CN103432073A - Tumor-targeted nanometer preparation and preparation method thereof - Google Patents
Tumor-targeted nanometer preparation and preparation method thereof Download PDFInfo
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- CN103432073A CN103432073A CN2013104181177A CN201310418117A CN103432073A CN 103432073 A CN103432073 A CN 103432073A CN 2013104181177 A CN2013104181177 A CN 2013104181177A CN 201310418117 A CN201310418117 A CN 201310418117A CN 103432073 A CN103432073 A CN 103432073A
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Abstract
The invention relates to a tumor-targeted nanometer preparation and a preparation method thereof. The tumor-targeted nanometer preparation is prepared from the following components: active medicines, fat-soluble emulsifiers, oil-phase substrates, water-soluble proteins, polyethylene glycol materials, tumor-targeted oligopeptide and cross-linking agents. A core oil-phase can be used for remarkably improving the solubility of slightly-soluble active medicine and improving the medicine carrying capacity of the preparation; water-soluble protein shell can be used for remarkably improving the stability of the preparation and obtaining a good slow release effect by virtue of crosslinking; the preparation can be used for remarkably improving the tumor-targeting capacity after being modified by the tumor-targeted oligopeptide. The tumor-targeted nanometer preparation has the characteristics of high medicine carrying capacity, better stability in comparison with the normal nanoemulsion and high biocompatibility, has tumor targeting performance, and can be used for improving the curative effect of the medicine.
Description
Technical field: the present invention relates to a kind of novel nanometer that nano-emulsion is template of take with core-shell structure and pass drug carrier, there is the cancer target characteristic, belong to the research of novel nano targeted drug formulation art.
Background technology: at present, the nanoscale medicine delivery system of numerous kinds is developed, and its advantage comprises: (1) increases the dissolubility of insoluble drug; (2) improve medicine and see through cell biological film ability, improve and absorb and improve bioavailability; (3) control drug release and improve medicine stability; (4) targeting site-specific delivery of drugs, improve curative effect, reduces the toxic and side effects of medicine; (5) can change medicine pharmacokinetics character and in distribution of each organ or tissue etc.This class nano-carrier comprises liposome, nanoparticle, polymer micelle etc., although these carriers have solved the problem that medicinal application exists from some aspect, all has certain shortcoming, comprises that poor stability, drug loading are low etc.For example solid nanoparticle can only be at surperficial medicine carrying, and the stability that this has limited greatly drug loading and has reduced medicine can not discharge medicine flexibly.The drug loading of general nanoparticle and liposome can not surpass 10%, in order to reach therapeutic effect, must need to increase dosage or administration number of times, not only to sufferer, bring misery, due to the picked-up of more adjuvants, certainly will increase the system toxicity of preparation, bring drug risk.Microemulsion, nano-emulsion preparation can obtain higher drug loading by contrast, but the use of exhibiting high surface activating agent, cosurfactant has increased the potential toxicity of preparation, meanwhile the relatively poor easy breakdown of emulsion of its stability, gathering.
By contrast, the nano-carrier with core-shell structure is being exploited to solve the low shortcoming of passing carrier drug loading, and generally these carriers are all by forming with various material parcel colloidal particles or drop etc.Inspired by this, exploitation is intended in this research is a kind ofly to take nano-emulsion as basis, has the novel nano carrier of core-shell structure, and by medicine dissolution, in oil phase, forming nanoparticle is the medicine carrying kernel, realizes high drug load; Utilize the albumen clad surface to form hydrophilic protection softgel shell, lecithin is auxiliary simultaneously stablizes oil phase, and uses the alkaline-earth metal ions crosslinking protein, realizes high stability.Due to adding of cross-linking agent, surface forms firm softgel shell, and the sustained release performance of this nano-carrier is also carried greatly, and also has good biocompatibility as the albumen of capsule casing material, and the amino that surface protein is a large amount of and carboxyl also provide more decorating site.By tumor-targeting short peptide modified to surface protein have site on, thereby make nano-carrier there is the activity of cancer target, improve the accumulation of carrier at tumor locus, thereby improve the effect for the treatment of tumor.
Summary of the invention: the object of the invention is to provide a kind of nanometer formulation that passes through the mediated targeted tumor tissues of iRGD that utilizes albumen to have core-shell structure as stabilizing agent and preparation method thereof.The route of administration of said preparation is intravenous injection, for antineoplaston.
Technical scheme of the present invention is as follows:
The invention provides a kind of cancer target nanometer formulation, the ratio of weight and number of its key component and each component is: 1 part of active medicine, fat-soluble emulsifier 2-4 part, oil phase substrate 100-150 part, water-solubility protein 20-30 part, Polyethylene Glycol material part 0.3-0.6 part, cancer target small peptide 0.1-0.4 part, 0.004 part of cross-linking agent, wherein the ratio of weight and number of preferred key component is: 1 part of active medicine, 3.5 parts of fat-soluble emulsifiers, 135 parts of oil phase substrates, water-solubility protein 20-30 part, 0.45 part of Polyethylene Glycol material, 0.25 part of cancer target small peptide, 0.004 part of cross-linking agent.
Optional one or more from soybean oil, Semen Maydis oil, hydrogenated corn oil, soybean oil, Oleum Arachidis hypogaeae semen, olive oil, oleic acid polyethyleneglycol glyceride, linoleic acid polyethyleneglycol glyceride, Labraso, the saturated glyceride of ethoxylation, Miglyol 812N, medium chain triglycerides of described oil phase substrate, wherein preferred oil phase substrate is oleic acid polyethyleneglycol glyceride and soybean oil.
Described active medicine can be selected from one or more of paclitaxel, Docetaxel, irinotecan, 5-fluorouracil, carmustine, amycin, phenesterin, piposulfan, tamoxifen, lomustine, gamlogic acid, rubescensine A, podophyllotoxin, and wherein preferred active medicine is paclitaxel.
Described cross-linking agent is bivalence or trivalent metal ion, and wherein preferred cross-linking agent is calcium chloride.
Described fat-soluble emulsifier is a kind of of Ovum Gallus domesticus Flavus lecithin, soybean lecithin, polysorbate85, sorbester p18, sorbester p17, two ethyl stearte base ethoxy methylsulfuric acid ammonium methyl, oil-soluble lanoline, and wherein preferred fat-soluble emulsifier is Ovum Gallus domesticus Flavus lecithin.
Optional one or more in Semen sojae atricolor protein isolate, whey isolate protein, beta lactoglobulin, gamma globulin, bovine serum albumin, alpha-lactalbumin, 11s glycinin, b-companion globulin, human albumin of described water-solubility protein, wherein preferred water-solubility protein is beta lactoglobulin, soybean protein isolate and whey isolate protein.
Described Polyethylene Glycol material is maleimide-Polyethylene Glycol-butanimide (MAL-PEG-NHS).
Described small peptide can be selected from a kind of in iRGD (aminoacid sequence is CRGDKGPDC), F3 (aminoacid sequence is CKDEPQRRSARLSAKPAPPKPEPKPKKAPAKK), Angiopep-2 (aminoacid sequence is TFFYGGSRGKRNNFKTEEY), and wherein preferred cancer target small peptide is the iRGD peptide.
The present invention also provides the preparation method of described cancer target nanometer formulation, and it is made by following steps:
(1) utilize and ultrasonicly medicine, cross-linking agent and fat-soluble emulsifier are dissolved in to oil phase substrate to form oil phase stand-by;
(2) water-solubility protein is dissolved in pure water, after the boiling water bath degeneration, cooling adjusting pH value, to 6.0-11.0, forms water stand-by;
(3) after above-mentioned oil phase, water are mixed, high speed dispersion high pressure homogenize, add hydroxyethyl piperazine second sulfacid buffer salt, obtains reactant liquor one;
(4) iRGD and NHS-PEG-MAL are dissolved in hydroxyethyl piperazine second sulfacid buffer, regulate pH value to 7.0 stirring reaction in 4 ℃ of nitrogen environments and within 12 hours, obtain reactant liquor two;
(5) reactant liquor two is joined in reactant liquor one again, regulate pH value to 8.5, under 4 ℃ of conditions, stirring reaction is 2 hours.
The present invention finally provides the application of described cancer target nanometer formulation in preparing anti-tumor medicinal preparation.
The present invention utilizes the Polyethylene Glycol material (NHS-PEG-MAL) with bifunctional group that the cancer target small peptide is connected with albumen.The functional group of the Polyethylene Glycol material of bifunctional group comprises succinimido and dimaleoyl imino, wherein dimaleoyl imino reacts bonding with the sulfydryl in the target short peptide aminoacid sequence under the condition of pH6.8-7.2, and succinimido reacts bonding with the amino in the water-solubility protein aminoacid sequence under the condition of pH8.0-9.0.
Beneficial effect: the kernel oil phase can improve the dissolubility of slightly solubility active medicine significantly, improves the Drug loading capacity of preparation; The water-solubility protein shell can improve significantly the stability of preparation and obtain slow release effect preferably through crosslinked; Preparation can significantly improve the cancer target ability after cancer target is short peptide modified.
The accompanying drawing explanation:
Fig. 1 is the particle size distribution figure that embodiment 1 makes the cancer target nanometer formulation
Fig. 2 is the Zero Energy Thermonuclear Assembly (Zeta) potential diagram that embodiment 1 makes the cancer target nanometer formulation
Fig. 3 is the scanning electron microscope (SEM) photograph that embodiment 1 makes the cancer target nanometer formulation
Fig. 4 is the transmission electron microscope picture that embodiment 1 makes the cancer target nanometer formulation
Fig. 5 is the curve chart that embodiment 1 makes cancer target nanometer formulation, commercially available formulation for paclitaxel inhibition tumor growth.
The specific embodiment:
Prescription:
Preparation method:
15mg paclitaxel and 52.5mg Ovum Gallus domesticus Flavus lecithin are joined in 2ml oleic acid polyethyleneglycol glyceride, ultrasonic to clear, add 60 μ l calcium chloride solutions (4M), vortex 5 minutes.The 300mg beta lactoglobulin is added in the 15ml pure water, stir 30 minutes.After dissolving fully, the airtight boiling water bath that is placed in heats 30 minutes, within every 10 minutes, takes out and stirs 30 seconds.Add the 15ml pure water after cooling, with the 0.5M sodium hydroxide solution, regulate pH to 9.0.Add subsequently the oil phase that vortex is good, disperse 30 seconds with high speed disperser 10000rpm, and with high pressure homogenizer under the 700bar condition, homogenizing 120 seconds, adding hydroxyethyl piperazine second sulfacid buffer salt to make final concentration is 20mM, obtains reactant liquor one.3.75mgiRGD and 6.75mgNHS-PEG-MAL are dissolved in 0.5ml hydroxyethyl piperazine second sulfacid buffer (20mM), regulate pH value to 7.0 stirring reaction in 4 ℃ of nitrogen environments and within 12 hours, obtain reactant liquor two.Reactant liquor two is joined in 2ml reactant liquor one again, with the 0.5M sodium hydroxide, regulate pH value to 8.5, under 4 ℃ of conditions, stirring reaction is 2 hours, and finally obtains target product.
In embodiment 1-embodiment 6, preparation-obtained cancer target nanometer formulation utilizes dynamic light scattering nanometer particle size instrument to measure particle diameter, particle diameter polydispersity coefficient and Zero Energy Thermonuclear Assembly (Zeta) current potential; Utilize scanning electron microscope and transmission electron microscope to be characterized.In embodiment 1, preparation-obtained cancer target nanometer formulation particle diameter is 206.3 ± 3.1nm, and polydispersity coefficient is 0.142 ± 0.031, and the Zero Energy Thermonuclear Assembly (Zeta) current potential is-33.41 ± 2.06mV (as shown in Figure 1 and Figure 2).Its mode of appearance as shown in Figure 3, Figure 4.
The mice that utilizes the tumor heterotopic transplantation is investigated the antitumous effect of the cancer target nanometer formulation for preparing in embodiment 1, and result as shown in Figure 5.The inhibition tumor growth effect of the cancer target nanometer formulation the present invention relates to is significantly higher than commercial preparation.
Embodiment 2
Prescription:
Preparation method:
15mg paclitaxel and 52.5mg Ovum Gallus domesticus Flavus lecithin are joined in the 2ml soybean oil, ultrasonic to clear, add 60 μ l calcium chloride solutions (4M), vortex 5 minutes.The 300mg beta lactoglobulin is added in the 15ml pure water, stir 30 minutes.After dissolving fully, the airtight boiling water bath that is placed in heats 30 minutes, within every 10 minutes, takes out and stirs 30 seconds.Add the 15ml pure water after cooling, with the 0.5M sodium hydroxide solution, regulate pH to 9.0.Add subsequently the oil phase that vortex is good, disperse 30 seconds with high speed disperser 10000rpm, and with high pressure homogenizer under the 700bar condition, homogenizing 120 seconds, adding hydroxyethyl piperazine second sulfacid buffer salt to make final concentration is 20mM, obtains reactant liquor one.3.75mgiRGD and 6.75mgNHS-PEG-MAL are dissolved in 0.5ml hydroxyethyl piperazine second sulfacid buffer (20mM), regulate pH value to 7.0 stirring reaction in 4 ℃ of nitrogen environments and within 12 hours, obtain reactant liquor two.Reactant liquor two is joined in 2ml reactant liquor one again, with the 0.5M sodium hydroxide, regulate pH value to 8.5, under 4 ℃ of conditions, stirring reaction is 2 hours, and finally obtains target product.
Embodiment 3
Prescription:
Preparation method:
15mg paclitaxel and 52.5mg Ovum Gallus domesticus Flavus lecithin are joined in 2ml oleic acid polyethyleneglycol glyceride, ultrasonic to clear, add 60 μ l calcium chloride solutions (4M), vortex 5 minutes.The 450mg whey isolate protein is added in the 15ml pure water, stir 30 minutes.After dissolving fully, the airtight boiling water bath that is placed in heats 30 minutes, within every 10 minutes, takes out and stirs 30 seconds.Add the 15ml pure water after cooling, with the 0.5M sodium hydroxide solution, regulate pH to 9.0.Add subsequently the oil phase that vortex is good, disperse 30 seconds with high speed disperser 10000rpm, and with high pressure homogenizer under the 700bar condition, homogenizing 120 seconds, adding hydroxyethyl piperazine second sulfacid buffer salt to make final concentration is 20mM, obtains reactant liquor one.3.75mgiRGD and 6.75mgNHS-PEG-MAL are dissolved in 0.5ml hydroxyethyl piperazine second sulfacid buffer (20mM), regulate pH value to 7.0 stirring reaction in 4 ℃ of nitrogen environments and within 12 hours, obtain reactant liquor two.Reactant liquor two is joined in 2ml reactant liquor one again, with the 0.5M sodium hydroxide, regulate pH value to 8.5, under 4 ℃ of conditions, stirring reaction is 2 hours, and finally obtains target product.
Embodiment 4
Prescription:
Preparation method:
15mg paclitaxel and 52.5mg Ovum Gallus domesticus Flavus lecithin are joined in 2ml oleic acid polyethyleneglycol glyceride, ultrasonic to clear, add 60 μ l calcium chloride solutions (4M), vortex 5 minutes.The 450mg beta lactoglobulin is added in the 15ml pure water, stir 30 minutes.After dissolving fully, the airtight boiling water bath that is placed in heats 30 minutes, within every 10 minutes, takes out and stirs 30 seconds.Add the 15ml pure water after cooling, with the 0.5M sodium hydroxide solution, regulate pH to 9.0.Add subsequently the oil phase that vortex is good, disperse 30 seconds with high speed disperser 10000rpm, and with high pressure homogenizer under the 700bar condition, homogenizing 120 seconds, adding hydroxyethyl piperazine second sulfacid buffer salt to make final concentration is 20mM, obtains reactant liquor one.3.75mgiRGD peptide and 6.75mgNHS-PEG-MAL are dissolved in 0.5ml hydroxyethyl piperazine second sulfacid buffer (20mM), regulate pH value to 7.0 stirring reaction in 4 ℃ of nitrogen environments and within 12 hours, obtain reactant liquor two.Reactant liquor two is joined in 2ml reactant liquor one again, with the 0.5M sodium hydroxide, regulate pH value to 8.5, under 4 ℃ of conditions, stirring reaction is 2 hours, and finally obtains target product.
Prescription:
Preparation method:
15mg paclitaxel and 52.5mg Ovum Gallus domesticus Flavus lecithin are joined in the 2ml soybean oil, ultrasonic to clear, add the saturated calcium chloride solution of 60 μ l (4M), vortex 5 minutes.The 450mg soybean protein isolate is added in the 15ml pure water, stir 30 minutes.After dissolving fully, the airtight boiling water bath that is placed in heats 30 minutes, within every 10 minutes, takes out and stirs 30 seconds.Add the 15ml pure water after cooling, with the 0.5M sodium hydroxide solution, regulate pH to 9.0.Add subsequently the oil phase that vortex is good, disperse 30 seconds with high speed disperser 10000rpm, and with high pressure homogenizer under the 700bar condition, homogenizing 120 seconds, adding hydroxyethyl piperazine second sulfacid buffer salt to make final concentration is 20mM, obtains reactant liquor one.3.75mgiRGD and 6.75mgNHS-PEG-MAL are dissolved in 0.5ml hydroxyethyl piperazine second sulfacid buffer (20mM), regulate pH value to 7.0 stirring reaction in 4 ℃ of nitrogen environments and within 12 hours, obtain reactant liquor two.Reactant liquor two is joined in 2ml reactant liquor one again, with the 0.5M sodium hydroxide, regulate pH value to 8.5, under 4 ℃ of conditions, stirring reaction is 2 hours, and finally obtains target product.
Prescription:
Preparation method:
15mg paclitaxel and 52.5mg Ovum Gallus domesticus Flavus lecithin are joined in the 2ml soybean oil, ultrasonic to clear, add the saturated calcium chloride solution of 60 μ l (4M), vortex 5 minutes.The 300mg whey isolate protein is added in the 15ml pure water, stir 30 minutes.After dissolving fully, the airtight boiling water bath that is placed in heats 30 minutes, within every 10 minutes, takes out and stirs 30 seconds.Add the 15ml pure water after cooling, with the 0.5M sodium hydroxide solution, regulate pH to 9.0.Add subsequently the oil phase that vortex is good, disperse 30 seconds with high speed disperser 10000rpm, and with high pressure homogenizer under the 700bar condition, homogenizing 120 seconds, adding hydroxyethyl piperazine second sulfacid buffer salt to make final concentration is 20mM, obtains reactant liquor one.3.75mgiRGD peptide and 6.75mgNHS-PEG-MAL are dissolved in 0.5ml hydroxyethyl piperazine second sulfacid buffer (20mM), regulate pH value to 7.0 stirring reaction in 4 ℃ of nitrogen environments and within 12 hours, obtain reactant liquor two.Reactant liquor two is joined in 2ml reactant liquor one again, with the 0.5M sodium hydroxide, regulate pH value to 8.5, under 4 ℃ of conditions, stirring reaction is 2 hours, and finally obtains target product.
Claims (10)
1. a cancer target nanometer formulation, it is characterized in that, the ratio of weight and number of its key component and each component is: 1 part of active medicine, fat-soluble emulsifier 2-4 part, oil phase substrate 100-150 part, water-solubility protein 20-30 part, Polyethylene Glycol material part 0.3-0.6 part, cancer target small peptide 0.1-0.4 part, 0.004 part of cross-linking agent, wherein the ratio of weight and number of preferred key component is: 1 part of active medicine, 3.5 parts of fat-soluble emulsifiers, 135 parts of oil phase substrates, water-solubility protein 20-30 part, 0.45 part of Polyethylene Glycol material, 0.25 part of cancer target small peptide, 0.004 part of cross-linking agent.
2. cancer target nanometer formulation according to claim 1, it is characterized in that, optional one or more from soybean oil, Semen Maydis oil, hydrogenated corn oil, soybean oil, Oleum Arachidis hypogaeae semen, olive oil, oleic acid polyethyleneglycol glyceride, linoleic acid polyethyleneglycol glyceride, Labraso, the saturated glyceride of ethoxylation, Miglyol 812N, medium chain triglycerides of described oil phase substrate, wherein preferred oil phase substrate is oleic acid polyethyleneglycol glyceride and soybean oil.
3. cancer target nanometer formulation according to claim 1, it is characterized in that, described active medicine can be selected from one or more of paclitaxel, Docetaxel, irinotecan, 5-fluorouracil, carmustine, amycin, phenesterin, piposulfan, tamoxifen, lomustine, gamlogic acid, rubescensine A, podophyllotoxin, and wherein preferred active medicine is paclitaxel.
4. cancer target nanometer formulation according to claim 1, is characterized in that, described cross-linking agent is bivalence or trivalent metal ion salts, and wherein preferred cross-linking agent is calcium chloride.
5. cancer target nanometer formulation according to claim 1, it is characterized in that, described fat-soluble emulsifier can be selected from a kind of of Ovum Gallus domesticus Flavus lecithin, soybean lecithin, polysorbate85, sorbester p18, sorbester p17, two ethyl stearte base ethoxy methylsulfuric acid ammonium methyl, oil-soluble lanoline, and wherein preferred fat-soluble emulsifier is Ovum Gallus domesticus Flavus lecithin.
6. cancer target nanometer formulation according to claim 1, it is characterized in that, optional one or more from Semen sojae atricolor protein isolate, whey isolate protein, beta lactoglobulin, gamma globulin, bovine serum albumin, alpha-lactalbumin, 11s glycinin, b-companion globulin, human albumin of described water-solubility protein, wherein preferred water-solubility protein is beta lactoglobulin, soybean protein isolate and whey isolate protein.
7. cancer target nanometer formulation according to claim 1, is characterized in that, described Polyethylene Glycol material is maleimide-Polyethylene Glycol-butanimide (MAL-PEG-NHS).
8. cancer target nanometer formulation according to claim 1, it is characterized in that, described cancer target small peptide can be selected from a kind of in iRGD (aminoacid sequence is CRGDKGPDC), F3 (aminoacid sequence is CKDEPQRRSARLSAKPAPPKPEPKPKKAPAKK), Angiopep-2 (aminoacid sequence is TFFYGGSRGKRNNFKTEEY), and wherein preferred cancer target small peptide is the iRGD peptide.
9. the preparation method of cancer target nanometer formulation according to claim 1, is characterized in that, it is made by following steps:
(1) utilize and ultrasonicly medicine, cross-linking agent and fat-soluble emulsifier are dissolved in to oil phase substrate to form oil phase stand-by;
(2) water-solubility protein is dissolved in pure water, after the boiling water bath degeneration, cooling adjusting pH value, to 6.0-11.0, forms water stand-by;
(3) after above-mentioned oil phase, water are mixed, high speed dispersion high pressure homogenize, add hydroxyethyl piperazine second sulfacid buffer salt, obtains reactant liquor one;
(4) iRGD and NHS-PEG-MAL are dissolved in hydroxyethyl piperazine second sulfacid buffer, regulate pH value to 7.0 stirring reaction in 4 ℃ of nitrogen environments and within 12 hours, obtain reactant liquor two;
(5) reactant liquor two is joined in reactant liquor one again, regulate pH value to 8.5, under 4 ℃ of conditions, stirring reaction is 2 hours.
10. the application of cancer target nanometer formulation according to claim 1, is characterized in that, the application of described nanometer formulation in preparing anti-tumor medicinal preparation.
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| CN106924731A (en) * | 2015-12-30 | 2017-07-07 | 复旦大学 | One kind is based on PDT and chemotherapeutic combination tumor targeted therapy system |
| CN108159396A (en) * | 2018-01-26 | 2018-06-15 | 广州加原医药科技有限公司 | A kind of phycocyanin nanometer formulation and preparation method thereof |
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| CN108853054A (en) * | 2018-06-29 | 2018-11-23 | 天津中医药大学 | A kind of gambogicacid nano structured lipid carrier and preparation method thereof of cyclic peptide modification |
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| CN106220735A (en) * | 2015-09-11 | 2016-12-14 | 中山大学 | A kind of preparation and application of cathepsin B activation type targeting anti-tumor polypeptide |
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| CN108309943A (en) * | 2018-04-02 | 2018-07-24 | 中国药科大学 | A kind of compound preparation based on drug granule |
| CN108309943B (en) * | 2018-04-02 | 2021-05-04 | 中国药科大学 | Compound preparation based on medicine particles |
| CN108853054A (en) * | 2018-06-29 | 2018-11-23 | 天津中医药大学 | A kind of gambogicacid nano structured lipid carrier and preparation method thereof of cyclic peptide modification |
| CN110872341A (en) * | 2019-12-10 | 2020-03-10 | 温州医科大学 | FGFR 1-targeted antagonistic short peptide |
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Application publication date: 20131211 |