrasonic time is 2min, obtains the second mixed solution;
(4) the first mixed solution described in 583 μ l steps (2) is joined in described second mixed solution of 2.5ml step (3), ultrasonic 2min is carried out with the power of the frequency of 20kHz and 35W with ultrasonic cell disruption instrument, obtain the 3rd mixed solution, described 3rd mixed solution is carried out centrifugal treating, described centrifugal be ultrafiltration 2-3 time in the ultra-filtration centrifuge tube of 10kDa at molecular cut off, centrifugal rotational speed is under 6000rpm, centrifugation time is 2min, collect supernatant and obtain indocyanine green composite nanometer particle (CCINPs), described indocyanine green composite nanometer particle comprises indocyanine green (ICG), hydrophobic polymer PLGA, polyglycol derivatization phospholipid DSPE-PEG and cancer cell membrane, described indocyanine green ICG by described hydrophobic polymer PLGA around and form class spherical structure with described hydrophobic polymer PLGA, described polyglycol derivatization phospholipid DSPE-PEG to be interspersed in described cancer cell membrane and to form imitated vesicle structure with described cancer cell membrane, described near-spherical structure is coated in described imitated vesicle structure.
The cell endocytic experiment of Application Example 1 indocyanine green composite nanometer particle (CCINPs)
The indocyanine green composite nanometer particle (CCINPs) obtained to the embodiment of the present invention 1 carries out cell endocytic experiment, and with free ICG in contrast, operating procedure is as follows:
(1) MCF-7 breast cancer cell is inoculated in 2 group of 8 porocyte culture plate, every hole 2 × 10
4individual small cell, the DMEM culture medium of every hole culture medium 200 μ L; After cell culture 24h is adherent, the DMEM culture medium more renewed, adds the CCINPs of 200 μ l containing 18 μ g/ml ICG in every hole of experimental group, adds the free ICG of 200 μ l containing 18 μ g/mL, continue cultivation 2 hours in every hole of matched group;
(2) cultivate after 2 hours, sop up the supernatant in orifice plate, rinse cell with PBS (phosphate buffer), and carry out transfect cell core with Hochest 33258 dyestuff, finally 8 orifice plates are placed in laser confocal microscope
Observe under (Leica TCS SP5 model) and take pictures.
The experimental result of tumor-targeting as shown in Figure 4, blueness represents the fluorescence of nucleus Hoeches 33258, redness represents the fluorescence of ICG, first of Fig. 4 is classified as the cell endocytic result of free ICG, second of Fig. 4 is classified as the cell endocytic result of CCINPs, the composite shell be made up of cancer cell membrane due to ICG coated, shown CCINPs nano-particle effectively can improve the targeting of indocyanine green to tumor cell, the gathering of ICG can be prevented simultaneously, improve the stability of ICG, extend its circulation time in vivo, in the secondary series of therefore Fig. 2, the red fluorescent of ICG is apparently higher than the matched group of first row, above result shows, the ICG of CCINPs phase specific ionization has efficient tumor-targeting.
The animal targeting experiment of Application Example 2CCINPs
At two groups of female BAl BIc/c nude mice (in 4-6 week, body weight is 15 – 20mg) subcutaneous injection 1 × 10
6individual MCF-7 breast cancer cell, treats that gross tumor volume reaches 50mm
3during left and right, (gross tumor volume computing formula is: length of tumor × (tumor width)
2/ 2), the CCINPs (ICG concentration is 0.05mg/kg) of one group of nude mice tail vein injection 0.2ml wherein, as experimental group, other one group of nude mice tail vein injection 0.2ml dissociates indocyanine green (ICG) (quality of the ICG injected in two groups is the same) as a control group, took pictures under small animal living body imager after 0.5,6,24 hour observation, result as shown in Figure 5.
In Fig. 5, in figure, circled represents knub position, free ICG is in injection after 30 minutes, mainly be positioned at liver, weaken rapidly at 6h, 24h fluorescence, its reason is free ICG less stable, it can be removed fast in blood plasma, circulation time is short in vivo, and indocyanine green lacks tumor cell targeting specific simultaneously, and knub position does not have ICG enrichment;
Indocyanine green composite nanometer particle (CCINPs) is positioned at liver and the tumor vicinity of Mus in injection after 30 minutes, tumor region its fluorescence signal after injection CCINPs6h and 24h strengthens gradually, significantly can reduce ICG medicine in vivo after further confirmation CCINPs wraps up ICG to remove and degraded, simultaneously by the passive target effect that bag is produced by the close same sex adhesive attraction of cancer cell membrane and tumor EPR effect, significantly improve the Targeting Effect of medicine.
These results suggest that, targeting when indocyanine green composite nanometer particle (CCINPs) provided by the invention is applied to animal carcasses is better.
The above embodiment only have expressed several embodiment of the present invention, and it describes comparatively concrete and detailed, but therefore can not be interpreted as the restriction to the scope of the claims of the present invention.It should be pointed out that for the person of ordinary skill of the art, without departing from the inventive concept of the premise, can also make some distortion and improvement, these all belong to protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.
Claims (10)
1. an indocyanine green composite nanometer particle, it is characterized in that, described indocyanine green composite nanometer particle comprises indocyanine green, hydrophobic polymer, polyglycol derivatization phospholipid and cancer cell membrane, described indocyanine green by described hydrophobic polymer around and form class spherical structure with described hydrophobic polymer, described polyglycol derivatization phospholipid to be interspersed in described cancer cell membrane and to form imitated vesicle structure with described cancer cell membrane, described near-spherical structure is coated in described imitated vesicle structure, described indocyanine green, the mass ratio of hydrophobic polymer and polyglycol derivatization phospholipid is (0.25-1.5): 1:(0.09-0.27), described cancer cell membrane derives from cancerous cell, the number of described cancerous cell and the mass ratio of polyglycol derivatization phospholipid are (10
8-10
9): 180 μ g.
2. indocyanine green composite nanometer particle as claimed in claim 1, it is characterized in that, the mass ratio of described hydrophobic polymer and described polyglycol derivatization phospholipid is 1:(0.15-0.21).
3. indocyanine green composite nanometer particle as claimed in claim 1, it is characterized in that, the particle diameter of described indocyanine green composite nanometer particle is 90-180nm.
4. indocyanine green composite nanometer particle as claimed in claim 1, it is characterized in that, described cancer cell membrane comprise in hepatoma carcinoma cell, breast cancer cell, lung carcinoma cell, cervical cancer cell one or more, described hydrophobic polymer is selected from one or more of Poly(D,L-lactide-co-glycolide, polylactic acid and polycaprolactone, to be Polyethylene Glycol by covalent bond be connected with phospholipid substance described polyglycol derivatization phospholipid obtains, and the molecular weight of described Polyethylene Glycol is 200 ~ 20000.
5. a preparation method for indocyanine green composite nanometer particle, is characterized in that, comprises the following steps:
(1) get cancerous cell, extract cancer cell membrane;
(2) imitated vesicle structure is prepared: compared for (10 with polyglycol derivatization phospholipid by the number of cancerous cell by the cancer cell membrane after extracting
8-10
9): 180 μ g weigh, and are dissolved in the first solvent, and ultrasonic 3-6min under ice bath, obtains the first mixed solution;
(3) class spherical inner core is prepared: indocyanine green is dissolved in the second solvent and obtains indocyanine green solution, hydrophobic polymer is dissolved in the 3rd solvent and obtains hydrophobic polymer solution, hydrophobic polymer dropwise is joined in indocyanine green solution, carry out ultrasonic 2-4min with ultrasound wave, obtain the second mixed solution;
(4) cancerous cell vesicle solution described in step (2) is joined in described second mixed solution of step (3), ultrasonic mixing 2-4min, obtain the 3rd mixed solution, described 3rd mixed solution is carried out centrifugal treating, collect supernatant and obtain indocyanine green composite nanometer particle, described indocyanine green composite nanometer particle comprises indocyanine green, hydrophobic polymer, polyglycol derivatization phospholipid and cancer cell membrane, described indocyanine green by described hydrophobic polymer around and form class spherical structure with described hydrophobic polymer, described polyglycol derivatization phospholipid to be interspersed in described cancer cell membrane and to form imitated vesicle structure with described cancer cell membrane, described near-spherical structure is coated in described imitated vesicle structure, wherein, described indocyanine green, the mass ratio of hydrophobic polymer and polyglycol derivatization phospholipid is (0.25-1.5): 1:(0.09-0.27).
6. the preparation method of indocyanine green composite nanometer particle as claimed in claim 5, it is characterized in that, in step (1), in step (1), described extraction cancer cell membrane is specially: get postdigestive cancerous cell, add the Tris-HCl hypotonic buffer solution of pH=7.5, homogenizing is broken, low-speed centrifugal 5-10min, collect supernatant, high speed centrifugation 15-30min, regather supernatant, again ultracentrifugation 40-60min is carried out to supernatant, collecting precipitation, and use buffer solution washing and precipitating, obtain the cancer cell membrane after purification, the centrifugal force of wherein said low-speed centrifugal is 3200g, described ultracentrifugal centrifugal force is 20000g, the centrifugal force of described ultracentrifugation is 100 000g.
7. the preparation method of indocyanine green composite nanometer particle as claimed in claim 5, it is characterized in that, described first solvent is one or more in ethanol, first alcohol and water, described second solvent is one or more in ethanol, water or methanol, and described 3rd solvent is one or more in acetonitrile and acetone.
8. the preparation method of indocyanine green composite nanometer particle as claimed in claim 5, it is characterized in that, the mass ratio of described hydrophobic polymer and described polyglycol derivatization phospholipid is 1:(0.15-0.21).
9. the preparation method of indocyanine green composite nanometer particle as claimed in claim 5, it is characterized in that, ultrasonic described in step (2), (3), (4) is adopt ultrasonic cell disruption instrument to carry out with the power of the frequency of 20kHz and 35W.
10. the application of indocyanine green composite nanometer particle in preparation tumor thermotherapy medicine.
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