CN102580109A - Anti-cancer drug carrier and method for producing same - Google Patents
Anti-cancer drug carrier and method for producing same Download PDFInfo
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Abstract
The invention discloses an anti-cancer drug carrier and a method for producing same. The key points of the technical scheme of the invention are that: the targeted anti-cancer drug carrier which has controllable sustainable drug release is a targeted microorganism body which contains calcium phosphate, and has a structure that the microorganism body wraps the calcium phosphate, and targeted molecules are then added at the outer part of the microorganism body. The invention also discloses the method for producing the targeted anti-cancer drug carrier which has controllable sustainable drug release. The anti-cancer drug carrier more pertinently treats cancer cells, has higher safety for the human body, and is non-toxic. The anti-cancer drug carrier has the advantages of simple production technology, strong innovation and practicability and the like.
Description
Technical field
The present invention relates to a kind of anti-cancer medicament carrier and technology of preparing thereof, particularly a kind of controlled sustainability and have anti-cancer medicament carrier of targeting property and preparation method thereof.
Background technology
Realizing that drug selectivity ground acts on diseased region, and accurately controlled release or slow release as required, prolong drug action time reduce input dosage under the prerequisite of curative effect satisfying, thereby alleviate toxic reaction, is the world of medicine's long-term aim.Carrier medicament combines pharmaceutics, material science and clinical medicine to grow up just for realizing this goal a kind of emerging form of medication.Controllable release is one of main target of inorganic nano pharmaceutical carrier research, and drug controllable release can alleviate medicine to Normocellular effect and reduce untoward reaction, improves drug effect, alleviates patient's misery.A kind of ideal pharmaceutical carrier need possess following performance: excellent biological compatibility; Sufficiently long blood circulation time; Targeted drug is to lesions position specifically; Stimulating responsive as along with pH or variation of temperature, slowly discharges medicine; Can in cell, carry medicine effectively, further get into specific organelle.
Mostly the material that is used for drug controllable release at present is high-molecular organic material, utilizes organic high molecular polymer to process sustained-release preparation as the carrier or the medium of active ingredient, thereby realizes the controllable release of active ingredient.Though the application of high-molecular organic material aspect controllable release makes significant progress with research; But because low, the poor chemical stability of organic material mechanical strength, part organic material biocompatibility are undesirable; Even certain toxicity is arranged, its application is limited to.As in the osteopathia therapeutic process, organic support material can't have the dual function of focus filling and medicament slow release concurrently.And inorganic bio has unique application prospect because of its excellent biological compatibility and biological degradability, and wherein, synthos especially receive extensive concern as the research of pharmaceutical carrier, have become one of focus in the lithotroph field of medical materials.Synthos have following advantage as pharmaceutical carrier: 1. close with skeleton, tooth composition, have excellent biological compatibility and biological degradability.In addition, an important chemical characteristic of synthos is exactly a pH sensitivity, is to receive the far-reaching inorganic matter of acid-base condition.Normal cell and tissue physiology's environment PH are 7.4, and under this environment, synthos are more stable, can not discharge contained medicine normal structure is worked the mischief.And the pH value of microenvironment is respectively 6 and 4.5 in outer microenvironment of general tumor tissues and the cancerous cell; Under this weak acid environment; Synthos can slowly be degraded and discharged its load cancer therapy drug, therefore, have the characteristic of controllable release medicine as anti-cancer medicament carrier with synthos.2. has unique loose structure; And have huge specific surface area and high surface as nano material; Biopharmaceutical macromolecular drugs such as ability adhesion and transferrin matter, polypeptide class, immunomodulator, vaccine; Medicine is slowly discharged from the carrier inside duct, and control drug release rate through changing porosity and aperture.3. chemical stability is fine, with many medicines chemically reactive not, can be used as the slow-released carrier of multiple medicine.4. itself also has antitumaous effect, makes it aspect treatment of cancer, have vast potential for future development.
The more important thing is that yeast parcel synthos make that as a kind of anti-cancer medicament carrier this pharmaceutical carrier is safer.Because yeast cells has double membrane structure, the good compatibility is not only arranged, and wrap synthos and carrying medicament thereof with yeast, avoided medicine seepage before being transported to the focus zone.Outside the yeast that has wrapped up synthos, add targeted molecular in addition, more targeted for the treatment of cancerous cell, further reduce side effect, improve drug effect.
So far do not see the report that is used for the controllable release cancer therapy drug about the targeted microorganisms body that contains synthos as anti-cancer medicament carrier.
Summary of the invention
The object of the invention is the anti-cancer medicament carrier that a kind of controlled sustainability is provided and has targeting property, and this anti-cancer medicament carrier has more specific aim for the treatment of cancerous cell, and human body is had higher safety, and the avirulence of carrier own.
Technical scheme of the present invention is; A kind of targeting antitumor pharmaceutical carrier with controlled sustainability drug release; It is characterized in that: this carrier is the targeted microorganisms body that contains synthos, and its structure is microbial body parcel synthos, and outside microbial body, adds targeted molecular.
Described anti-cancer medicament carrier is characterized in that: described microbial body is a yeast cells.
Described anti-cancer medicament carrier is characterized in that: described synthos are: tricalcium phosphate, tetracalcium phosphate, OCP, hydroxyapatite, calcium hydrogen phosphate, dalcium biphosphate or calcium pyrophosphate.
Described anti-cancer medicament carrier is characterized in that: described targeted molecular is: polypeptide, antibody or bio-ligand, described polypeptide are rgd peptide; Described antibody is altheine enzyme or pegaspargase; Described bio-ligand is a dextran; Carboxymethyl polysaccharide; Lactose; Enoxolone; Folic acid; Alendronic acid; Indomethacin; Triphenylphosphine; Chlorpropamide; N-(3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-morpholine propoxyl group) quinazoline-4-amine; 4-(4-methyl isophthalic acid-piperazine) methyl-N-4-methyl-3-4-(3-pyridine)-2-pyrimdinyl-amino phenyl-aniline methanesulfonic acid or N-(3-chloro-4-((3-fluorophenyl) methoxyl group) phenyl)-6-(5-(((2-(mesyl) ethyl) amino) methyl)-2-furyl)-4-quinazoline amine two tosilate.
A kind of preparation has the method for the targeting antitumor pharmaceutical carrier of controlled sustainability drug release, it is characterized in that preparation process is following: (1), yeast cells is cultivated: inoculate in single bacterium colony to the yeast cells culture medium, cell grows to the stable growth phase; (2), the ionic calcium soln of yeast and 10-200mmol/l puts into test tube, its mixed solution is put into jolting in the constant temperature shaking table, jolting speed 10-600r/min, temperature 10-60 ° of C, jolting time 1-120h; (3), centrifugal, the washing, the collecting precipitation part, the phosphate solution that adds 10-200mmol/l is afterwards put into jolting in the constant temperature shaking table, jolting speed 10-600r/min, temperature 10-60 ° of C, jolting time 1-120h; (4), centrifugal collecting precipitation, washing, drying, obtain the yeast cells of phosphoric acid calcium salt; (5), in the NaCl of 0.5mol/l aqueous solution, dispose the PAH solution of 5mg/ml and the PSS solution of 5mg/ml respectively; The yeast cells of phosphoric acid calcium salt is replaced in above-mentioned two kinds of solution that configure; Soak 5min in every kind of solution, washing is three times when changing other a kind of solution; (6), add targeted molecular.
The said method for preparing anti-cancer medicament carrier is characterized in that: said culture medium is: yeast extract powder peptone glucose (YPD) culture medium or Luria-Bertani (LB) culture medium.
The said method for preparing anti-cancer medicament carrier is characterized in that: said ionic calcium soln is: calcium chloride solution, calcium nitrate solution, calcium sulphate soln, calcium bicarbonate solution, aqua calcis or calcium acetate solution.
The said method for preparing anti-cancer medicament carrier is characterized in that: said phosphate solution is: sodium radio-phosphate,P-32 solution, disodium phosphate soln, sodium dihydrogen phosphate, potassium phosphate solution, dipotassium hydrogen phosphate solution, potassium dihydrogen phosphate, ammonium dihydrogen phosphate or ammonium dibasic phosphate solution.
The said method for preparing anti-cancer medicament carrier is characterized in that: the concentration of used targeted molecular is 0.1-5mol/L.
The useful effect that the present invention has is: (1), be reflected under the situation that microorganism participates in and in aqueous solution and saccharide solution, carry out mild condition, environmental friendliness; (2), be that a kind of cost is low, production technology simple to operate; (3), a kind of new experimental basis is provided, also important reference and directive function is provided to the mechanism in the research biosynthesis to the research of biological synthesis method; (4), the product of preparation has drug controllable sustainability and targeting property.In a word, the present invention has environmental friendliness, and the preparation process is simple, strong innovation, advantage such as practical.
Description of drawings
Fig. 1 is the HRTEM figure of the interior hydroxyapatite of resulting cell in the embodiment of the invention 1;
The specific embodiment mode
The present invention has following examples:
Embodiment 1:
At first, bakery yeast is cultivated: inoculate in single bacterium colony to the microbial cell culture medium, culture medium is the YPD culture medium, behind the cultivation 24h.Pour the calcium nitrate solution of 100mmol/l into, put into the constant temperature shaking table, in 30 ° of C of temperature, 30h vibrates under the speed of 200r/min vibration.Centrifuge washing three times, collecting precipitation adds the 50mmol/l sodium phosphate aqueous solution afterwards, and its mixed solution is put into the constant temperature shaking table, and in 30 ° of C of temperature, 60h vibrates under the speed of 200r/min vibration.After stopping to stir,, wash, can make the yeast cells of hydroxyl apatite the centrifugal collection of the product in the beaker.Fig. 1 is the HRTEM figure of hydroxyapatite in this cell, can find out that it is uniform nano-scale particle.In the NaCl of 0.5mol/l aqueous solution, dispose the PAH solution of 5mg/ml and the PSS solution of 5mg/ml respectively; The yeast cells of hydroxyl apatite is replaced in above-mentioned two kinds of solution that configure; Soak 5min in every kind of solution; Washing is three times when changing other a kind of solution, and outside one deck is the PAH film.Utilize the folic acid targeted molecular of electrostatic attraction mixing 5mol/l, centrifuge washing can obtain product.
Wherein, the YPD medium component is: yeast extract 10 g/l, peptone 20 g/l, glucose 20 g/l.
Embodiment 2:
At first, bakery yeast is cultivated: inoculate in single bacterium colony to the microbial cell culture medium, culture medium is the YPD culture medium; After cultivating 24h, pour the calcium chloride solution of 100mmol/l into, put into the constant temperature shaking table; In 40 ° of C of temperature, 60h vibrates under the speed of 200r/min vibration.Centrifuge washing three times, collecting precipitation adds the 50mmol/l ammonium dibasic phosphate aqueous solution afterwards, and its mixed solution is put into the constant temperature shaking table, and in 40 ° of C of temperature, 120h vibrates under the speed of 200r/min vibration.After stopping to stir,, wash, can make the yeast cells of phosphoric acid eight calcium the centrifugal collection of the product in the beaker.In the NaCl of 0.5mol/l aqueous solution, dispose the PAH solution of 5mg/ml and the PSS solution of 5mg/ml respectively; The yeast cells of phosphoric acid eight calcium is replaced in above-mentioned two kinds of solution that configure; Soak 5min in every kind of solution; Washing is three times when changing other a kind of solution, and outside one deck is the PAH film.Utilize the Alendronic Acid targeted molecular of electrostatic attraction mixing 5mol/l, centrifuge washing can obtain product.
Wherein, the YPD medium component is: yeast extract 10 g/l, peptone 20 g/l, glucose 20 g/l.
Embodiment 3:
At first, bakery yeast is cultivated: inoculate in single bacterium colony to the microbial cell culture medium, culture medium is the LB culture medium; After cultivating 24h, pour the calcium acetate solution of 50mmol/l into, put into the constant temperature shaking table; In 50 ° of C of temperature, 24h vibrates under the speed of 200r/min vibration.Centrifuge washing three times, collecting precipitation adds 100mmol/l sodium hydrogen phosphate aqueous solution afterwards, and its mixed solution is put into the constant temperature shaking table, and in 50 ° of C of temperature, 48h vibrates under the speed of 200r/min vibration.After stopping to stir,, wash, can make the yeast cells of phosphoric acid DFP the centrifugal collection of the product in the beaker.In the NaCl of 0.5mol/l aqueous solution, dispose the PAH solution of 5mg/ml and the PSS solution of 5mg/ml respectively; The yeast cells of phosphoric acid DFP is replaced in above-mentioned two kinds of solution that configure; Soak 5min in every kind of solution; Washing is three times when changing other a kind of solution, and outside one deck is the PAH film.Utilize the rgd peptide targeted molecular of electrostatic attraction mixing 5mol/l, centrifuge washing can obtain product.
Wherein, the LB medium component is: yeast extract 5 g/l, tryptone 10 g/l, sodium chloride 10 g/l.
Embodiment 4:
At first, bakery yeast is cultivated: inoculate in single bacterium colony to the microbial cell culture medium, culture medium is the YPD culture medium; After cultivating 24h, pour the calcium chloride solution of 100mmol/l into, put into the constant temperature shaking table; In 35 ° of C of temperature, 80h vibrates under the speed of 200r/min vibration.Centrifuge washing three times, collecting precipitation adds the 40mmol/l sodium phosphate aqueous solution afterwards, and its mixed solution is put into the constant temperature shaking table, and in 35 ° of C of temperature, 120h vibrates under the speed of 200r/min vibration.After stopping to stir,, wash, can make the yeast cells of hydroxyl apatite the centrifugal collection of the product in the beaker.In the NaCl of 0.5mol/l aqueous solution, dispose the PAH solution of 5mg/ml and the PSS solution of 5mg/ml respectively; The yeast cells of hydroxyl apatite is replaced in above-mentioned two kinds of solution that configure; Soak 5min in every kind of solution; Washing is three times when changing other a kind of solution, and outside one deck is the PAH film.Utilize the pegaspargase targeted molecular of electrostatic attraction mixing 5mol/l, centrifuge washing can obtain product.
Wherein, the YPD medium component is: yeast extract 10 g/l, peptone 20 g/l, glucose 20 g/l.
Embodiment 5:
At first, bakery yeast is cultivated: inoculate in single bacterium colony to the microbial cell culture medium, culture medium is the YPD culture medium; After cultivating 24h, pour the calcium chloride solution of 100mmol/l into, put into the constant temperature shaking table; In 45 ° of C of temperature, 30h vibrates under the speed of 200r/min vibration.Centrifuge washing three times, collecting precipitation adds the 100mmol/l sodium phosphate aqueous solution afterwards, and its mixed solution is put into the constant temperature shaking table, and in 45 ° of C of temperature, 50h vibrates under the speed of 200r/min vibration.After stopping to stir,, wash, can make the yeast cells of hydroxyl apatite the centrifugal collection of the product in the beaker.In the NaCl of 0.5mol/l aqueous solution, dispose the PAH solution of 5mg/ml and the PSS solution of 5mg/ml respectively; The yeast cells of hydroxyl apatite is replaced in above-mentioned two kinds of solution that configure; Soak 5min in every kind of solution; Washing is three times when changing other a kind of solution, and outside one deck is the PAH film.Utilize the indomethacin targeted molecular of electrostatic attraction mixing 5mol/l, centrifuge washing can obtain product.
Wherein, the YPD medium component is: yeast extract 10 g/l, peptone 20 g/l, glucose 20 g/l.
Embodiment 6:
At first, bakery yeast is cultivated: inoculate in single bacterium colony to the microbial cell culture medium, culture medium is the LB culture medium; After cultivating 24h, pour the calcium nitrate solution of 100mmol/l into, put into the constant temperature shaking table; In 55 ° of C of temperature, 30h vibrates under the speed of 200r/min vibration.Centrifuge washing three times, collecting precipitation adds the 100mmol/l sodium phosphate aqueous solution afterwards, and its mixed solution is put into the constant temperature shaking table, and in 55 ° of C of temperature, 20h vibrates under the speed of 200r/min vibration.After stopping to stir,, wash, can make the yeast cells of phosphoric acid eight calcium the centrifugal collection of the product in the beaker.In the NaCl of 0.5mol/l aqueous solution, dispose the PAH solution of 5mg/ml and the PSS solution of 5mg/ml respectively; The yeast cells of phosphoric acid eight calcium is replaced in above-mentioned two kinds of solution that configure; Soak 5min in every kind of solution; Washing is three times when changing other a kind of solution, and outside one deck is the PAH film.Utilize the chlorpropamide targeted molecular of electrostatic attraction mixing 5mol/l, centrifuge washing can obtain product.
Wherein, the LB medium component is: yeast extract 5 g/l, tryptone 10 g/l, sodium chloride 10 g/l.
Claims (9)
1. targeting antitumor pharmaceutical carrier with controlled sustainability drug release, it is characterized in that: this carrier is the targeted microorganisms body that contains synthos, its structure is microbial body parcel synthos, and outside microbial body, adds targeted molecular.
2. anti-cancer medicament carrier according to claim 1 is characterized in that: described microbial body is a yeast cells.
3. anti-cancer medicament carrier according to claim 1 is characterized in that: described synthos are: tricalcium phosphate, tetracalcium phosphate, OCP, hydroxyapatite, calcium hydrogen phosphate, dalcium biphosphate or calcium pyrophosphate.
4. anti-cancer medicament carrier according to claim 1 is characterized in that: described targeted molecular is: polypeptide, antibody or bio-ligand, described polypeptide are rgd peptide, and described antibody is altheine enzyme, pegaspargase; Described bio-ligand is a dextran; Carboxymethyl polysaccharide; Lactose; Enoxolone; Folic acid; Alendronic acid; Indomethacin; Triphenylphosphine; Chlorpropamide; N-(3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-morpholine propoxyl group) quinazoline-4-amine; 4-(4-methyl isophthalic acid-piperazine) methyl-N-4-methyl-3-4-(3-pyridine)-2-pyrimdinyl-amino phenyl-aniline methanesulfonic acid or N-(3-chloro-4-((3-fluorophenyl) methoxyl group) phenyl)-6-(5-(((2-(mesyl) ethyl) amino) methyl)-2-furyl)-4-quinazoline amine two tosilate.
5. method for preparing the described anti-cancer medicament carrier of claim 1 is characterized in that preparation process is following: (1), yeast cells is cultivated: inoculate in single bacterium colony to the yeast cells culture medium, cell grows to the stable growth phase; (2), the ionic calcium soln of yeast and 10-200mmol/l puts into test tube, its mixed solution is put into jolting in the constant temperature shaking table, jolting speed 100-600r/min, temperature 10-60 ° of C, jolting time 1-120h; (3), centrifugal, the washing, the collecting precipitation part, the phosphate solution that adds 10-200mmol/l is afterwards put into jolting in the constant temperature shaking table, jolting speed 100-600r/min, temperature 10-60 ° of C, jolting time 1-120h; (4), centrifugal collecting precipitation, washing, drying, obtain the yeast cells of phosphoric acid calcium salt; (5), in the NaCl of 0.5mol/l aqueous solution, dispose the PAH solution of 5mg/ml and the PSS solution of 5mg/ml respectively; The yeast cells of phosphoric acid calcium salt is replaced in above-mentioned two kinds of solution that configure; Soak 5min in every kind of solution, washing is three times when changing other a kind of solution; (6), add targeted molecular.
6. the method for preparing anti-cancer medicament carrier according to claim 5 is characterized in that: said culture medium is: yeast extract powder peptone dextrose culture-medium or Luria-Bertani culture medium.
7. the method for preparing anti-cancer medicament carrier according to claim 5 is characterized in that: said ionic calcium soln is: calcium chloride solution, calcium nitrate solution, calcium sulphate soln, calcium bicarbonate solution, aqua calcis or calcium acetate solution.
8. the method for preparing anti-cancer medicament carrier according to claim 5 is characterized in that: said phosphate solution is: sodium radio-phosphate,P-32 solution, disodium phosphate soln, sodium dihydrogen phosphate, potassium phosphate solution, dipotassium hydrogen phosphate solution, potassium dihydrogen phosphate, ammonium dihydrogen phosphate or ammonium dibasic phosphate solution.
9. the method for preparing anti-cancer medicament carrier according to claim 5 is characterized in that: the concentration of used targeted molecular is 0.1-5mol/l.
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| CN106344927A (en) * | 2016-09-27 | 2017-01-25 | 大连理工大学 | Folate-modified medicine-carrying hydroxylapatite and preparation method thereof |
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| CN114159466A (en) * | 2022-01-07 | 2022-03-11 | 浙江大学 | Hydroxyapatite/saccharomycete biological hybrid material and preparation method and application thereof |
| CN114159466B (en) * | 2022-01-07 | 2023-02-14 | 浙江大学 | Hydroxyapatite/saccharomycete biological hybrid material and preparation method and application thereof |
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| CN102580109B (en) | 2013-11-06 |
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