CN101721709A - Calcium phosphate and amphiphilic polymer composite medicament-carrying nano-microsphere, preparation method and application - Google Patents
Calcium phosphate and amphiphilic polymer composite medicament-carrying nano-microsphere, preparation method and application Download PDFInfo
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Abstract
The invention relates to a calcium phosphate and amphiphilic polymer composite medicament-carrying nano-microsphere, a preparation method and application in medicament carriers. Specifically, the calcium phosphate and amphiphilic polymer composite medicament-carrying nano-microsphere can carry different kinds of medicaments; the medicament-carrying nano-microsphere is modified by a modifier to have multi-functional characteristics such as tumor targeting function, reversing medicament-resistant function and medical diagnosis function; and the application of the composite medicament-carrying nano-microsphere comprises diagnosis and therapy for diseases. The calcium phosphate and amphiphilic polymer composite medicament-carrying nano-microsphere has the advantages of simple preparation, high bioavailability, strong sustained-release function, controllable degradation time, good biocompatibility of materials and the like, and has stronger medicinal therapy and diagnosis functions and can be used as a safe and effective clinical medicament.
Description
Technical field
The invention belongs to fields of nano material application, be specifically related to calcium phosphate and amphiphilic polymer composite medicament-carrying nano-microsphere, preparation method and be used to prepare carrier medicament.
Background technology
The route of administration and the method for pharmaceutical preparation are most important to drug effect, are important research project of field of medicaments and improve the utilization rate and the curative effect of medicine and reduce side effects of pharmaceutical drugs always.Nano medicament carrying system is the main application form of nanotechnology aspect drug conveying, controlled release, it is meant adopts suitable pharmaceutics technology and method that medicine and pharmaceutic adjuvant are made the colloidal state grain drug-supplying system of particle diameter in the 1-1000nm scope, comprise nanoparticle, primitive forms such as nanosphere, nanocapsule.Active component (medicine, bioactive substance etc.) is distributed in particle inside by dissolving, package action or is positioned at the surface of particle by adsorption.Nano-carrier has height targeting, medicine sustained release, improves the advantage that indissoluble is separated medicine dissolution rate and absorbance, can increase medicine stability, raising curative effect of medication and reduction toxic and side effects in vivo.Simultaneously can join specific targeted molecular,, combine with the cell surface specific receptor, realize three grades of targeted of gene/medicine by targeted molecular as ligands specific, monoclonal antibody etc. at the nano grain surface coupling.
Polymer and polymer latex beam system mainly comprise amphiphilic polymer of modification and block copolymer.The supramolecular aggregation with hydrophobic cores and hydrophilic shell that microphase-separated forms takes place in aqueous medium by amphipathic nature polyalcohol.This nano-micelle in pharmaceutical field mainly as the solubilization carrier of insoluble drug; avoid the agent of micromolecule surface active agent solubilization (as tween; polyoxyethylene castor oil) untoward reaction; its hydrophobic kernel can also protect medicine not degrade; and the control drug slow discharges; the hydrophilic shell then helps the long-time circulation of nano-micelle in blood to reach tumor; the targeting of tissue such as inflammation; many new synthetic multifunctional polymer micellar system have appearred in recent years; it not only can be used as the gene delivery system, and can also realize that carrying altogether of indissoluble water medicine and gene is total to treatment.Polymer micelle is mainly the physical method that is insoluble in the water drug encapsulation: direct dissolution method, dialysis and emulsion process.Choosing of method depends primarily on the dissolubility of amphipathic copolymer in water.Good water solubility then adopts direct dissolution method, otherwise adopts dialysis.Medicine can be written into micellar kernel by methods such as physically trapping and chemical bond.
Calcium phosphate is subjected to using widely because of the characteristic with excellent biological compatibility, degradability, bone conduction and synosteosis ability and safety non-toxic.The performance of calcium phosphate depends on its factors such as pattern, thing phase, structure and degree of crystallinity again to a great extent, and the compound good characteristic of high polymer can the introducing of calcium phosphate and polymer prepares the Nano microsphere that pattern is controlled, medicine carrying is powerful in the middle of the Calcium Phosphate System.People such as Zhang are that end-capping reagent has prepared higher hydroxyapatite (HAP) nanometer rods [Zhang YJ, the Lu JJ.Crystal Growth ﹠amp of specific surface area with polyvinylpyrrolidone (PVP); Design, 2008,8 (7): 2101-2107]; People such as Zhu are in water/glycol system, with micromolecule surfactant sodium lauryl sulphate (SDS) is that the pattern adjusting control agent has prepared flower-shaped calcium hydrogen phosphate, and it is changed into HAP and make its pattern well be kept [Ma MG, Zhu YJ and Chang J.J.Phys.Chem.B, 2006,110:14226-14230]; Mann etc. are template with the polyacrylic acid (PAA) that is the nanocages state in aqueous solution, prepared polymer/calcium phosphate composite Nano capsule by biomineralization, this material has characteristic [the Perkin KK of pH response, Turner JL, Wooley KL and MannS.Nano Let ters, 2005,5 (7): 1457-1461].
Summary of the invention
The present invention aims to provide the purposes of a kind of calcium phosphate and amphiphilic polymer composite medicament-carrying nano-microsphere, preparation method and preparation carrier medicament, and wherein nano-particle is by amphiphilic copolymer and calcium phosphate [Ca
3(PO
4)
2] complex formed.
The composite medicament-carrying nano-microsphere of calcium phosphate provided by the present invention and amphipathic nature polyalcohol, the wherein complex formed by amphipathic nature polyalcohol and calcium phosphate of Nano microsphere, and bag medicine carrying thing; The percentage by weight of described amphipathic nature polyalcohol, calcium phosphate and the medicine carrying thing that wraps is followed successively by 1%-60%, 0.1%-60% and 0.1%-50%; The particle diameter of described calcium phosphate and amphipathic nature polyalcohol composite nano-microsphere between 1-100000nm, the preferred 5-5000nm of particle diameter wherein.
Calcium phosphate of the present invention and amphiphilic polymer composite medicament-carrying nano-microsphere, it is characterized in that the described Nano microsphere of forming by amphipathic nature polyalcohol and calcium phosphate form and preparation method is preferably as follows:
Under 0～60 ℃, amphipathic nature polyalcohol is added in the water, is mixed with mass fraction and is 0.1～5% solution A; In solution A, add soluble calcium salt CaCl
2, stirring and forming calcium ion concentration is the solution B of 0.005～1M; In solution B, drip or pour into the soluble phosphoric acid saline solution (NH that concentration is 0.005～1M
4)
2HPO
4, making calcium ion and phosphate anion mol ratio is 1: 1～1.67: 1, pH value is controlled at 7～12 simultaneously; Continue stirring reaction, then with the centrifugal collection of milky reactant liquor, with deionized water and dehydrated alcohol cyclic washing, vacuum drying obtains calcium phosphate/amphipathic nature polyalcohol composite porous nanoparticles.
Calcium phosphate of the present invention and amphiphilic polymer composite medicament-carrying nano-microsphere, it is characterized in that calcium phosphate and amphipathic nature polyalcohol composite nano-microsphere not only comprise absorption method and solvent evaporation method to the bag support method of medicine, also comprise dialysis, pH gradient method, multi-emulsion method, complex coacervation etc., its bag to medicine carries order can be in the preparation process of calcium phosphate and amphipathic nature polyalcohol composite nano-microsphere preparation back or Nano microsphere, as can preparing drug-carrying polymer micelle earlier, and then with the compound preparation medicine carrying of calcium phosphate micro-nano ball.
Main method wherein is preferably as follows:
(1) bag medicine carrying thing in the Nano microsphere preparation process
Method for optimizing wherein contains the solution A 1 of the medicine that amphiphilic polymers that percentage by weight is 0.1-5% and percentage by weight be 0.1-5% for configuration earlier; Or configuration contains the amphiphilic polymers nanoparticle of bag medicine carrying thing, prepares the amphiphilic polymers nanoparticle solution A 2 that medicine carrying that percentage by weight is 0.1-5% and percentage by weight are 0.1-5% then; In solution A 1 or A2, add soluble calcium salt CaCl respectively again
2, stir 0.5-24h, forming calcium ion concentration is the solution B of 0.005-1mol/L; Adding concentration in the solution B then is (the NH of 0.005-1mol/L
4)
2HPO
4Solution, (NH
4)
2HPO
4Solution and solution B volume ratio are 1/3-3/3, use ammonia to regulate pH value and are 7-12, continue stirring reaction 0-24h, centrifugal collection, and washing, drying obtains calcium phosphate and amphiphilic polymer composite medicament-carrying nano-microsphere.
(2) bag medicine carrying thing after the Nano microsphere preparation
Bag support method to water soluble drug is preferably:
At room temperature with exsiccant calcium phosphate and amphipathic nature polyalcohol composite nano-microsphere and the aqueous solution that contains water soluble drug, the weight percent concentration of described calcium phosphate and amphipathic nature polyalcohol composite nano-microsphere and water soluble drug is respectively 0.1-99% and 0.1-50%, stir 0.5-24h, the calcium phosphate and the amphipathic nature polyalcohol composite nano-microsphere of centrifugal collection bag medicine carrying thing.
Bag support method to fat-soluble medicine is preferably:
In the mixed solvent that elder generation is water-soluble with fat-soluble medicine (weight percent concentration 0.1-30%) and ethanol is formed, described water and alcoholic acid volume ratio are 1/3-4/3; Add exsiccant calcium phosphate and the compound porous Nano microsphere of amphipathic copolymer then, the weight percent concentration of described calcium phosphate and amphipathic nature polyalcohol composite nano-microsphere and water soluble drug is respectively 0.1-99% and 0.1-50%, stir 0.5-24h, the calcium phosphate and the amphipathic nature polyalcohol composite nano-microsphere of centrifugal collection bag medicine carrying thing.
Solvent evaporated method preferred version wherein is:
Earlier fat-soluble medicine (weight percent concentration 0.1-30%) is dissolved in the organic solvent such as chloroform oil phase, water will be got then in exsiccant calcium phosphate and the water-soluble solution of amphipathic nature polyalcohol composite nano-microsphere, at last water and oil phase are mixed stirring, the weight percent concentration of described calcium phosphate and amphipathic nature polyalcohol composite nano-microsphere and water soluble drug is respectively 0.1-99% and 0.1-50%, and the volume ratio of described oil phase organic solvent and aqueous solution is 1/3-5/3; Behind the solvent flashing, the calcium phosphate and the amphipathic nature polyalcohol composite nano-microsphere of centrifugal collection bag medicine carrying thing.
Calcium phosphate of the present invention and amphiphilic polymer composite medicament-carrying nano-microsphere is characterized in that used amphipathic nature polyalcohol, comprise polyester, polyamino acid, polylactic acid and phospholipid and copolymer thereof.
Wherein be preferably polycaprolactone (PCL), pluronic (PEO-PPO-PEO), polyamino acid (PAGA), polyethylene glycol-lactic acid (PEG-PLA), Polyethylene Glycol-(polylactic acid-co-polyglycolic acid) (PEG-PLGA), polyethylene glycol-aspartic acid (PEG-PASP), polyethylene glycol-glutamic acid (PEG-PGA), Polyethylene Glycol-poly-D-lysine (PEG-PLL), polyethylene glycol-aziridine (PEG-PEI), poly (l-lactic acid)-b-Polyethylene Glycol-b-poly (l-lactic acid) (PLLA-b-PEG-b-PLLA), polylactic acid-b-polyethylene-b-polylactic acid (PLA-b-PEG-b-PLA), PEG-b-PLGA-b-PLL, PEG-b-PLGA-b-PEI, the PEG-pluronic, among phospholipid-PLL or the phospholipid-PEI etc. any, the high polymer weight average molecular weight is less than 1,000,000, preferred 0.2-20 ten thousand.
Calcium phosphate of the present invention and amphiphilic polymer composite medicament-carrying nano-microsphere can be realized controlled delivery of pharmaceutical agents is discharged by the particle diameter and the inner loose structure of control microsphere.Medicine can form the comparatively environment of sealing through the parcel of composite nano-microsphere, can strengthen the medicine stability of factor to external world; And nano drug-carrying microsphere can also increase the biological stability of medicine, makes medicine keep the integrity of its structure before arriving site of action.
Calcium phosphate of the present invention and amphiphilic polymer composite medicament-carrying nano-microsphere, can to calcium phosphate and amphipathic copolymer composite medicament-carrying nano-microsphere to be modified and make it have targeting, used modification preparation comprises antibody ligand (tumor associated antigen mark), albumen and enzyme (enzyme mark), hormone, peptide class, gene and micromolecule preparation etc.
Modify preparation and can be preferably alpha-fetoprotein, carcinoembryonic antigen, tissue polypeptide antigen, amylase, lactic acid dehydrogenase, ribonuclease, 5-nucleotidase, thyroliberin, vassopressin, growth hormone, transforming growth factor, estrogen, progestogen, catecholamines and derivant thereof, ras gene family and expression product thereof, myc gene family and expression product thereof, EGF-R ELISA, RB gene and p53 gene, folic acid, tamoxifen or magnetic-particle.
More preferably integrate element, transmembrane peptides, transferrins, alpha-fetoprotein, transforming growth factor, estrogen, progestogen, EGF-R ELISA, p53 gene, folic acid, tamoxifen, magnetic-particle, rhodamine and quantum dot.
Calcium phosphate of the present invention and amphiphilic polymer composite medicament-carrying nano-microsphere, described medicine can be organic drug, water soluble drug, water-insoluble drug, gene, probe and diagnostic reagent.
Its Chinese medicine is preferably paclitaxel, indometacin, anti-folic acid class (as methotrexate), anti-purine class (as mercaptopurine), anti-miazines is (as fluorouracil, ftorafur), nucleotide reducing enzyme inhibitor (as hydroxyurea), deoxyribonucleotide polymerase depressant (as ancitabine), directly the medicine of influence and destruction dna structure and function thereof is (as chlormethine, cyclophosphamide, formylmerphalan, cisplatin, mitomycin, camptothecine), the synthetic medicine of Profilin matter is (as amycin, the L-asparaginase, daunorubicin, mithramycin), influence the medicine (vinblastine that microtubular protein assembling and spindle fiber form, etoposide), quantum dot, fluorescent dye or therapeutic gene.
More preferably paclitaxel, indometacin, methotrexate, mercaptopurine, fluorouracil, ftorafur, hydroxyurea, ancitabine, chlormethine, cyclophosphamide, formylmerphalan, cisplatin, mitomycin, camptothecine, amycin, L-asparaginase, daunorubicin, mithramycin, vinblastine, etoposide, p53 gene.
Calcium phosphate of the present invention and amphiphilic polymer composite medicament-carrying nano-microsphere is characterized in that application aspect pharmaceutical carrier comprises to the resistant characterization of the sending of medicine, slow controlled release, reversing tumor cell and to the diagnosis and the treatment of disease.
Composite medicament-carrying nano-microsphere can change the route of administration of medicine, makes route of administration and administering mode variation; Can protect medicines such as peptide class, protein or antisensenucleic acids not by enzymolysis or hydrolysis as calcium phosphate and amphipathic nature polyalcohol composite nano-microsphere, make the medicine can be oral, and reduce dosage and number of times.Simultaneously, utilize the targeting of composite medicament-carrying nano-microsphere can when increasing local drug concentration, reduce the concentration of medicine, thereby reduced the general toxicity of medicine at other positions of whole body.Moreover medicine is by behind the nanorize, and the increase of absolute absorption amount can make dosage reduce, and can reach the purpose that reduces poisonous side effect of medicine equally; And composite medicament-carrying nano-microsphere also can make the fluctuation of blood drug level reduce to the slow releasing function of medicine, thereby improves the safety and the bioavailability of medicine.
Calcium phosphate of the present invention and amphiphilic polymer composite medicament-carrying nano-microsphere and application aspect pharmaceutical carrier is characterized in that carrying by the medicament-carrying nano-microsphere bag aspect the diagnosis of disease or diagnostic reagents such as finishing antibody ligand, albumen, polypeptide, small peptide, magnetic nanoparticle, quantum dot or fluorescent probe are realized.
Calcium phosphate of the present invention and amphiphilic polymer composite medicament-carrying nano-microsphere are not only can realize the bag of medicine is carried, and can realize that common bag to medicine and gene carries and sends and reaches the common treatment of medicine and gene.
Compare with existing material, calcium phosphate of the present invention and amphiphilic polymer composite medicament-carrying nano-microsphere have following advantage:
(1) composite medicament-carrying nano-microsphere combines the characteristic of calcium phosphate and amphiphilic copolymer, has that preparation is simple, drug encapsulation convenient, characteristics such as, good biocompatibility strong to the slow controlled release ability of medicine.
(2) composite medicament-carrying nano-microsphere can be distinguished or while water soluble medicament-entrapping or fat-soluble medicine, overcome the general shortcoming that only is fit to bag year fat-soluble medicine of amphiphilic copolymer, enlarge the scope of application of amphiphilic copolymer, also enlarged the scope of application of calcium phosphate simultaneously.
(3) composite medicament-carrying nano-microsphere is easy to the bag support method of water soluble drug, only needs when adopting absorption method Nano microsphere is mixed vibration with the solution that contains medicine, can reduce the loss to pharmaceutically active, helps keeping the curative effect of medicine.
(4) composite medicament-carrying nano-microsphere is all higher to the envelop rate and the carrying drug ratio of water soluble drug or fat-soluble medicine, and envelop rate can reach more than 95%, therefore can reduce the loss of medicine; Composite medicament-carrying nano-microsphere is powerful to the slow control-release function of medicine, and its release to medicine can be controlled by particle diameter, the size of regulating the inner aperture of microsphere of regulating Nano microsphere, the factors such as molecular weight of regulating high polymer.
(5) composite medicament-carrying nano-microsphere is wide as the scope of application of pharmaceutical carrier, is embodied in to wrap to carry a different pharmaceutical and carry out treatment of diseases, can wrap again to carry or the finishing diagnostic reagent carries out the diagnosis of disease, also can carry out the common diagnosis and the treatment of disease simultaneously.
(6) composite medicament-carrying nano-microsphere can use as medicine or genophore simultaneously.
Description of drawings
Fig. 1. carry the calcium phosphate of mitoxantrone and the TEM photo of PEG-PLA composite nano-microsphere;
Fig. 2. the calcium phosphate of year mitoxantrone and PEG-PLA composite nano-microsphere are to the release profiles of mitoxantrone;
Fig. 3. carry mitoxantrone calcium phosphate and PEG-PLA composite nano-microsphere accumulating in breast cancer cell MCF-7 and breast carcinoma mdr cell MDR/RES MCF-7;
Specific implementation method
Provide embodiments of the invention below, be to further specify, rather than limit the scope of the invention of the present invention.
Embodiment 1:
(molecular weight is 10000, and the mPEG chain segment molecular weight is 2000, LA/GA=5: 5) be added in the 20ml water, 37 ℃ are stirred 1h down, make polymer dissolution, obtain solution A with the copolymer (mPEG-b-PLGA) of 0.2g polyethylene glycol-lactic acid and hydroxyacetic acid; Add the CaCl2 solution of 10ml 0.5M in the A, stir 0.5h, obtain solution B; 10ml 0.3M (NH4) 2HPO4 aqueous solution is dropped to solution B, and the pH value of reaction solution is controlled at 10 with ammonia in this process, and temperature is 37 ℃; Dropwise, reaction solution is centrifugal, use deionized water wash 3 times, use absolute ethanol washing 1 time, then at 37 ℃ of following vacuum drying 24h, obtain calcium phosphate/mPEG-b-PLGA composite Nano porous ball.
Embodiment 2:
Adopting absorption method that water soluble drug is wrapped carries:
At room temperature get exsiccant calcium phosphate and polyethylene glycol-lactic acid (PEG-PLA) composite nano-microsphere 100mg mixes with the aqueous solution 15ml that contains the water soluble drug mitoxantrone (medicament contg 10mg/ml), stir 0.5-24h, centrifugal collection bag carries the calcium phosphate and the PEG-PLA composite nano-microsphere of mitoxantrone.Carry out calcium phosphate and PEG-PLA composite nano-microsphere then to the mensuration of entrapment efficiency, carrying drug ratio, the analysis of Nano microsphere particle diameter and the detection of pharmaceutically active.The particle diameter of calcium phosphate and PEG-PLA composite nano-microsphere is about 200nm, and its envelop rate to mitoxantrone is 90%.
Embodiment 3:
Adopting absorption method that fat-soluble medicine is wrapped carries:
In the mixed solvent of the fat-soluble medicine paclitaxel is water-soluble and ethanol (volume ratio 1: 1) (drug level 1mg/ml); At room temperature get exsiccant calcium phosphate and polyethylene glycol-aspartic acid (PEG-PASP) composite nano-microsphere 100mg mixes with the above-mentioned solution 15ml that contains paclitaxel, stir 0.5-24h, centrifugal collection bag carries the calcium phosphate and the PEG-PASP composite nano-microsphere of paclitaxel.Carry out calcium phosphate and PEG-PASP composite nano-microsphere then to the mensuration of entrapment efficiency, carrying drug ratio, the analysis of Nano microsphere particle diameter and the detection of pharmaceutically active.The particle diameter of calcium phosphate and PEG-PASP composite nano-microsphere is about 30nm, and its envelop rate to paclitaxel is 85%.
Embodiment 4:
Adopting solvent evaporation method that fat-soluble medicine is wrapped carries:
Earlier fat-soluble medicine indometacin (mass percent concentration 2%) is dissolved in and gets oil phase among the chloroform 25ml, then exsiccant calcium phosphate/Polyethylene Glycol-poly-D-lysine (PEG-PLL) composite nano-microsphere 100mg is dissolved in and gets water in the 50ml phosphate buffered solution, at last water and oil phase are mixed stirring, behind the solvent flashing, centrifugal collection bag carries the calcium phosphate/PEG-PLL composite nano-microsphere of indometacin.Carry out calcium phosphate/PEG-PLL composite nano-microsphere then to the mensuration of entrapment efficiency, carrying drug ratio, the analysis of Nano microsphere particle diameter and the detection of pharmaceutically active.The particle diameter of calcium phosphate/PEG-PLL composite nano-microsphere is about 30nm, and its envelop rate to indometacin is 90%.
Embodiment 5:
Before composite nano-microsphere preparation, medicine is wrapped year:
Fat-soluble medicine paclitaxel 5mg and 100mg PEG-PLGA (weight average molecular weight 10,000) are dissolved in the 3ml dimethyl sulfoxide, adding 10ml water mixes, put into molecular cut off then and be 12000 the bag filter 5-12h that dialyses, finally being formulated as mass fraction is the drug-carrying polymer micelle solution A of 0.1-5%; Add soluble calcium salt again in solution A, stir 0.5-24h, forming calcium ion concentration is the solution B of 0.005-1M; Adding concentration in the solution B then is the soluble phosphoric acid saline solution of 0.005-1M, and the control pH value is 7-12; Add soluble phosphate at last, continue stirring reaction 0-24h, centrifugal collection, washing, drying obtains calcium phosphate/PEG-PLGA composite medicament-carrying nano-microsphere.
Embodiment 6:
Adopting the pH gradient method that water soluble drug is wrapped carries:
Draw an amount of 9g/L sodium chloride injection and join that jolting is dissolved mitoxantrone hydrochloride fully in the Mitoxantrone Hydrochloride bottle; The mitoxantrone hydrochloride aqueous solution that dissolving is good is placed on heating 10min in the water-bath (55 ℃～60 ℃); Draw 2mL in advance in water-bath the calcium phosphate/Polyethylene Glycol after the preheating-poly-D-lysine (PEG-PLL) composite nano-microsphere suspension (50mg/ml) join in the mitoxantrone hydrochloride solution, add sodium carbonate liquor then, shake up and heating in water-bath (55 ℃～60 ℃); Mixed solution fills nitrogen and stirs 10min behind 55 ℃～60 ℃ balance 10min, and centrifugal collection bag carries the calcium phosphate/PEG-PLL composite nano-microsphere of mitoxantrone.Carry out calcium phosphate/PEG-PLL composite nano-microsphere then to the mensuration of entrapment efficiency, carrying drug ratio, the analysis of Nano microsphere particle diameter and the detection of pharmaceutically active.The particle diameter of calcium phosphate/PEG-PLL composite nano-microsphere is about 300nm, and its envelop rate to mitoxantrone hydrochloride is 96%.
Embodiment 7:
Dressing agents such as use transferrins Tf carry out finishing to calcium phosphate/amphiphilic polymer composite medicament-carrying nano-microsphere makes it have targeting:
Get the 1ml bag and carry calcium phosphate/polyethylene glycol-aziridine (PEG-PEI) composite nano-microsphere (50mg/ml) of methotrexate, add phosphate buffered solution (pH=7.4) 15ml, Tf mixes with 1mg cancer target preparation transferrins, drip 2ml 1-ethyl-3 (3-dimethyl propyl) carbodiimide hydrochloride (EDC), 4 ℃ are reacted 4h down.Centrifugal collection is carried calcium phosphate/PEG-PEI composite nano-microsphere of methotrexate through the bag that Tf modifies.The modification of transferrins Tf can increase the targeting of calcium phosphate/PEG-PEI composite medicament-carrying nano-microsphere to the most tumors cell, increases the cross-cell membrane ability of Nano microsphere, and the medicine that bag carries is played a role to a greater extent.
Embodiment 8:
Dressing agents such as use transforming growth factor carry out finishing to calcium phosphate/amphiphilic polymer composite medicament-carrying nano-microsphere makes it have targeting:
Get calcium phosphate/polyethylene glycol-aziridine (PEG-PEI) composite nano-microsphere (50mg/ml) that the 1ml bag carries ancitabine, add phosphate buffered solution (pH=7.4) 15ml, mix with 1mg cancer target preparation transforming growth factor, drip 2ml 1-ethyl-3 (3-dimethyl propyl) carbodiimide hydrochloride (EDC), 4 ℃ are reacted 4h down.The bag that centrifugal collection is modified through transforming growth factor carries calcium phosphate/PEG-PEI composite nano-microsphere of methotrexate.The modification of transforming growth factor can increase the targeting of calcium phosphate/PEG-PEI composite medicament-carrying nano-microsphere to the most tumors cell, increases the cross-cell membrane ability of Nano microsphere, and the medicine that bag carries is played a role to a greater extent.
Embodiment 9:
Preparation has the calcium phosphate/amphiphilic polymer composite medicament-carrying nano-microsphere of medical diagnosis and treatment function:
At room temperature get triblock copolymer (PEG-b-PLGA-b-PLL) the composite nano-microsphere 100mg and aqueous solution 15ml (the medicament contg 10mg/ml that contains water soluble drug amycin and magnetic nanoparticle of exsiccant calcium phosphate/Polyethylene Glycol-(polylactic acid-co-polyglycolic acid)-poly-D-lysine, magnetic nanoparticle content 1mg/ml) mixes, stir 0.5-24h, centrifugal collection bag carries amycin and has the calcium phosphate of nuclear-magnetism video picture function/PEG-b-PLGA-b-PLL composite nano-microsphere.Carry out the analysis of the calcium phosphate/entrapment efficiency of PEG-b-PLGA-b-PLL composite nano-microsphere, the mensuration of carrying drug ratio, particle diameter and the detection of pharmaceutically active then.The particle diameter of calcium phosphate/PEG-b-PLGA-b-PLL composite nano-microsphere is about 200nm, and its envelop rate to amycin is 90%.
Calcium phosphate/PEG-b-PLGA-b-PLL composite magnetic medicine carrying micro-nano ball not only has antitumor drug to the tumor treatment function, and has the nuclear-magnetism video picture function of magnetic nanoparticle, and can be used as the MRI diagnostic reagent.
Embodiment 10:
At room temperature get triblock copolymer (PEG-b-PLGA-b-PLL) the composite nano-microsphere 100mg and aqueous solution 15ml (the medicament contg 10mg/ml that contains water soluble drug fluorouracil and water-soluble quantum dot of exsiccant calcium phosphate/Polyethylene Glycol-(polylactic acid-co-polyglycolic acid)-poly-D-lysine, quantum dot content 1mg/ml) mixes, stir 0.5-24h, centrifugal collection bag carries fluorouracil and has the calcium phosphate of fluorescence imaging function/PEG-b-PLGA-b-PLL composite nano-microsphere.Carry out the analysis of the calcium phosphate/entrapment efficiency of PEG-b-PLGA-b-PLL composite nano-microsphere, the mensuration of carrying drug ratio, particle diameter and the detection of pharmaceutically active then.The particle diameter of calcium phosphate/PEG-b-PLGA-b-PLL composite nano-microsphere is about 200nm, and its envelop rate to fluorouracil is 90%.
Calcium phosphate/PEG-b-PLGA-b-PLL composite magnetic medicine carrying micro-nano ball not only has antitumor drug to the tumor treatment function, and has the fluorescence imaging function of quantum dot.
Embodiment 11:
Calcium phosphate/amphipathic nature polyalcohol composite nano-microsphere is as the application of medicine and genophore.
(MCF-7/MIT BCAP37/MDR) has the function of reversing drug resistance to calcium phosphate/PEG-PLA composite nano-microsphere that prepared bag carries mitoxantrone to drug-fast breast cancer cell.Calcium phosphate/PEG-PLA composite nano-microsphere can increase cancer therapy drug accumulating in tumor cell, see accompanying drawing 3, improve the toxicity of cancer therapy drug to non-drug resistance and drug-resistant tumor cell, drug resistance that to a certain extent can the reversing tumor cell, can increase cell membrane fluidity, improve the cell membrane permeability of medicine, and suppress or minimizing P-gp albumen effluxing the effect substrate, suppress MDRI, MRP and the GST-pmRNA level of mdr cell and reduce P-gp albumen, the ATP level that the ABCG2 effect of effluxing is required.Calcium phosphate/PEG-PLA composite nano-microsphere can change pharmacokinetics and tissue distribution parameter in the body of model drug, can the significant prolongation model drug in rat and the intravital blood circulation time of mice, change the drug distribution of each internal organs in the body.
The present invention open and the preparation of calcium phosphate/amphiphilic polymer composite medicament-carrying nano-microsphere of disclosing and the application aspect pharmaceutical carrier can be by using for reference this paper disclosure.Although the preparation of calcium phosphate/amphiphilic polymer composite medicament-carrying nano-microsphere of the present invention and the application aspect pharmaceutical carrier are described by preferred embodiment, but those skilled in the art obviously can change method as herein described in not breaking away from content of the present invention, spirit and scope, more particularly, the replacement that all are similar and change apparent to those skilled in the artly, they are regarded as being included in spirit of the present invention, scope and the content.
Claims (12)
1. the composite medicament-carrying nano-microsphere of calcium phosphate and amphipathic nature polyalcohol, the wherein complex formed by amphipathic nature polyalcohol and calcium phosphate of Nano microsphere, and bag medicine carrying thing; The percentage by weight of described amphipathic nature polyalcohol, calcium phosphate and the medicine carrying thing that wraps is followed successively by 1%-60%, 0.1%-60% and 0.1%-50%; The particle diameter of described calcium phosphate and amphipathic nature polyalcohol composite nano-microsphere is 1-100000nm.
2. calcium phosphate as claimed in claim 1 and amphiphilic polymer composite medicament-carrying nano-microsphere, the particle diameter that it is characterized in that described calcium phosphate and amphipathic nature polyalcohol composite nano-microsphere is 5-5000nm.
3. calcium phosphate as claimed in claim 1 and amphiphilic polymer composite medicament-carrying nano-microsphere, it is characterized in that the described Nano microsphere of forming by amphipathic nature polyalcohol and calcium phosphate form and preparation method is preferably as follows:
Under 0～60 ℃, amphipathic nature polyalcohol is added in the water, is mixed with mass fraction and is 0.1～5% solution A; In solution A, add soluble calcium salt CaCl
2, stirring and forming calcium ion concentration is the solution B of 0.005～1M; In solution B, drip or pour into the soluble phosphoric acid saline solution (NH that concentration is 0.005～1M
4)
2HPO
4, making calcium ion and phosphate anion mol ratio is 1: 1～1.67: 1, pH value is controlled at 7～12 simultaneously; Continue stirring reaction, then with the centrifugal collection of milky reactant liquor, with deionized water and dehydrated alcohol cyclic washing, vacuum drying obtains calcium phosphate/amphipathic nature polyalcohol composite porous nanoparticles.
4. calcium phosphate as claimed in claim 1 and amphiphilic polymer composite medicament-carrying nano-microsphere is characterized in that described amphipathic nature polyalcohol is polyester, polyamino acid, polylactic acid and phospholipid and copolymer thereof.
5. calcium phosphate as claimed in claim 2 and amphiphilic polymer composite medicament-carrying nano-microsphere, it is characterized in that described amphipathic nature polyalcohol is preferably polycaprolactone, pluronic, poly-(α-4-ammonia butyl)-left-handed (L)-glycol acid, polyethylene glycol-lactic acid, the copolymer of polyethylene glycol-lactic acid and hydroxyacetic acid, the polyethylene glycol-aspartic acid, polyethylene glycol-glutamic acid, Polyethylene Glycol-poly-D-lysine, the polyethylene glycol-aziridine, poly-left-handed (L)-lactic acid, the triblock copolymer of Polyethylene Glycol and poly (l-lactic acid), polylactic acid, the triblock copolymer of Polyethylene Glycol and polylactic acid, in the triblock copolymer of the triblock copolymer of Polyethylene Glycol-(copolymer of polylactic acid and hydroxyacetic acid)-poly-D-lysine or Polyethylene Glycol-(copolymer of polylactic acid and hydroxyacetic acid)-polymine any, described amphipathic nature polyalcohol weight average molecular weight 0.2-＜1,000,000.
6. calcium phosphate as claimed in claim 1 and amphiphilic polymer composite medicament-carrying nano-microsphere, it is characterized in that described calcium phosphate and amphipathic copolymer composite medicament-carrying nano-microsphere modify, the antibody ligand that described modification preparation is the tumor associated antigen mark, as albumen or enzyme, hormone, peptide class, gene or the micromolecule preparation of enzyme mark.
7. calcium phosphate as claimed in claim 1 and amphiphilic polymer composite medicament-carrying nano-microsphere is characterized in that described medicine is organic drug, water soluble drug, water-insoluble drug, gene, fluorescent probe or diagnostic reagent; Wherein more preferably paclitaxel, indometacin, methotrexate, mercaptopurine, fluorouracil, ftorafur, hydroxyurea, ancitabine, chlormethine, cyclophosphamide, formylmerphalan, cisplatin, mitomycin, camptothecine, amycin, L-asparaginase, daunorubicin, mithramycin, vinblastine, etoposide or p53 gene.
8. the preparation method of calcium phosphate as claimed in claim 1 and amphiphilic polymer composite medicament-carrying nano-microsphere, it is characterized in that calcium phosphate and amphipathic nature polyalcohol Nano microsphere carry out drug encapsulation or carry out drug encapsulation simultaneously in the preparation process of preparation calcium phosphate and amphipathic nature polyalcohol Nano microsphere, the bag support method is as follows:
(1) bag medicine carrying thing in the Nano microsphere preparation process
Configuration earlier contains the solution A 1 of the medicine that amphiphilic polymers that percentage by weight is 0.1-5% and percentage by weight be 0.1-5%; Or configuration contains the amphiphilic polymers nanoparticle of bag medicine carrying thing, prepares the amphiphilic polymers nanoparticle solution A 2 that medicine carrying that percentage by weight is 0.1-5% and percentage by weight are 0.1-5% then; In solution A 1 or A2, add soluble calcium salt CaCl respectively again
2, stir 0.5-24h, forming calcium ion concentration is the solution B of 0.005-1mol/L; Adding concentration in the solution B then is (the NH of 0.005-1mol/L
4)
2HPO
4Solution, (NH
4)
2HPO
4Solution and solution B volume ratio are 1/3-4/3, use ammonia to regulate pH value and are 7-12, continue stirring reaction 0-24h, centrifugal collection, and washing, drying obtains calcium phosphate and amphiphilic polymer composite medicament-carrying nano-microsphere;
(2) bag medicine carrying thing after the Nano microsphere preparation
Bag support method to water soluble drug is:
At room temperature, with exsiccant calcium phosphate and amphipathic nature polyalcohol composite nano-microsphere and the aqueous solution that contains water soluble drug, the weight percent concentration of described calcium phosphate and amphipathic nature polyalcohol composite nano-microsphere and water soluble drug is respectively 0.1-99% and 0.1-50%, stir 0.5-24h, the calcium phosphate and the amphipathic nature polyalcohol composite nano-microsphere of centrifugal collection bag medicine carrying thing;
Bag support method to fat-soluble medicine is:
In the water-soluble and ethanol of fat-soluble medicine, make the mixed solution of the fat-soluble medicine that contains 0.1-30% weight, described water and alcoholic acid volume ratio are 1/3-4/3; In above-mentioned mixed solution, add exsiccant calcium phosphate and the compound porous Nano microsphere of amphipathic copolymer then, make the calcium phosphate and the compound porous Nano microsphere of amphipathic copolymer that contain 0.1-20% weight in the solution, stir 0.5-24h, the calcium phosphate and the amphipathic nature polyalcohol composite nano-microsphere of centrifugal collection bag medicine carrying thing, the weight percent concentration of wherein said calcium phosphate and amphipathic nature polyalcohol composite nano-microsphere and water soluble drug is respectively 0.1-99% and 0.1-50%;
Perhaps, to contain the aqueous solution stirring of fat-soluble medicine organic solvent with the calcium phosphate that contains 0.1-20% and the amphipathic nature polyalcohol composite nano-microsphere of 0.1-30% weight, behind the solvent flashing, the calcium phosphate and the amphipathic nature polyalcohol composite nano-microsphere of centrifugal collection bag medicine carrying thing; The volume ratio of described organic solvent and aqueous solution is 1/3-5/3;
Described medicine is as described in the claim 7.
9. the preparation method of calcium phosphate as claimed in claim 8 and amphiphilic polymer composite medicament-carrying nano-microsphere is characterized in that described medicine is organic drug, water soluble drug, water-insoluble drug, gene, fluorescent probe or diagnostic reagent.
10. calcium phosphate as claimed in claim 1 and amphiphilic polymer composite medicament-carrying nano-microsphere are used to prepare carrier medicament.
11. purposes as claimed in claim 10, it is characterized in that described carrier medicament be the resistant characterization medicine of delivering drugs, sustained and controlled release medicament, reversing tumor cell, to the medicine of the diagnosis or the treatment of disease.
12. purposes as claimed in claim 10, the diagnostic medicine that it is characterized in that described disease are to wrap by calcium phosphate and amphiphilic polymer composite medicament-carrying nano-microsphere to carry or finishing antibody ligand, albumen, polypeptide, small peptide, magnetic nanoparticle, quantum dot or fluorescent probe diagnostic reagent again.
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