CN109602907A - A kind of silica nodule nanoparticle pharmaceutical carrier and its diagnoses and treatment preparation and preparation method - Google Patents
A kind of silica nodule nanoparticle pharmaceutical carrier and its diagnoses and treatment preparation and preparation method Download PDFInfo
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Abstract
The invention discloses a kind of silica nodule nanoparticle pharmaceutical carrier and its diagnoses and treatment preparation and preparation methods.The carrier is vesica be self-assembly of by Amphipatic fluorescent molecule and siliceous complex liposome doping aquation, with lipid bilayer structure；The Amphipatic fluorescent molecule is to connect the compound that hydrophobic long-chain and fluorophor are formed by core, key of glycerine skeleton structure；The siliceous complex liposome is formed by siliceous inorganic precursor, hydrophobic lipid chain and by the linking group that the two is coupled；The siliceous inorganic precursor hydrolytic condensation of siliceous complex liposome forms the surface that inorganic silicate reticular structure is distributed in vesica.There is high stability with the diagnoses and treatment preparation that the carrier contains medicine preparation and combine two kinds of pH value, photothermal response medicine controlled releasing mechanism, and enhance the stability of fluorophor；Chemotherapy and photo-thermal therapy are combined, the recurrence rate of tumour is effectively reduced.
Description
Technical field
The invention belongs to biomedical materials fields, and in particular to a kind of silica nodule nanoparticle pharmaceutical carrier and have
High stability and the silica nodule nano target diagnoses and treatment preparation of drug controlled-releasing function and preparation method thereof.
Background technique
Carrying out diagnoses and treatment using nanoparticle platform is one of the important means for the treatment of of cancer.Wherein, for liposome
Using relatively broad.Liposome, when referring to that phosphatide is dispersed in water, Electronic Speculum observation can form multi-layer vesicles, and each layer is equal
For lipid bilayer, the closure vesica to be formed is separated by water phase between vesica center and each layer.It can be by natural or artificial synthesized
Lipid composition, such molecule are all made of tail portion two parts of hydrophilic head and lipophilic, and wall thickness is generally 5~7nm.
Since the chemical component of cell membrane is mainly lipoid and protein, liposome is within a very long time by as biology
The model of film studies the property of cell membrane.However, liposome still has certain problems as nano-medicament carrier, system
Still there is great difficulty in standby technology and industrialized production, and poor for water soluble drug encapsulation rate, and drug is easily from lipid
It is leaked in body, therefore, it is difficult to be commercialized, and the synthesis at home such as required raw material such as lecithin cholesterol and purification are at present still
In the exploratory stage, lack mature preparation process.Silica nodule due to its surface silicates layer (siloxane network) effect, this
Kind inorganic framework makes silica nodule morphologically more stable than traditional liposome.The network structure of siloxanes can then lead to
Fourier transform infrared spectroscopy is crossed to measure, stretching vibration is in 1100 and 950cm-1Absorption peak respectively correspond siloxane network
Si-O-Si the and Si-OH group of structure, due to the silicone hydroxyl not being condensed in the presence of part, silica nodule is often with apparent negative
Zeta potential prevents to some extent being easy cohesion because of electroneutral also to destructurized situation.As receiving
Rice pharmaceutical carrier, the system that silica nodule is utilized as gene transfection, the carrier of optical dynamic therapy medicine and immunization therapy
With load medicine chemotherapy, high activity, hypotoxicity, high encapsulation rate drugloading rate and good serum compatibility are shown in an experiment, this
Striking contrast is formd with other lipids without silanization.Therefore, silica nodule, which can consider, is combined with liposome and two
The advantages of silicon oxide nanoparticle, and respective disadvantage is overcome, it is a kind of ideal pharmaceutical carrier.
The treatment methods such as traditional chemotherapy, radiotherapy there are poor selectivity, toxic side effect is big the problems such as.Photo-thermal therapy is one
Kind has the non-invasive cancer therapy of application prospect.Due to the excellent permeability of near-infrared laser fill-in light heat therapy and
Pinpoint lethal, a large amount of research is all conceived to the exploitation suitable near-infrared photo-thermal therapy agent of size.Meanwhile it is most close
Infrared photo-thermal therapy agent can produce near-infrared fluorescent by the excitation of near infrared band light, therefore near infrared light heat cure is same
When can also pass through that the imaging function of near-infrared fluorescent molecule is synchronous to carry out diagnosis and treatment integration.Currently, clinically for tumour
Traditional therapy mainly has operation to cut off, radiotherapy and chemotherapy, but there is certain limitation, such as operation risk
Higher, the adverse reaction of chemicotherapy is larger, lacks specificity, or be easy to appear drug resistance, and traditional treatment method is for transfer
Function of tumor afterwards is limited, therefore malignant tumour lethality is difficult to be effectively controlled.Photo-thermal therapy based on nano material,
Because its tumour-specific is high, wound is small and the advantages such as few intercurrent disease, gradually cause the extensive concern of academia.And photo-thermal is controlled
Acceptable and chemotherapy, the synergistic treatments such as immunotherapy are treated, the multi-functional diagnosis and treatment agent for effectively antagonizing tumour is become.Nanometer photo-thermal material
Material is developed so far, and organic dyestuff wins extensive concern with its extremely low bio-toxicity and preferable photothermal conversion efficiency, at present compared with
More research hotspots is lain also on organic dyestuff substance, however organic dyestuff substance is repeatedly held afterwards near infrared light
Easily there is the case where photobleaching, the light conversion efficiency of dyestuff is substantially reduced, and is unfavorable for reusing, and individual organic dyestuff
Substance enters is difficult to stable arrival position in need for the treatment of in vivo, therefore, constructs nano platform by being assembled into nanoparticle
System carries out photo-thermal therapy and diagnosis and treatment integration, these photo-thermal nanometer diagnosis and treatment agent have good photothermal conversion efficiency, Er Qieneng
Connect the modes such as other materials by surface modification or key and realize multifunctional application, shows splendid treatment in animal experiments
Effect, worth people continue to explore, and have long-range prospect.
Treatment for tumour, simple photo-thermal therapy are easy to cause recurrence, and are difficult to inhibit the transfer of tumour, and
Simple chemotherapy then cannot achieve controlled-release effect, higher for the tissue and organ toxicity of non-tumour.Therefore, by photo-thermal therapy
It is a kind of more effective strategy with " combination therapy " that chemotherapy combines.It is loaded with the nanometer of chemotherapeutics and photothermal conversion drug
Particle system can be with target tumor region, and cooperates with and inhibit the efficiency of tumour more efficient than single therapy.Traditional combining is controlled
Treating preferred light thermit powder is methine cyanine type dye, and nano-carrier often uses thermal sensitive liposome, such as two palmityl phosphatide
Phatidylcholine (DPPC), the double dominant of liposome and thermotherapy is utilized effectively to improve therapeutic effect in it, reduces the secondary work of poison
With liposome membrane structure changes to adjust the release of drug when mainly by means of different temperatures.
The early stage of major disease, especially tumour is to improve its cure rate, and improve survival of patients matter with accurate diagnosis
The key point of amount.With the development of molecular image technology, early diagnosis of the nano molecular probe in disease, active medicine sieve
The many aspects such as choosing and Real-Time Evaluation therapeutic effect all play increasingly important role.And in the treatment side of disease
Face, the research using nanotechnology as the drug-loading system of anti-tumor drug also have been achieved with major progress.The target of Nano medication
The characteristics such as tropism, slow release and controlled capability and possible blood-brain barrier penetrability, have it compared with classic chemotherapy drug
There is significant advantage.
Therefore, using nanoparticle building " diagnosis and treatment integration " platform, the validity and safety for the treatment of are advanced optimized
Property, improved in the genotoxic potential problem of existing nanoparticle, caused by reduction carrier band chemotherapeutics discharges in advance
Building new antitumoral nano-carrier system is explored in side effect, and carries out diagnosing and treating on this basis with important meaning
Justice.
Summary of the invention
The photo-thermal effect of fluorescent dye in conjunction with chemotherapeutics photo-thermal controlled-release, is being improved target-oriented drug by the present invention
Meanwhile the purpose of photo-thermal therapy and chemotherapy combined treatment is realized, both fusions advantage reduces tumor recurrence.Meanwhile it utilizing
The high stability of silica nodule, reduces the unexpected release of drug.
An object of the present invention is to provide a kind of silica nodule nanometer using fine and close silicate network structure as outer shell
Particle to improve the stability and biological safety of nanoparticle, while assigning the included stronger anti-light bleaching energy of dyestuff
Power.
The second object of the present invention is to provide a kind of while having multiple stimulation response type drug controlled-releasing function and photo-thermal-
The integrated nano-drug preparation of the diagnoses and treatment of chemotherapy combined therapeutic effect, to solve chemotherapeutics half-life short, medicine target
Tropism and side effect is poor, high recurrence rate of single therapy mode tumour, diagnostic reagent and therapeutic reagent need separately administration, existing
There is the problems such as intellectual drug delivery system stability is poor.(1) increase tumor chemotherapeutic drug in the enrichment of tumor locus, reduce medicine
Object side effect enhances biological safety；(2) curative effect can be improved in combination therapy strategy, reduces tumor recurrence；(3) diagnosis and treatment one are realized
It is inconvenient using bring to reduce drug for body.
The purpose of the present invention is what is be achieved through the following technical solutions:
A kind of silica nodule nanoparticle pharmaceutical carrier, the carrier are by Amphipatic fluorescent molecule and siliceous complex lipid
Body doping, aquation (hydrolytic condensation), be self-assembly of, vesica with lipid bilayer structure；The Amphipatic fluorescent
Molecule is to connect the compound that hydrophobic long-chain and fluorophor are formed by core, key of glycerine skeleton structure；It is described siliceous compound
Liposome is formed by siliceous inorganic precursor, hydrophobic lipid chain and by the linking group that the two is coupled；Siliceous complex liposome
Siliceous inorganic precursor hydrolytic condensation form the surface that inorganic silicate reticular structure is distributed in vesica.Amphipatic fluorescent point
The hydrophilic radical of son is entrained between the hydrophilic radical of siliceous complex liposome, constitutes the outer layer of lipid bilayer and interior
Layer；The hydrophobic long-chain doping arrangement of the hydrophobic lipid chain and fluorescence amphiphile, amphiphilic molecule of siliceous complex liposome together constitutes lipid
Middle layer between the internal layer and outside of bilayer；Middle layer is to contain the space of dewatering medicament, and the cavity on the inside of internal layer is
Contain the space of hydrophilic drugs.
Further prioritization scheme are as follows: the inorganic precursor of siliceous complex liposome contains (EtO)3Si structure, (EtO)3Si
Structure number is 1~3；The hydrophobic lipid chain number that siliceous complex liposome includes is 1~3, and the hydrophobic lipid chain is
Hydrophobic aliphatic chain or cholesterol；Linking group in siliceous complex liposome is amino acid or oligopeptides.EtO is ethyoxyl.
Further prioritization scheme are as follows: the glycerine skeleton structure in Amphipatic fluorescent molecule selects glycerol monostearate
Ester belongs to polyol type nonionic surfactant, and preparation process is the glycerolysis reaction of natural oil, and product is usually used in
Foaming agent, emulsifier, no overt toxicity, molecular weight 358.56
Further, the vesica entity diameter of the carrier is 50~150nm.
Further, the fluorophor is methine cyanine fluorochrome.
A kind of silica nodule nano target diagnoses and treatment preparation with drug controlled-releasing function, by silicon described in claim 1
Plastid nanoparticle pharmaceutical carrier loads drug composition.
Further, the drug of loading include but is not limited to adriamycin, mitomycin, taxol, camptothecine, fluorine urine it is phonetic
Pyridine, methotrexate (MTX), Chlorambucil, oxaliplatin, cordycepin, Irinotecan, Sorafenib, Gefitinib, modafinil,
Docetaxel, curcumin, glaucocalyxin A, podophyllotoxin.
A kind of preparation method of the silica nodule nano target diagnoses and treatment preparation with drug controlled-releasing function, including it is following
Step:
1) preparation of fluorescent dye；
2) fluorescent dye and being coupled for valence for glycerine skeleton structure obtain Amphipatic fluorescent molecule；
3) Amphipatic fluorescent molecule and siliceous complex lipid doping aquation form silica nodule nanoparticle pharmaceutical carrier；
4) anticancer drug is contained in silica nodule nanoparticle pharmaceutical carrier.
Further, the fluorescent dye is methine cyanine fluorochrome, specific steps are as follows:
1) by Fischer addition, substitution reaction prepares methine cyanine fluorochrome: structure 1 is passed through with ketone
The indoline structure 2 that Fischer addition prepares, by substitution reaction acquisition structure 3 and structure 4, structure 3 and containing altogether
The methine conjugated chain micromolecular structure 5 of vibration structure, which is scattered under nitrogen protection in acetic anhydride, is stirred to react to obtain knot for 120 DEG C
The indoline structures alone of structure 6, structure 6 and the other end, which is scattered in triethylamine, occurs substitution reaction generation structure 7 to get first
River cyanine fluorochrome 7；
2) covalent coupling of methine cyanine type dye and glycerine skeleton structure: step 1) is made by chemical coupling reaction
Standby structure 7 is coupled to the secondary carbon of glycerine skeleton structure, thus by methine cyanine type dye modification to glycerine class skeleton structure
On；It carries out needing to protect the primary carbon of structure 8 to obtain structure 9 with high steric-hindrance amino structural compounds in the step process, then in 4- diformazan
It is connected under aminopyridine and the catalysis of 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride by substitution reaction secondary
Structure 10 is obtained on hydroxyl on carbon；Structure 11 then is obtained using trifluoroacetic acid deprotection high steric-hindrance amino structural compounds, then
Remaining primary carbon is replaced to obtain structure 12 using acid anhydrides class formation.Obtain Amphipatic fluorescent molecule；
3) aquation is adulterated with siliceous complex lipid: by the Amphipatic fluorescent molecule and siliceous complex liped of step 2) preparation
Plastid is scattered in organic solvent, after revolving film forming, carries out aquation at 50~60 DEG C with deionized water and in water phase mesoscale eddies
And ultrasonication, it places overnight, the silica nodule nanoparticle pharmaceutical carrier is formed by hydrolysis, condensation, self assembly step；
4) anticancer drug is contained in silica nodule nanoparticle pharmaceutical carrier: the silica nodule nanoparticle of step 3) preparation
Sub- pharmaceutical carrier removes the ammonium sulfate of outer aqueous phase, then with drug incubation, complete Active loading process, be with phosphate buffer
Eluant, eluent removes the drug of unentrapped by -50 column method of sephadex G；
Wherein the structure of 1~structure of structure 12 is as shown in Figure of description 8 and 9.
Ketone used in step 1) includes but is not limited to methyl isopropyl Ketone, butanone, ethyl isopropyl ketone；Made
Indoline structure includes but is not limited to indoles, benzindole, thiazole, benzothiazole, naphthothiazoles, imidazoles, quinoline；Made
Methine conjugated chain includes but is not limited to pentadienal contracting diphenylamine hydrochloride, the double benzene imines mono-hydrochloric salts of malonaldehyde.
High steric-hindrance amino structural compounds used in step 2) include but unlimited 4,4'- dimethoxytrityl chloromethanes,
Triphenylchloromethane, used acid anhydrides class formation include but is not limited to succinic anhydride, malonic anhydride, glutaric anhydride.
Organic solvent used in step 3) includes but is not limited to dimethyl sulfoxide, methanol, ethyl alcohol, propyl alcohol, three chloromethanes
Alkane, methylene chloride.
The medicine controlled releasing that there is heretofore described preparation the multiple stimulation of pH value responsiveness, photothermal response to respond
Function.
Heretofore described preparation has the function of chemotherapy and photo-thermal combination therapy.
Heretofore described preparation has the function of there is structural defence and illumination to protect fluorophor.For
The drug contained prevents from discharging in advance.
Beneficial effects of the present invention:
One of the advantages of the present invention is that glycerine skeleton structure and silica nodule shell structurre has been used to examine as nano target
Disconnected treatment platform, improves the biological safety of nanoparticle, stability.The encapsulation rate and load of anticancer drug are improved simultaneously
Dose, and key even by way of improve the stability and encapsulation rate of fluorescent dye, ensure that its photothermal conversion efficiency,
Increase substantially methine cyanine type dye photothermal conversion efficiency in practical applications and photo-thermal therapy and imaging effect.
Advantages of the present invention second is that near-infrared fluorescence imaging and photo-thermal-chemotherapy combined treatment are incorporated in by the preparation
Together, diagnosis and treatment integration is realized, the distribution for the treatment of and monitoring drug under realization is image-guided, and convenient for evaluation therapeutic effect.
Advantages of the present invention third is that the preparation has preferable stability and simultaneously for pH and temperature sensitive
Medicine controlled releasing, it is possible to reduce drug leaks in advance, improves drug in the enrichment of tumor tissues, reduces the toxic side effect of drug.
Advantages of the present invention fourth is that the preparation organically combines photo-thermal therapy and chemotherapy by control release, improve
Therapeutic effect, reduces tumor recurrence, plays a certain protective role simultaneously for normal body tissue.
Detailed description of the invention
Fig. 1 is silica nodule nanoparticle pharmaceutical carrier the schematic diagram of the section structure；
Fig. 2 is the preparation flow schematic diagram of preparation described in embodiment 1.
Fig. 3 is the transmission electron microscope picture of the obtained preparation of embodiment 1.Said preparation is nano spherical particle, and entity diameter is about
100 nanometers, uniform particle sizes, it is seen that apparent nucleocapsid spline structure and outer layer compact texture.
Fig. 4 is the near-infrared fluorescence imaging of mice with tumor tumor locus after said preparation prepared by tail vein injection embodiment 1
Figure.Specific experiment process is as described in Example 2.Behind 8 hours after injecting said preparation, the near-infrared fluorescent signal of tumor locus
Reach most strong.
Fig. 5 is that the photo-thermal heating of said preparation prepared by embodiment 1 and the in vitro effects of structural stability are evaluated.It is specific real
It is as described in Example 3 to test process, left figure (A) shows that after multiple irradiation, silica nodule group is compared to undoped with complex liposome group
And fluorescent dye group increasing extent of temperature is bigger merely, stability is also higher.Right figure (B) shows after being handled with surfactant, silicon
The partial size of plastid group keeps more preferable compared to traditional liposomal group.
Fig. 6 is the in vitro effects evaluation of the multiple stimulation response type medicine controlled releasing of preparation prepared by embodiment 1.It is specific real
It is as described in Example 4 to test process.Left figure (A) reflects the drug control of said preparation excellent pH value responsiveness and temperature-responsive
Effect is released, right figure (B) reflects the excellent photothermal response medicine controlled releasing effect of said preparation.
Fig. 7 is the preparation for preparing of embodiment 1 to the treatment effectiveness evaluation of the subcutaneous implantation tumor of mice with tumor, and ordinate is to survey
Measure the ratio of same day gross tumor volume and the 0th day tumor size.Specific experiment process is as described in Example 5.The photo-thermal of said preparation and
Chemotherapy combined treatment melts tumour completely, and the recurrence without finding tumour；
Fig. 8 is each structural formula of compound of 1 step 1) of embodiment；
Label 1~7 respectively represents structure 1~7；
Fig. 9 is each structural formula of compound of 1 step 2) of embodiment；
Label 8~12 respectively represents structure 8~12；
Figure 10 is the siliceous complex lipid structural schematic diagram.
Specific embodiment
As shown in Figure 1, 2, a kind of silica nodule nanoparticle pharmaceutical carrier, the carrier be by Amphipatic fluorescent molecule and
Vesica that siliceous complex liposome doping aquation is self-assembly of, with lipid bilayer structure；The Amphipatic fluorescent
Molecule is to connect the compound that hydrophobic long-chain and fluorophor are formed by core, key of glycerine skeleton structure；It is described siliceous compound
Liposome is formed by siliceous inorganic precursor, hydrophobic lipid chain and by the linking group that the two is coupled；Siliceous complex liposome
Siliceous inorganic precursor hydrolytic condensation form the surface that inorganic silicate reticular structure is distributed in vesica.Amphipatic fluorescent point
The hydrophilic radical of son is entrained between the hydrophilic radical of siliceous complex liposome, constitutes the outer layer of lipid bilayer and interior
Layer；The hydrophobic long-chain doping arrangement of the hydrophobic lipid chain and fluorescence amphiphile, amphiphilic molecule of siliceous complex liposome together constitutes lipid
Middle layer between the internal layer and outside of bilayer；Middle layer is to contain the space of dewatering medicament, and the cavity on the inside of internal layer is
Contain the space of hydrophilic drugs.
The inorganic precursor of siliceous complex liposome contains (EtO)3Si structure, (EtO)3Si structure number is 1~3；Contain
The hydrophobic lipid chain number that silicon complex liposome includes is 1~3, and the hydrophobic lipid chain is hydrophobic aliphatic chain or cholesterol；
Linking group in siliceous complex liposome is amino acid or oligopeptides.
Glycerine skeleton structure in Amphipatic fluorescent molecule preferably uses glycerin monostearate (glycerine and hydrophobic length
Chain link even forms).Fluorophor is preferably methine cyanine fluorochrome.
It is made of the silica nodule nanoparticle pharmaceutical carrier loading drug a kind of with the siliceous of drug controlled-releasing function
Body nano target diagnoses and treatment preparation.The drug of loading include but is not limited to adriamycin, mitomycin, taxol, camptothecine,
Fluorouracil, methotrexate (MTX), Chlorambucil, oxaliplatin, cordycepin, Irinotecan, Sorafenib, Gefitinib, Mo Da
Non- Buddhist nun, docetaxel, curcumin, glaucocalyxin A, podophyllotoxin.
The preparation method and effect of invention formulation, the specific embodiment of the invention are described in detail below by way of specific embodiment
Cited the embodiments are used only to illustrate the invention, is not intended to limit the contents of the present invention.
Embodiment 1
A kind of preparation method of heretofore described preparation is as shown in Fig. 1, comprising the following steps:
1) synthesis of methine cyanine dyes: the indoline structure that structure 1 and ketone are prepared by Fischer addition
2, structure 3 and structure 4, structure 3 and the methine conjugated chain micromolecular structure containing resonant structure are obtained by substitution reaction
5 are scattered in acetic anhydride under nitrogen protection and are stirred to react to obtain structure 6, the indoline structure list of structure 6 and the other end for 120 DEG C
Body, which is scattered in triethylamine, occurs substitution reaction generation structure 7 to get methine cyanine fluorochrome 7, and each compound structure is as schemed
Shown in 8；
Concrete operations are as follows:
By 0.57g phenylhydrazine, 50ml round-bottomed flask, heating stirring is added in 1.68ml 3- methyl -2- butanone and 3ml glacial acetic acid
3h obtains buff oily liquids, is washed repeatedly after cooling with solution of potassium carbonate, and methylene chloride is added and is spin-dried for obtaining pale yellow colored solid
Body 2,3,3- tri-methyl indole quinoline.Take the iodine second of 2,3,3- tri-methyl indole quinoline (structure 2 in Fig. 8) and 1.2 equivalents of 1 equivalent
Alkane is added o-dichlorohenzene and is heated to 110 degree of reflux 12 hours under nitrogen protection, uses acetone washing solid product after cooling, claims
Make product 1 (structure 4 in Fig. 8).Neighbour two is added in the 6- bromocaproic acid of the 2,3,3- tri-methyl indole quinoline and 1.2 equivalents that separately take 1 equivalent
Chlorobenzene is heated to 110 DEG C under nitrogen protection and flows back 12 hours, washs solid product, referred to as product 2 with ethyl acetate after cooling
(structure 3 in Fig. 8).By product 2,5ml acetic acid, 5ml acetic anhydride and 1 mM of N- (5 (phenyl amino) -2-4- pentadienyl)
Anilinechloride is heated to 120 DEG C under nitrogen protection and flows back 4 hours, and ether washing is added after cooling, and then methanol dissolves,
Solvent is removed under reduced pressure, obtains crude product.10ml triethylamine and 10ml ethyl alcohol will be added in crude product again, adds product 1, often
Temperature stirring 3 hours.Revolving removes solvent, and ether washing is added, and purifies to obtain target dyestuff with the mode that column chromatographs and (tie in Fig. 8
Structure 7).Agent prescription is unfolded: methanol: methylene chloride=1:10, Rf are about 0.2.
Synthetic route chart described above such as Figure 11.
2) it the coupling of glycerine skeleton structure and dyestuff: is coupled by the structure 7 that chemical coupling reaction prepares step 1)
To the secondary carbon of glycerine skeleton structure, thus by the modification to glycerine class skeleton structure of methine cyanine type dye；Carry out the step
It needs to protect the primary carbon of structure 8 to obtain structure 9 with high steric-hindrance amino structural compounds in the process, then in 4-dimethylaminopyridine and 1-
The catalysis of (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride is lower to be connected on the hydroxyl in secondary carbon by substitution reaction
Obtain structure 10.Structure 11 then is obtained using trifluoroacetic acid deprotection high steric-hindrance amino structural compounds, reuses acid anhydrides class formation
Remaining primary carbon is replaced to obtain structure 12 to get Amphipatic fluorescent molecule is arrived, each compound structure is as shown in Figure 9.
Concrete operations are as follows:
Weigh 1g glycerin monostearate and 1.417g4,4'- dimethoxytrityl chloromethanes to be dissolved in 10mL anhydrous
In pyridine, it is placed in oscillator and is heated to 50 degree of oscillations 18 hours, it is then that mixture is cooling, it pours into mixture of ice and water, uses
Chloroform extracts three times, removes insoluble sludge, is washed with deionized water three times, is obtained on primary carbon with anhydrous sodium sulfate dry filter
The protected glycerin monostearate structure of hydroxyl.Solvent is removed under reduced pressure, then uses ethyl acetate/petroleum ether=2:1 expansion
The purification of agent silica gel column chromatography, obtains required product.Then, the protected monostearate of hydroxyl for being 1:1:0.4:2 by equivalent proportion
Glyceride structure, dyestuff, 4-dimethylaminopyridine, 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride are jointly molten
Solution is stirred at room temperature 24 hours, after solvent is removed under reduced pressure in 10ml chloroform, with methylene chloride/methanol=15:1 solvent column layer
Analysis purification, obtained product are dissolved in 10ml chloroform, and the trifluoroacetic acid for being slow added into 25 times of equivalents sloughs blocking group, obtains
To product and succinic anhydride and 4-dimethylaminopyridine appropriate chloroform is dissolved in the equivalent proportion of 1:5:5, be stirred at room temperature 24
Hour then washed with aqueous ammonium chloride solution, extracted with chloroform, after filtering, solvent be removed under reduced pressure, with methylene chloride/methanol=
The solvent column Chromatographic purification of 15:1 obtains final product, referred to as product 3 (structure 12 in Fig. 9).
The nuclear magnetic data of product 3: 1H NMR (CDCl3,400MHz), δ 11.00 (t, J=7.3Hz, 1H) 7.37 (t, J=
7.2Hz, 1H), 4.16 (p, J=7.3Hz, 3H), 4.08 (s, 1H), 2.79-2.59 (m, 5H), 2.42-2.20 (m, 2H),
2.02 (d, J=6.8Hz, 1H), 1.84 (s, 1H), 1.73 (d, J=25.5Hz, 2H), 1.63 (d, J=8.7Hz, 1H), 1.44
(s, 1H), 1.33 (s, 3H), 1.34-1.22 (m, 19H), 0.98-0.82 (m, 5H) .MS theoretical value 1170.48, experiment value [M]+=
1172.1。
Synthetic route chart described above such as Figure 12.
3) building of silica nodule: product 3 and the complex liposome for forming silica nodule are codissolved in chloroform with the molar ratio of 3:7
Ratio with methanol is in the solution of 3:1.Then organic solvent is removed in vacuum rotary evaporator, obtains resulting lipid
Film.After be dried in vacuum overnight, aquation about 30 minutes in 60 DEG C of deionized water are vortex oscillation 20 minutes, super with sonde-type
Sound instrument is further ultrasonically treated 5 minutes in ice bath.The then self-assembling formation structural integrity by way of hydrolysis, condensation, self assembly
Silica nodule.
The step of hydrolytic condensation self assembly, predominantly places in 37 DEG C of incubators overnight, mainly has during this following
Step
A, it hydrolyzes: such as (EtO) in Fig. 23Substitution reaction occurs for Si structure, is changed into key on element silicon and connects three hydroxyls
Structure.
B, be condensed, if key connects the structure of three hydroxyls on the element silicon in Fig. 2, adjacent silicone hydroxyl structure some
Polymerization (condensation reaction) occurs between hydroxyl, forms signal fine and close silicate network structure shown in Fig. 2.In above two mistakes
Any chemical reaction does not occur for Cheng Zhong, product 3.
C, self assembly, siliceous complex liposome and product 3 after hydrolytic condensation, due to respectively including water-wet side
(silicone hydroxyl structure and acid anhydrides) and hydrophobic side (aliphatic chain), therefore organic molecule spontaneously forms similar cell film in the solution
The bilayer of structure.Water-wet side is outside, including hydrophobic side, forms the membrane structure of the similar following figure.
4) contain adriamycin: the load for doxorubicin hydrochloride is implemented by ammonium sulphate gradient scheme.Drug and total rouge
The molar ratio of matter is 1:10.Using phosphate buffer as eluant, eluent, the Ah of unentrapped is removed by -50 column method of sephadex G
Mycin.Obtained product is fitted into the bag filter that molecule interception is 1000kDa, in phosphate buffer (0.01M, pH=
Dialyse 48h in 7.2-7.4), and constantly replaces dialyzate, finally obtains pure medicine-carried nano particles.
Embodiment 2
The toy near-infrared fluorescence imaging effect assessment of preparation prepared by embodiment 1, mainly includes the following steps:
(1) foundation of nude mice by subcutaneous tumor model: by HT-29 cell with every nude mice 2 × 106The amount of a cell is inoculated in
The big leg outer side of BALB/c nude mice is subcutaneous, and nude mice is raised under SPF grades of environment；
(2) tumor size grows to about 100mm3When, prepared by the embodiment 1 through 100 μ L 4mg/mL of tail vein injection should
Preparation, the different time of difference upon administration, with the fluorescence intensity of toy near-infrared fluorescence imaging system detection tumor locus
Signal.
Imaging results are as shown in Fig. 4, and after injecting said preparation, the near infrared signal of tumor locus is gradually increased, and 8
Hour near-infrared fluorescent signal reaches most strong, and disperse is in entire tumor locus, and relative to before administration and traditional liposomal group
And undoped silica nodule structure group, tumour can be more clear imaging, illustrate said preparation have good near-infrared fluorescent at
The effect of picture.
Embodiment 3
(1) investigation of photo-thermal heating stability: by the silica nodule nano particle of isoconcentration, fluorescent dye and undoped with multiple
It closes liposome solutions 3ml and quartz colorimetric utensil is added, with the wavelength and 2W/cm of 808 ± 10nm2Output power continuous wave two
The near-infrared laser of pole pipe irradiates, and with digital thermometer and thermocouple probe every the solution temperature of measurement in 10 seconds, measures altogether
It then cools to room temperature within 10 minutes, in triplicate.Increasing extent of temperature after recording irradiation in 10 minutes.The experiment needs parallel real three times
It tests.
(2) investigation of structural stability: the nonionic surfactant triton x-100 of different volumes ratio is added
It is dissolved in the different nanoparticles in PBS and serum, then Malvern Zetasizer Nano-ZS90 is used in 37 DEG C of incubations
Measure the partial size of nanoparticle.The experiment equally needs parallel laboratory test three times.
As a result as shown in Figure 5.
Embodiment 4
The in-vitro evaluation of the multiple response type medicine controlled releasing effect of said preparation, including pH sensitive, temperature sensitivity and
The evaluation of light and heat-sensitive medicine controlled releasing, it is described that steps are as follows:
(1) firstly, research light and heat-sensitive medicine controlled releasing effect.In order to study light-triggered adriamycin release, will contain
The silica nodule nanoparticle of adriamycin is suspended in the phosphate buffer solution of 1mL, then in different time points (0,60,130,
200 and 270min) use near infrared light (808nm, 2W/cm2) irradiation 10 minutes.Before and after each irradiation, dispersion liquid is collected, from
The heart takes supernatant to measure the doxorubicin content released, to calculate the cumulant of nano particle release adriamycin.Control group is then
Do not irradiate near infrared light.
(2) next, the adriamycin release of research temperature and pH triggering, the silica nodule nanoparticle that adriamycin is loaded
It is suspended in the phosphate buffer solution of 1mL and adjusts pH and be 7.4 and 5.0 and be loaded in bag filter, respectively 25,37 and 41
It is incubated for 24 hours at DEG C.A certain amount of dialyzate was taken to measure the release amount of medicine at the time point 1,2,4,8 hours time points.
Experimental result is as shown in Fig. 6, it is seen that the release amount of medicine at 41 DEG C is maximum, and acidic environment can be with one
Determine degree and improves drug release, and in 10 minutes of near infrared light, release amount of medicine can then be promoted rapidly.It is comprehensive
Upper described, which will not obviously discharge in the case where shining in vivo without near infrared light, and have near infrared light
Due to there is the fluorescent dye with photothermal conversion effect in the case where being irradiated, tumor locus temperature can be increased, be reached
The purpose of temperature sensitivity release.Also, higher release ratio can be reached under the acidic micro-environment and higher temperature of tumour
Rate, description of test said preparation have reached good stimuli responsive type medicine controlled releasing effect.
Embodiment 5
The oncotherapy effect assessment of said preparation, key step are as described below:
(1) foundation of nude mice by subcutaneous tumor model: by HT-29 cell with every nude mice 4 × 106The amount of a cell is inoculated in
The big leg outer side of BALB/c nude mice is subcutaneous, and nude mice is raised under SPF grades of environment；
(2) when tumor size reaches about 100-120mm3When, mouse is equally divided into 5 groups, every group 6, every group passes through respectively
Tail vein injects the said preparation of 100 μ L 2mg/mL respectively, 100 μ L 2mg/mL do not contain the said preparation or list of adriamycin
Pure doxorubicin hydrochloride (drugloading rate that dosage is equivalent to said preparation), control group are injected 200 μ L phosphate buffers and are subject to
Laser irradiation.
(3) for needing the experimental group of photo-thermal therapy, upon administration for 24 hours, the laser irradiation tumour for being 808nm with wavelength
Position 10min, laser power settings 2W/cm2。
(4) every three days with the length and width of vernier caliper measurement tumour, gross tumor volume is approximately equal to long multiplied by wide square
Divided by two.
Experiment as shown in Fig. 7, injects phosphate buffer and is subject to the control group of laser irradiation, tumour growth is rapid；
Simple injection adriamycin and simple injection contain the nanoparticle of adriamycin, and tumour growth is by being inhibited very little；Injection does not have
Laser irradiation is given after containing the said preparation of adriamycin, tumour is ablated to, but tumour recurs；When injection is mounted with
After giving laser irradiation after the said preparation of adriamycin, tumour is fallen by thorough ablation, and does not recur, this illustrates the system
Agent has the effect of good photo-thermal therapy, and the adriamycin that said preparation loads can play the collaboration for preventing tumor recurrence
The effect for the treatment of.
Claims (10)
1. a kind of silica nodule nanoparticle pharmaceutical carrier, it is characterised in that: the carrier is by Amphipatic fluorescent molecule and siliceous
Complex liposome doping, aquation, be self-assembly of, vesica with lipid bilayer structure；The Amphipatic fluorescent point
Son is to connect the compound that hydrophobic long-chain and fluorophor are formed by core, key of glycerine skeleton structure；The siliceous complex liped
Plastid is formed by siliceous inorganic precursor, hydrophobic lipid chain and by the linking group that the two is coupled；Siliceous complex liposome
Siliceous inorganic precursor hydrolytic condensation forms the surface that inorganic silicate reticular structure is distributed in vesica.
2. silica nodule nanoparticle pharmaceutical carrier according to claim 1, it is characterised in that: the nothing of siliceous complex liposome
Machine precursor contains (EtO)3Si structure, (EtO)3Si structure number is 1 ~ 3；The hydrophobic lipid chain that siliceous complex liposome includes
Number is 1 ~ 3, and the hydrophobic lipid chain is hydrophobic aliphatic chain or cholesterol；Linking group in siliceous complex liposome is
Amino acid or oligopeptides.
3. silica nodule nanoparticle pharmaceutical carrier according to claim 1, it is characterised in that: in Amphipatic fluorescent molecule
Glycerine skeleton structure selects glycerin monostearate.
4. silica nodule nanoparticle pharmaceutical carrier according to claim 1, it is characterised in that: the vesica entity of the carrier
Diameter is 50 ~ 150nm.
5. silica nodule nanoparticle pharmaceutical carrier according to claim 1, it is characterised in that: the fluorophor is methine
Cyanine fluorochrome.
6. a kind of silica nodule nano target diagnoses and treatment preparation with drug controlled-releasing function, it is characterised in that: by claim 1
The silica nodule nanoparticle pharmaceutical carrier loads drug composition.
7. a kind of silica nodule nano target diagnoses and treatment preparation with drug controlled-releasing function, it is characterised in that: the drug of loading
Including but not limited to adriamycin, mitomycin, taxol, camptothecine, fluorouracil, methotrexate (MTX), Chlorambucil, Ao Shali
Platinum, cordycepin, Irinotecan, Sorafenib, Gefitinib, modafinil, docetaxel, curcumin, glaucocalyxin A, podophyllotoxin
Element.
8. a kind of preparation method of the silica nodule nano target diagnoses and treatment preparation with drug controlled-releasing function, it is characterised in that:
The following steps are included:
1) preparation of fluorescent dye；
2) fluorescent dye and being coupled for valence for glycerine skeleton structure obtain Amphipatic fluorescent molecule；
3) Amphipatic fluorescent molecule and siliceous complex lipid doping aquation form silica nodule nanoparticle pharmaceutical carrier；
4) anticancer drug is contained in silica nodule nanoparticle pharmaceutical carrier.
9. the preparation side of the silica nodule nano target diagnoses and treatment preparation according to claim 8 with drug controlled-releasing function
Method, it is characterised in that: the fluorescent dye is methine cyanine fluorochrome, specific steps are as follows:
1) by Fischer addition, substitution reaction prepares methine cyanine fluorochrome: structure 1 and ketone are added by Fischer
At the indoline structure 2 prepared, structure 3 and structure 4, structure 3 and time containing resonant structure are obtained by substitution reaction
Methyl conjugated chain micromolecular structure 5 is scattered in acetic anhydride 120 DEG C under nitrogen protection and is stirred to react to obtain structure 6, structure 6 with
The indoline structures alone of the other end, which is scattered in triethylamine, occurs substitution reaction generation structure 7 to get methine cyanine fluorochrome
Material 7；
2) knot prepared by step 1) the covalent coupling of methine cyanine type dye and glycerine skeleton structure: is reacted by chemical coupling
Structure 7 is coupled to the secondary carbon of glycerine skeleton structure, thus by the modification to glycerine class skeleton structure of methine cyanine type dye；It carries out
It needs to protect the primary carbon of structure 8 to obtain structure 9 with high steric-hindrance amino structural compounds in the step process, then in 4-dimethylaminopyridine
With the hydroxyl being connected under the catalysis of 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride by substitution reaction in secondary carbon
On obtain structure 10, then using trifluoroacetic acid deprotection high steric-hindrance amino structural compounds obtain structure 11, reuse anhydride knot
Structure replaces remaining primary carbon to obtain structure 12 to get Amphipatic fluorescent molecule is arrived；
3) aquation is adulterated with siliceous complex lipid: by the Amphipatic fluorescent molecule and siliceous complex liposome point of step 2 preparation
It dissipates in organic solvent, after revolving film forming, carries out aquation at 50 ~ 60 DEG C with deionized water and simultaneously ultrasound is broken in water phase mesoscale eddies
It is broken, it places overnight, the silica nodule nanoparticle pharmaceutical carrier is formed by hydrolysis, condensation, self assembly step；
4) anticancer drug is contained in silica nodule nanoparticle pharmaceutical carrier: the silica nodule nanoparticle drug of step 3) preparation
Carrier remove outer aqueous phase ammonium sulfate, then with drug incubation, complete Active loading process, using phosphate buffer as eluant, eluent,
The drug of unentrapped is removed by -50 column method of sephadex G；
Wherein the structure of 1 ~ structure of structure 12 is as shown in Figure of description 8 and 9.
10. the preparation of the silica nodule nano target diagnoses and treatment preparation according to claim 9 with drug controlled-releasing function
Method, it is characterised in that:
Ketone used in step 1) includes but is not limited to methyl isopropyl Ketone, butanone, ethyl isopropyl ketone；Used Yin
Diindyl quinoline structure includes but is not limited to indoles, benzindole, thiazole, benzothiazole, naphthothiazoles, imidazoles, quinoline；Used secondary first
Base conjugated chain includes but is not limited to pentadienal contracting diphenylamine hydrochloride, the double benzene imines mono-hydrochloric salts of malonaldehyde；
High steric-hindrance amino structural compounds used in step 2 include but unlimited 4,4'- dimethoxytrityl chloromethanes triphen
Base chloromethanes, used acid anhydrides class formation include but is not limited to succinic anhydride, malonic anhydride, glutaric anhydride；
Organic solvent used in step 3) includes but is not limited to dimethyl sulfoxide, methanol, ethyl alcohol, propyl alcohol, chloroform, two
Chloromethanes.
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| CN110368504A (en) * | 2019-08-23 | 2019-10-25 | 北京大学第三医院 | A kind of production gas-thermal sensitivity silica nodule and its preparation method and application |
| CN116603101A (en) * | 2023-07-20 | 2023-08-18 | 北京大学第三医院（北京大学第三临床医学院） | Gold-siliceous body-polycaprolactone scaffold system and preparation method and application thereof |
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| CN103861123A (en) * | 2012-12-17 | 2014-06-18 | 中国科学院深圳先进技术研究院 | Diagnosis-treatment integrated nanometer material, diagnosis-treatment integrated nanometer preparation and preparation method of nanometer preparation |
| CN105920625A (en) * | 2016-04-19 | 2016-09-07 | 中山大学 | Preparation method of diagnosis and treatment preparation integrating ultrasound contrast and thermal therapy |
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| CN103301482A (en) * | 2013-06-27 | 2013-09-18 | 深圳先进技术研究院 | Amphipathy tri-block polypeptide ICG (Indocyanine Green) loaded micelle and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110368504A (en) * | 2019-08-23 | 2019-10-25 | 北京大学第三医院 | A kind of production gas-thermal sensitivity silica nodule and its preparation method and application |
| CN110368504B (en) * | 2019-08-23 | 2021-10-29 | 北京大学第三医院 | Gas-generating-heat-sensitive silica body and preparation method and application thereof |
| CN116603101A (en) * | 2023-07-20 | 2023-08-18 | 北京大学第三医院（北京大学第三临床医学院） | Gold-siliceous body-polycaprolactone scaffold system and preparation method and application thereof |
| CN116603101B (en) * | 2023-07-20 | 2023-10-03 | 北京大学第三医院（北京大学第三临床医学院） | Gold-siliceous body-polycaprolactone scaffold system and preparation method and application thereof |
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