CN104840422A - Long circulating ceramose and preparation method thereof - Google Patents
Long circulating ceramose and preparation method thereof Download PDFInfo
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- CN104840422A CN104840422A CN201410054892.3A CN201410054892A CN104840422A CN 104840422 A CN104840422 A CN 104840422A CN 201410054892 A CN201410054892 A CN 201410054892A CN 104840422 A CN104840422 A CN 104840422A
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- long circulating
- silica nodule
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- nodule
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Abstract
The purpose of the invention is providing a long circulating ceramose and a preparation method thereof. The long circulating ceramose is a lipid bilayer structure composed of lipid and a long-circulating functional molecule, and the lipid is formed by ceramose. The surface of the long circulating ceramose has a silicate network structure, so the stability of the long circulating ceramose is better than that of common liposome. The long-circulating functional molecule is introduced to substantially prolong the blood circulation time of the long circulating ceramose. The long circulating ceramose can be used as a carrier for clinic treatment agents and medical developers, and the preparation method of the long circulating ceramose has the advantages of simplicity and low cost, and is suitable for wide popularization application.
Description
Technical field
The invention belongs to biomedical materials field, be specifically related to a kind of long circulating silica nodule and preparation method thereof.
Technical background
It is simple that liposome has preparation as a kind of pharmaceutical carrier, avirulence, and non-immunogenicity reacts, biodegradable, and is easy to realize the characteristics such as targeting.Liposome in vivo can drug loosed time, improves curative effect and does not increase toxicity.Long circulating liposomes surface is modified with the Polyethylene Glycol linear long chain structure of macromolecule usually.Its circulation time in blood significantly improves compared with conventional liposome, as can prolong drug half-life medicament curative effect enhancement after pharmaceutical carrier.Although the existence of above advantage, the practical application of liposome is still faced with problems.Be in particular in that liposome is in storage process, aggregation of particles and phospholipid are easy to the reasons such as oxydrolysis can make it destructurized; Enter after in body, due to the effect of the various materials such as the albumin in blood, opsonin, antibody, liposome may break, and causes the quick seepage of entrapped drug, very soon by some enzyme materials degraded and macrophage engulf, target tissue can not be arrived and play a role.Therefore, developing stable liposome is that it moves towards practical prerequisite as pharmaceutical carrier, and tool is of great significance.
Silica nodule is the novel organic-inorganic nanocomposite of a class, and it is by (Chemistry Letters, 1999,7, the 661-662) that connected the amphipathic molecule between silicate material and surfactant by covalent bond and construct.These materials have great development potentiality because hydridization precursor compound can form 3 D stereo network structure in self assembling process, and namely inorganic layer and organic group are covalently bound by stable Si-C key.A kind of novel organic-inorganic nano hybrid " silica nodule " of nearest exploitation derives from organosiloxane, by preparing in conjunction with sol-gel and self assembling process, vesicle (the Chemistry Letters of silicate network covering surfaces can be formed in aqueous medium, 1999,7,661-662).Silica nodule has a spherical lipid bilayer membrane structure, as liposome (Angewandte ChemieInternational Edition, 1992,31 that phospholipid or synthesis lipid are formed, 709-726), and difference be that its surface is also coated with silicate network structure.Silica nodule, due to the existence of surface silicates layer, makes its stability significantly improve.
Based on above consideration, the present inventor designs a class long circulating silica nodule, and such long circulating silica nodule forms the double-layer of lipoid imitated vesicle structure formed of lipid and long circulating functional molecular by silica nodule.The vesicle surface formed has stable Si-O-Si network structure, thus greatly strengthens its stability.In addition, the existence of long circulating functional molecular makes its biocompatibility and blood circulation time greatly improve.Can be used as the carrier of clinical treatment agent and medical science developing agent, there is good application prospect.
Summary of the invention
The object of this invention is to provide the long circulating silica nodule that a class is made up of complex lipid and long circulating functional molecular.
Another object of the present invention is to provide the preparation method of above-mentioned long circulating silica nodule.
Long circulating silica nodule of the present invention, is characterized in that described silica nodule forms lipid and can have following structure:
Wherein silica nodule formation complex lipid comprises three parts, and comprise inorganic precursor, linking group and hydrophobic tail, when m is 1, n is 2 or 3; When n is 2, m is 1,2 or 3, Y is that 1-11, Z are selected from-CH
3or-CH
3cH
2, X representative connects any group of inorganic precursor and hydrophobic tail.
Long circulating silica nodule of the present invention, is characterized in that described silica nodule forms lipid and also can have following structure:
Wherein R
1be selected from C6 ~ C18 alkyl; R
2be selected from C6 ~ C18 alkyl; R
3be selected from-CO (CH
2)
2cONH (CH
2)
3si (X)
3,-CO (CH
2)
3cONH (CH
2)
3si (X)
3or-CONH (CH
2)
3si (X)
3, wherein X is selected from ethyoxyl or methoxyl group; A is 2 or 3; X
1be selected from-H ,-CH
3, CH
3o-, halogeno-group or-NO
2; Y
1be selected from H ,-CH
3, CH
3o-or halogeno-group.
Long circulating silica nodule of the present invention, it is characterized in that described silica nodule forms lipid and also can have following structure:
Wherein R
1be selected from C6 ~ C18 alkyl; R
2be selected from C6 ~ C18 alkyl; R
3be selected from-CO (CH
2)
2cONH (CH
2)
3si (X)
3,-CO (CH
2)
3cONH (CH
2)
3si (X)
3or-CONH (CH
2)
3si (X)
3, wherein X is selected from ethyoxyl or methoxyl group; A is 2 or 3; X
2be selected from-H ,-CH3, CH3O-or halogeno-group; M is the metal ion with porphyrin ring coordination.
Long circulating silica nodule of the present invention, the long circulating functional molecular comprised in its structure can be polyethyleneglycol modified phospholipid, polyethyleneglycol modified ganglioside, polyethyleneglycol modified sorbitol ester, the various fatty acid esters of Polyethylene Glycol, PLGA-PEG-PLGA, PEG-PLGA, poloxamers etc. have the amphiphile, amphiphilic molecule of hydrophilic polyglycol structure, also can be the ganglioside that polyvinyl alcohol is modified, the sorbitol ester that polyvinyl alcohol is modified, the various fatty acid esters of polyvinyl alcohol, polyvinyl alcohol-copolymer of poly lactic acid, polyvinyl alcohol-polylactide co polymer etc. has the amphiphile, amphiphilic molecule of hydrophilic polyethene alcohol structure.
Long circulating functional molecular of the present invention, is characterized in that the molecular weight ranges of contained Polyethylene Glycol or polyvinyl alcohol is 2000-10000.
Long circulating silica nodule of the present invention can by alcohol injection or thin film aquation legal system standby.
The alcohol injection prepared long circulating silica nodule and adopt of the present invention, its process comprises the following steps: be dissolved in acidic ethanol by the silica nodule of certain molar percentage formation lipid and long circulating functional molecular, under stirring in water bath, above-mentioned acid ethanol solution is injected aqueous vehicles, blank long circulating silica nodule can be formed through water bath sonicator and Probe Ultrasonic Searching more afterwards.
The thin film aquation method prepared long circulating silica nodule and adopt of the present invention, its process comprises the following steps: be dissolved in acidic ethanol by the complex lipid of certain molar percentage and long circulating functional molecular, and vacuum removes organic solvent and dried overnight.Lipid membrane 45 DEG C of Water Unders in aqueous vehicles bathe 30 minutes, after can form blank long circulating silica nodule through water bath sonicator and Probe Ultrasonic Searching again.
Of the present inventionly prepare in long circulating silica nodule process, silicone grease body forms the molar percentage of lipid and long circulating functional molecular, it is characterized in that silicone grease body forms the molar percentage of lipid can be 95%-99%, and the molar percentage of long circulating functional molecular can be 5%-1%.
Advantage of the present invention is that its surface of long circulating silica nodule has silicate network structure and large hydrophilic molecular structure.Silicate network structure makes its stability be better than conventional liposome, and long circulating functional molecular makes its biocompatibility and blood circulation time significantly improve.In addition, described long circulating silica nodule preparation method is simple, and cost is low, can meet the requirement of industrialization.
Fig. 1 is the transmission electron microscope picture with the long circulating silica nodule prepared by thin film aquation method in specific embodiment 1; Fig. 2 is the stability experiment of the long circulating silica nodule of specific embodiment 3 correspondence, in Fig. 2, (1) represents the change of size of long circulating silica nodule when different multiples surfactant TX-100 exists, and in Fig. 2, (2) represent the change of size of liposome when different multiples surfactant TX-100 exists prepared by traditional liposomal DSPC.Fig. 3 is the vitality test result that long circulating silica nodule and people's venous endothelial cell hatch rear cell.The graph of a relation of silicone content and time in Fig. 4 rat blood.Table 1 is the pharmacokinetic parameters of silicone content in blood.
Will be described in detail below with reference to example of the present invention, following instance is only used for the present invention is described, instead of limits the scope of the invention.
In ensuing example, the silica nodule with following structure forms lipid (CFL) and is chosen as representative:
Long circulating functional molecular with DSPE-PEG 2000 (DSPE-PEG-2000) for representative.
Embodiment 1 thin film aquation legal system is for long circulating silica nodule (molar percentage of CFL: DSPE-PEG-2000 is 95%: 5%)
(1) material and consumption: (6ml silica nodule consumption)
CFL∶5mg，DSPE-PEG-2000∶1mg
(2) preparation method:
According to above, weigh various lipid, first CFL is hydrolyzed in acid ethanol solution.Hatch 30 minutes at 40 DEG C after, the chloroformic solution containing DSPE-PEG-2000 to be joined in the lipid be hydrolyzed in an acidic solution and Homogeneous phase mixing.Then solvent Rotary Evaporators is removed, bottle wall forms thin film, under vacuo further dried overnight.Afterwards, the ultra-pure water of 6 milliliters is joined in bottle, in the water-bath of 45 DEG C, hatch 30 minutes.By mixture vortex 20 minutes, use Probe Ultrasonic Searching 5-10 minute subsequently, until obtain as clear as crystal solution.Before measurement, gained solution is at room temperature hatched 24 hours.
The form of embodiment 2 long circulating silica nodule
The morphosis of long circulating silica nodule is observed by transmission electron microscope (TEM) and scanning electron microscope (SEM).The model of scanning electron microscope (SEM) is Hitachi S-3400N, operating voltage 15kV.The INSTRUMENT MODEL of transmission electron microscope (TEM) is H-7650, and its accelerating potential is 100kV.The preparation of TEM sample is in 300 object copper mesh by injection particle suspension liquid (300 micromoles/milliliter).After hatching 10 minutes, after sample is dry, at room temperature by 4% (W/V) acetic acid uranium aqueous solution negative staining 5 minutes of fresh preparation and aseptic filtration.Then by copper mesh distilled water wash twice, with dry in atmosphere before observation of use instrument.Its result as shown in Figure 1.Micro analysis clearly confirms the formation of spherical vesicles.
The stability of embodiment 3 long circulating silica nodule
The morphological stability of long circulating silica nodule is undertaken evaluating by the dissolution experiment of surfactant.Briefly, Triton X-100 is joined in long circulating silica nodule suspension prepared in embodiment 1; The hydrated diameter of vesicle is measured with DLS.Result as shown in Figure 2.When the non-ionic surface active agent Triton X-100 of nearly 5 times of equivalents joins in the conventional liposome prepared by distearoyl phosphatidylcholine (DSPC), the hydrated diameter of vesicle sharply reduces, and shows that vesicle is destroyed.In contrast, after the TX-100 of interpolation 30 times of equivalents, in DLS analysis display embodiment 1, the silica nodule size of preparation has almost no change.This shows, long circulating silica nodule has very high stability.
The biocompatibility of embodiment 4 long circulating silica nodule
5%CO at 37 DEG C
2in environment by Human umbilical vein endothelial cells with 1 × 10
4the density of individual cells/well is seeded in 96 orifice plates.There is no the hole of cell as blank.Cultivate after 24 hours, culture medium is replaced by the fresh culture containing variable concentrations long circulating silica nodule.Often kind of concentration joins as parallel control in three holes, without the hole of long circulating silica nodule as negative control.24,48, after 72 hours, join in each hole in the MTT solution of 20 microlitres, and hatch 4 hours.Then, removing culture medium, adds the DMSO solution of 150 microlitres.The absorbance in each hole, 560nm place is recorded in by microplate reader (Multidkan MK3, Thermo).As shown in Figure 3, the long circulating silica nodule prepared by example 1 demonstrates the cytotoxicity very low to Human umbilical vein endothelial cells.When concentration reaches 0.5 mg/ml, the survival rate of Human umbilical vein endothelial cells remains on 90%.This shows that long circulating silica nodule has higher biocompatibility.
The removing in blood of embodiment 5 long circulating silica nodule
Extracting male Wistar rat 3, tail vein injection saline, after 5min, heart extracting blood, is placed in centrifuge tube-20 DEG C of stored frozen of heparin process, for subsequent use.Extracting male Wistar rat 3, implements the operation of jugular vein intubate, fasting, freely drink water 12 hours after, tail vein injection long circulating silica nodule dispersion liquid (concentration: 20mg/mL, injected dose: 0.5mL/).Respectively at after administration 0.01,0.5,1,2,4,8,12,24,36,48h gets blood, the blood sample volume of each time point collection is 0.3ml, is placed in the centrifuge tube of heparin process, and-20 DEG C of stored frozen are for subsequent use.Often blood sampling point blood sample (300 μ L), is first mixed and heated to liquid with 1mL perchloric acid all dry.And then mix with 1mL concentrated nitric acid, be settled to 5mL heat 1h at 70 DEG C after as liquid to be measured.In sample, silicon content measures (Fig. 4) through inductivity coupled plasma mass spectrometry (ICP-MS).Non-compartment model kinetic parameter is as time and the half-life (T in silicon concentration maximum (Cmax), blood in blood needed for silicon concentration drop by half
1/2), software that the analysis of the major parameter such as area (AUCtot) under time of stopping in vivo of element silicon and average residence time (MRT) and time graph is used is KineticaTM (table 1).Result illustrates that this long circulating cholesterol silica nodule has longer circulation time in rat body.
Table 1
Claims (10)
1. a long circulating silica nodule, is characterized in that its composition is divided into silica nodule to form lipid and long circulating functional molecular.
2. long circulating silica nodule according to claim 1, is characterized in that described silica nodule forms lipid and can have following structure:
Wherein silica nodule formation complex lipid comprises three parts, and comprise inorganic precursor, linking group and hydrophobic tail, when m is 1, n is 2 or 3; When n is 2, m is 1,2 or 3, Y is that 1-11, Z are selected from-CH3 or-CH
3cH
2, X representative connects any group of inorganic precursor and hydrophobic tail.
3. long circulating silica nodule according to claim 1, is characterized in that described silica nodule forms lipid and also can have following structure:
Wherein R
1be selected from C
6~ C
18alkyl; R
2be selected from C
6~ C
18alkyl; R
3be selected from-CO (CH
2)
2cONH (CH
2)
3si (X)
3,-CO (CH
2)
3cONH (CH
2)
3si (X)
3or-CONH (CH
2)
3si (X)
3, wherein X is selected from ethyoxyl or methoxyl group; A is 2 or 3; X
1be selected from-H ,-CH
3, CH
3o-, halogeno-group or-NO
2; Y
1be selected from H ,-CH
3, CH
3o-or halogeno-group.
4. long circulating silica nodule according to claim 1, is characterized in that described silica nodule forms lipid and also can have following structure:
Wherein R
1be selected from C
6~ C
18alkyl; R
2be selected from C
6~ C
18alkyl; R
3be selected from-CO (CH
2)
2cONH (CH
2)
3si (X)
3,-CO (CH
2)
3cONH (CH
2)
3si (X)
3or-CONH (CH
2)
3si (X)
3, wherein X is selected from ethyoxyl or methoxyl group; A is 2 or 3; X
2be selected from-H ,-CH
3, CH
3o-or halogeno-group; M is the metal ion with porphyrin ring coordination.
5. long circulating silica nodule according to claim 1, the long circulating functional molecular comprised in its structure can be polyethyleneglycol modified phospholipid, polyethyleneglycol modified ganglioside, polyethyleneglycol modified sorbitol ester, the various fatty acid esters of Polyethylene Glycol, PLGA-PEG-PLGA, PEG-PLGA, poloxamers etc. have the amphiphile, amphiphilic molecule of hydrophilic polyglycol structure, also can be the ganglioside that polyvinyl alcohol is modified, the sorbitol ester that polyvinyl alcohol is modified, the various fatty acid esters of polyvinyl alcohol, polyvinyl alcohol-copolymer of poly lactic acid, polyvinyl alcohol-polylactide co polymer etc. has the amphiphile, amphiphilic molecule of hydrophilic polyethene alcohol structure.
6. the long circulating functional molecular described in claim 1 or 5, is characterized in that the molecular weight ranges of contained Polyethylene Glycol or polyvinyl alcohol is 2000-10000.
7. long circulating silica nodule according to claim 1 can by alcohol injection or thin film aquation legal system standby.
8. the alcohol injection prepared long circulating silica nodule and adopt according to claim 7, its process comprises the following steps: 1. the silica nodule of certain molar percentage formation lipid and long circulating functional molecular are dissolved in acidic ethanol.2. under stirring in water bath, above-mentioned acid ethanol solution is injected aqueous vehicles and can form blank long circulating silica nodule through water bath sonicator and Probe Ultrasonic Searching.
9. the thin film aquation method prepared long circulating silica nodule and adopt according to claim 7, its process comprises the following steps: be 1. dissolved in acidic ethanol by the complex lipid of certain molar percentage and long circulating functional molecular, and vacuum removes organic solvent and dried overnight.2. lipid membrane 45 DEG C of Water Unders in aqueous vehicles bathe 30 minutes, after can form blank long circulating silica nodule through water bath sonicator and Probe Ultrasonic Searching again.
10. the silica nodule described in claim 8 or 9 forms the molar percentage of lipid and long circulating functional molecular, and it is characterized in that the molar percentage of silica nodule formation lipid can be 95%-99%, the molar percentage of long circulating functional molecular can be 5%-1%.
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Cited By (3)
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| CN106834355A (en) * | 2015-12-07 | 2017-06-13 | 北京大学 | A kind of cation complex lipid nanometer plate and its production and use |
| CN109420181A (en) * | 2017-08-23 | 2019-03-05 | 北京大学 | It is a kind of for tumour fluorescence imaging and photo-thermal/optical dynamic therapy multifunctional nanoparticle |
| 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 |
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