CN101927001B - Method for loading anti-cancer drug based on multifunctional polyamidoamine dendrimer - Google Patents
Method for loading anti-cancer drug based on multifunctional polyamidoamine dendrimer Download PDFInfo
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Abstract
The invention relates to a method for loading an anti-cancer drug based on multifunctional polyamidoamine dendrimer, which comprises the following steps of: (1) dissolving fifth generation of polyamidoamine dendrimer in a DMSO (Dimethylsulfoxide) solution, adding into a DMSO solution containing FI, dialyzing and freeze-drying; (2), dissolving FA in the DMSO solution, adding EDC (Dichloroethane), adding into a DMSO solution containing G5.NH2-FI, dialyzing and freeze-drying; (3) dissolving the freeze-dried product in a DMSO solution, adding triethylamine, adding into a DMSO solution containing acetic anhydride, dialyzing and freeze-drying to obtain G5.NHAc-FI-FA; and (4) dissolving G5.NHAc-FI-FA in water, adding a methanol solution containing 2-ME, and freeze-drying the supernatant to obtain the compound. After 2-ME is loaded by the method, the water solubility of 2-ME is increased, the release time of the drug is prolonged, and coated 2-ME has the same biological activity.
Description
Technical field
The invention belongs to the method field of load cancer therapy drug, particularly relate to a kind of method based on multi-functional polyamide-amide dendrimer load cancer therapy drug.
Background technology
Cancer chemotherapeutic often is faced with a such problem now, and cancer therapy drug has not only killed cancerous tissue, and can have side effects to organizing normally also.In addition, the water solublity of many cancer therapy drugs is bad, has seriously limited bioavailability of medicament.In the face of such problem, many drug delivery systems comprise that liposome, polymer micelle, nano-particle and dendrimer are used for packaging medicine, thereby have improved the dissolubility of medicine and realized the targeting transportation of medicine.Especially, as the macromole of one type of highly branched, monodispersity and synthetic property, dendrimer has obtained paying close attention to widely on the targeted drug transmission system.
Dendrimer (Dendrimers) is meant to have tree, and is highly branched, by molecule kernel, surface functional group and connect the synthetic property macromole that the two branching segment constitutes.Dendrimer have accurately control of size, non-immunogenicity, stable, under using dosage characteristics such as avirulence.Its kernel is hydrophobic space, can wrap up some medicines by physics; Terminal functionality can the many medicines of Electrostatic Absorption; Also can some medicines of chemical bonding; Simultaneously can modify different functional groups; As reduce toxic group (PEG, hydroxyl, acetyl group, carboxyl etc.), label (Fluorescein isothiocyanate (FITC), biotin) and targeting part (antibody, folic acid, RGD (Arg-Gly-Asp) polypeptide, galactose etc.), so just can form the multi-functional medicament-carried nano granule that toxicity is little, have labelling and targeting.But dendrimer is as the holdup time of pharmaceutical carrier prolong drug in blood, and control medicine rate of release in vivo protects medicine to avoid environmental disruption, has good slow releasing function and targeting property.This makes its application at pharmaceutical carrier have prospect preferably.
Dendrimer can be used as new drug carrier and medicine and forms the nano_scale particle drug-supplying system, and the combination of itself and medicine can be divided into two kinds: 1) chemical bonding; 2) physics parcel and absorption.The former is with the surface of medicine covalent bonding at dendrimer, yet covalent bonding generally all needs many step organic reactions, and covalent bond should can rupture drug release is come out under specific biotic factor.The latter's reaction is fairly simple, but medicine/dendrimer complex stability in vivo is faced with challenge again.
(2-methoxyestradiol is an estradiol physiological metabolism product in vivo 2-ME) to the 2-methoxyestradiol, is present in blood and the urine.Discover; 2-ME can suppress the propagation of the multiple mankind or animal tumor cell, and its anti-tumor activity is mainly realized radiating sensitivity through inducing tumor cell and endothelial cell apoptosis, inhibition cell proliferation, anti-angiogenic rebirth, enhancing tumor cell.2-ME has been proved to be a potential cancer therapy drug.Yet the water solublity of 2-ME is bad, has seriously limited its bioavailability in vivo.Therefore, for water solublity and the bioavailability that improves 2-ME,, use various pharmaceutical carriers that 2-ME is carried out load and be necessary in order to keep the inhibitory action of 2-ME to tumor.
Sum up present research, 2-ME by the research of pharmaceutical carrier institute load this respect also seldom.2008; [Desai KGH such as Desai KGH; Mallery SR, Schwendeman SP.Effect of formulation parameters on2-methoxyestradiol release from injectable cylindrical poly (DL-lactide-co-glycolide) implants.Eur J Pharm Biopharm 2008; 70:187-98] with injectable cylindric polylactic acid-glycolic guanidine-acetic acid copolymer (poly (lactic-co-glycolic acid); PLGA) as implant 2-ME is carried out load; Evidence; PLGA has not only improved the dissolubility of 2-ME to the load of 2-ME, and the release of 2-ME can last up to one month, has improved the bioavailability of 2-ME greatly.2009; People [Wang SH such as Wang SH; Shi XY, Chen XS, Baker JR.TherapeuticEfficacy of 2-Methoxyestradiol Microcrystals Encapsulated within Polyelectrolyte Multilayers.Macromol Biosci 2009; 9:429-36.] through layer-by-layer 2-ME is wrapped in the polymer multi-layer capsule; Though the dissolubility of 2-ME has improved; And has identical biological activity with pure medicine 2-ME; But the final 2-ME particle size that forms is big (about 1 μ m) too, is not suitable for the targeted therapy of cancerous tissue.(Shi X in our nearest work; Lee I; ChenX, Shen M, Xiao S; Zhu M, et al.Influence of dendrimer surface charge on the bioactivity of2-methoxyestradiol complexed with dendrimers.Soft Matter 2010; 6:2539-2545; Chinese invention patent; Application number: 200910199867.3.); We adopt the 5th to represent mask to have the dendrimer of different electric charges to wrap up the 2-ME molecule, and study the biological activity of the 2-ME molecule that is wrapped, and test shows; End group be acyl group, hydroxyl, amino, carboxyl the 5th generation dendrimer can wrap up the 2-ME molecule; But have only end group be the 2-ME molecule of dendrimer parcel of acyl group and hydroxyl to the toxic effect of cancer cell, and the surface for amino the 5th generation dendrimer because the toxicity that self amino causes, thereby be not suitable for pharmaceutical carrier.
Retrieval shows about the document and the patent results of multi-functional dendrimer load 2-ME medicine aspect both at home and abroad: at the document of also not finding with multi-functional dendrimer load 2-ME medicine.
Summary of the invention
Technical problem to be solved by this invention provides a kind of method based on multi-functional polyamide-amide (PAMAM) dendrimer load cancer therapy drug, and this method for preparing is simple, is suitable for suitability for industrialized production; Behind the load 2-ME; The water solubility of 2-ME improves greatly; Pharmaceutical release time has also prolonged, and is still had identical biological activity by the 2-ME of multi-functional dendrimer parcel, and the cancerous cell of those homofolic acid expression of receptor is had the lethal effect of targeting.
A kind of method based on multi-functional polyamide-amide (PAMAM) dendrimer load cancer therapy drug of the present invention comprises:
(1) with 52.0mg-55mg the 5th generation the polyamide-amide dendrimer be dissolved in the DMSO solution of 5mL-10mL; Under condition of stirring, dropwise add the DMSO solution that 5mL-10mL contains 3.9mg-4.2mgFI, reaction 24h-48h; Reaction solution is put into bag filter; In the PBS buffer, dialyse, in deionized water, dialyse again, at last the solution lyophilizing in the bag filter is promptly got G5.NH
2-FI;
(2) 2.55mg-2.9mgFA is dissolved in the middle of the DMSO solution of 5mL-10mL, adds 22.1mg-25mgEDC then, behind the stirring reaction 3h-5h, mixed solution is dropwise joined 5mL-10mL contain 35.0mg-40mg G5.NH at ambient temperature
2In the middle of the DMSO solution of-FI, stirring reaction 3-5 days, reaction solution is put into bag filter, in the PBS buffer, dialyse, in deionized water, dialyse again, at last the solution lyophilizing in the bag filter is promptly got G5.NH
2-FI-FA;
(3) with 26.3mg-28mg G5.NH
2-FI-FA is dissolved in the middle of the 5mL-10mL DMSO solution; Add the 52.74mg-56mg triethylamine, dropwise add 5mL-10mL then and contain in the DMSO solution of 44.35mg-48mg acetic anhydride stirring reaction 1-2 days; Reaction solution is put into bag filter; In the PBS buffer, dialyse, in deionized water, dialyse again, at last the solution lyophilizing in the bag filter is promptly got G5.NHAc-FI-FA;
(4) above-mentioned 10mg-12mgG5.NHAc-FI-FA is dissolved in the 1.5mL-2mL water; Add 300 μ L-400 μ L then and contain the methanol solution of 2-methoxyestradiol (2-ME); Vigorous stirring 12-24h; The centrifugal deposition of removing, the drug molecule that does not promptly wrap up is got the supernatant lyophilizing and is promptly got the 5.NHAc-FI-FA/2-ME complex; 2-ME: G5.NHAc-FI-FA mol ratio=10-12: 1 wherein.
Said is template with the 5th generation polyamide-amide dendrimer (source); On each dendrimer respectively with 5 Fluorescein isothiocyanates of covalent bonding (FITC) molecule, 5 folic acid (FA) molecule, remaining amino in dendrimer surface and excessive acetic acid acid anhydride (Ac) molecular reaction.
The molecule number of FITC and FA all is 5 among prepared each G5.NHAc-FI-FA of said step (3).
Said step (4) centrifugal condition is 7000rpm, 10min.
To preparation, medicament slow release and the neoplasm targeted therapy research of multi-functional polyamide-amide (PAMAM) dendrimer of load cancer therapy drug, we have done some tests:
(1) NMR test result
The NMR test result shows: with the 5th generation dendrimer be template, successfully synthesized multi-functional tree-shaped molecule G5.NHAc-FI-FA.Each strong FI that closes in dendrimer surface and the quantity of FA all are 5.Referring to description of drawings 1.
(2) UV-Vis test result
The UV-Vis collection of illustrative plates proved dendrimer G5.NHAc-FI-FA successfully load cancer therapy drug 2-ME, promptly successfully synthesized the G5.NHAc-FI-FA/2-ME complex.Referring to description of drawings 2.
(3) HPLC test result
The HPLC test result shows and is enclosed with 3.7 2-ME molecules in each G5.NHAc-FI-FA molecule.
(4) drug release result
The drug release curve shows: after the 2-ME drug molecule was wrapped up by dendrimer G5.NHAc-FI-FA, rate of release was slack-off.At pH is under 7.4 and 5.0 conditions, has only discharged 35% and 25% behind the 24h.Referring to description of drawings 3.
(5) phase contrast microscope result
The phase contrast microscope photo of KB cellular morphology shows: the G5.NHAc-FI-FA/2-ME complex is identical with the effect of the pure medicine 2-ME of same concentrations to the lethal effect of KB cell, explains after 2-ME is by the G5.NHAc-FI-FA load still have identical biological activity.Referring to description of drawings 4.
(6) fluorescence microscope result
The fluorescence microscope photo shows: after acting on KB-HFAR cell and KB-LFAR cell 1h respectively with the G5.NHAc-FI-FA/2-ME complex; The KB-HFAR cell has tangible fluorescence, explains that the G5.NHAc-FI-FA/2-ME complex has special targeting property to the KB-HFAR cell.Referring to description of drawings 5.
(7) the MTT cell viability is measured the result
The MTT cell viability is measured the result and is shown: after acting on KB-HFAR cell and KB-LFAR cell respectively with the G5.NHAc-FI-FA/2-ME complex; The lethal effect of the KB-HFAR cell of surface expression homofolic acid receptor is more obvious, explains that the G5.NHAc-FI-FA/2-ME complex has special therapeutic effect to the KB-HFAR cell.
With the 5th generation the polyamide-amide dendrimer be template, synthetic have target function and mark function the 5th generation dendrimer, and come physics to wrap up the 2-ME drug molecule with multi-functional dendrimer.The present invention relates to a ultimate principle: the 5th generation polyamide-amide dendrimer inside be a hydrophobic space, 2-ME is a water-fast medicine, dendrimer is wrapped in 2-ME in its internal cavities through hydrophobic interaction.
Beneficial effect
(1) method for preparing of the present invention is simple, is suitable for suitability for industrialized production; Select for use the 5th generation the polyamide-amide dendrimer size be 5.4nm, in blood circulation, can directly from kidney, discharge, do not need biodegradation;
(2) behind the multi-functional dendrimer load 2-ME of the present invention; The water solubility of 2-ME improves greatly; Pharmaceutical release time has also prolonged; 2-ME by multi-functional dendrimer parcel still has identical biological activity, and the cancerous cell of those homofolic acid expression of receptor is had the lethal effect of targeting.
Description of drawings
Fig. 1 is for the multi-functional dendrimer G5.NHAc-FI-FA's of the present invention preparation
1H NMR collection of illustrative plates.
Fig. 2 is the UV-Vis collection of illustrative plates of the multi-functional G5.NHAc-FI-FA/2-ME complex of the present invention's preparation.
Fig. 3 is the release profiles of 2-ME under different pH buffer conditions in the G5.NHAc-FI-FA/2-ME complex of the present invention's preparation.
The phase contrast microscope photo of the KB cell that Fig. 4 is respectively untreated (a), 2-ME (c), 10 μ L PBS (d), G5.NHAc-FI-FA (e) and the G5.NHAc-FI-FA/2-ME (f) of 1 μ L ethanol (b), 10 μ M handled, incubation time is 48h.Fig. 5 is respectively KB-HFAR cell (a), the G5.NHAc-FI-FA/2-ME complexes that handled with PBS, and ([the 2-ME]=KB-HFAR cell of 10mM) handling (b) and the fluorescence microscope photo of KB-LFAR cell (c), incubation time is 1h.
Fig. 6 behind complex and the cytosis 1h, cleans cell for the KB-HFAR cell and the cell viability of KB-LFAR cell after the G5.NHAc-FI-FA/2-ME complex is handled of mtt assay test, changes the culture fluid that does not contain complex, measures cell viability behind the cultivation 48h.
The specific embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in the restriction scope of the present invention.Should be understood that in addition those skilled in the art can do various changes or modification to the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
With the 5th generation the polyamide-amide dendrimer (52.0mg 0.002mmol) is dissolved in the 5mLDMSO solution, under condition of stirring, dropwise adds 5mL and contains FI (3.9mg, DMSO solution 0.01mmol).Reaction 24h puts into reaction solution in the bag filter (MWCO=10,000), and dialysis is 3 times in the PBS buffer, in deionized water, dialyses 3 times again, at last the solution lyophilizing in the bag filter is promptly got G5.NH
2-FI.
(2.55mg 0.00577mmol) is dissolved in the middle of the DMSO solution of 5mL, and (22.1mg 0.1154mmol), behind the stirring reaction 3h, dropwise joins 5mL with mixed solution and contains G5.NH at ambient temperature to add EDC then with FA
2-FI (35.0mg, in the middle of DMSO solution 0.00115mmol), stirring reaction 3 days; Reaction solution is put in the bag filter (MWCO=10,000), and dialysis is 3 times in the PBS buffer; In deionized water, dialyse 3 times again, at last the solution lyophilizing in the bag filter is promptly got G5.NH
2-FI-FA.
With G5.NH
2(26.3mg 0.00087mmol) is dissolved in the middle of the 5mL DMSO solution-FI-FA, adds triethylamine (52.74mg; 0.52128mmol), dropwise add 5mL then and contain acetic anhydride (44.35mg is in DMSO solution 0.4344mmol); Stirring reaction 1 day is put into reaction solution in the bag filter (MWCO=10,000); Dialysis is 3 times in the PBS buffer, in deionized water, dialyses 3 times again, at last the solution lyophilizing in the bag filter is promptly got G5.NHAc-FI-FA.
The NMR test result shows: with the 5th generation dendrimer be template, successfully synthesized multi-functional tree-shaped molecule G5.NHAc-FI-FA, strong respectively 5 FI molecules and 5 the FA molecules of having closed in each dendrimer surface.
The 5th generation polyamide-amide dendrimer (55.0mg) is dissolved in the 10mLDMSO solution, under condition of stirring, dropwise adds the DMSO solution that 10mL contains FI (4.2mg).Reaction 24h puts into reaction solution in the bag filter (MWCO=10,000), and dialysis is 3 times in the PBS buffer, in deionized water, dialyses 3 times again, at last the solution lyophilizing in the bag filter is promptly got G5.NH
2-FI.
FA (2.9mg) is dissolved in the middle of the DMSO solution of 10mL, adds EDC (25mg) then, behind the stirring reaction 3h, mixed solution is dropwise joined 10mL contain G5.NH at ambient temperature
2In the middle of the DMSO solution of-FI (40.0mg), stirring reaction 3 days is put into reaction solution in the bag filter (MWCO=10,000), and dialysis is 3 times in the PBS buffer, in deionized water, dialyses 3 times again, at last the solution lyophilizing in the bag filter is promptly got G5.NH
2-FI-FA.
With G5.NH
2-FI-FA (28mg) is dissolved in the middle of the 10mL DMSO solution, adds triethylamine (56mg), dropwise adds 10mL then and contains in the DMSO solution of acetic anhydride (48mg); Stirring reaction 1 day; Reaction solution is put in the bag filter (MWCO=10,000), and dialysis is 3 times in the PBS buffer; In deionized water, dialyse 3 times again, at last the solution lyophilizing in the bag filter is promptly got G5.NHAc-FI-FA.
The NMR test result shows: with the 5th generation dendrimer be template, successfully synthesized multi-functional tree-shaped molecule G5.NHAc-FI-FA, strong respectively 5 FI molecules and 5 the FA molecules of having closed in each dendrimer surface.
10mg G5.NHAc-FI-FA is dissolved in the 1.5mL water, and the 2-ME (with respect to dendrimer) that gets 10 molar equivalents is dissolved in the 300 μ L methanol, and above-mentioned two kinds of solution are mixed stirred overnight; Methanol solution is fully evaporated; Then with mixed solution centrifugal (7,000rpm, 10min).The 2-ME medicine that deposition is not promptly wrapped up is dissolved in the 1mL methanol solution, and carry out HPLC and analyze, thus the load capacity of definite medicine; Thereby supernatant is collected lyophilizing and is obtained the G5.NHAc-FI-FA/2-ME complex.
The UV-Vis collection of illustrative plates proved dendrimer G5.NHAc-FI-FA successfully load cancer therapy drug 2-ME, promptly successfully synthesized the G5.NHAc-FI-FA/2-ME complex.HPLC result shows and is enclosed with 3.7 2-ME molecules in each G5.NHAc-FI-FA molecule.
(pH=5.0 carries out slow release under pH=7.4), detects the dose that discharges through HPLC (HPLC) and studies its slow release effect to 2-ME at the buffer of 37 ℃, two kinds different pH with above-mentioned G5.NHAc-FI-FA/2-ME complex; The content of the 2-ME that wherein discharges detects through HPLC, and mobile phase is that linear gradient changes, and initial water/acetonitrile (v/v) is 66: 34, and stopping water/acetonitrile (v/v) is 30: 70.Time is 20mins, and flow velocity is 1mL/min.
The pure medicine 2-methoxyestradiol (2-ME) (10 μ M) of above-mentioned G5.NHAc-FI-FA/2-ME complex and same concentrations is acted on human epithelium's cancerous cell (KB cell) respectively; After cultivating 48h, detect cell viability through mtt assay and study the toxic action of G5.NHAc-FI-FA/2-ME complex the KB cell; Wherein the concentration of 2-ME is 5-10 μ M.
Above-mentioned G5.NHAc-FI-FA/2-ME complex is acted on the KB cell (KB-HFAR) of homofolic acid expression of receptor and the KB cell (KB-LFAR) of low folacin receptor expression respectively; Cultivate 1h, through the targeting property of fluorescence microscope research G5.NHAc-FI-FA/2-ME complex to KB-HFAR; Behind G5.NHAc-FI-FA/2-ME complex and cytosis 1h; Clean cell; And change the culture fluid that does not contain the G5.NHAc-FI-FA/2-ME complex, and continue cultured cell to 48h, utilize mtt assay to measure the special active anticancer of G5.NHAc-FI-FA/2-ME complex.
Said KB-LFAR cell obtained through KB-HFAR cell and FA are cultivated in advance in one day, and FA concentration is 2.5 μ M; During research targeting property, the time that the G5.NHAc-FI-FA/2-ME complex acts on KB-LFAR cell and KB-HFAR cell is 1h.When studying special active anticancer; Behind G5.NHAc-FI-FA/2-ME complex and cytosis 1h; Clean cell; And change the culture fluid that does not contain the G5.NHAc-FI-FA/2-ME complex, and continue cultured cell to 48h, utilize mtt assay to measure the special active anticancer of G5.NHAc-FI-FA/2-ME complex.
Claims (3)
1. method based on multi-functional polyamide-amide PAMAM dendrimer load cancer therapy drug comprises:
(1) with 52.0mg-55mg the 5th generation the polyamide-amide dendrimer be dissolved in the DMSO solution of 5mL-10mL; Under condition of stirring; Dropwise add 5mL-10mL and contain the DMSO solution of 3.9mg-4.2mg FITC; Reaction 24h-48h puts into bag filter with reaction solution and dialyses, and at last the solution lyophilizing in the bag filter is promptly got G5.NH
2-FI;
(2) 2.55mg-2.9mgFA is dissolved in the middle of the DMSO solution of 5mL-10mL, adds 22.1mg-25mgEDC then, behind the stirring reaction 3h-5h, mixed solution is dropwise joined 5mL-10mL contain 35.0mg-40mg G5.NH at ambient temperature
2In the middle of the DMSO solution of-FI, stirring reaction 3-5 days, reaction solution is put into bag filter dialyse, at last the solution lyophilizing in the bag filter is promptly got G5.NH
2-FI-FA;
(3) with 26.3mg-28mg G5.NH
2-FI-FA is dissolved in the middle of the 5mL-10mL DMSO solution; Add the 52.74mg-56mg triethylamine; Dropwise adding 5mL-10mL then contains in the DMSO solution of 44.35mg-48mg acetic anhydride; Stirring reaction 1-2 days, reaction solution is put into bag filter dialyse, at last the solution lyophilizing in the bag filter is promptly got G5.NHAc-FI-FA;
(4) above-mentioned 10mg-12mgG5.NHAc-FI-FA is dissolved in the 1.5mL-2mL water; Add 300 μ L-400 μ L then and contain the methanol solution of 2-methoxyestradiol 2-ME; Vigorous stirring 12-24h, the centrifugal deposition of removing is got the supernatant lyophilizing and is promptly got the G5.NHAc-FI-FA/2-ME complex; 2-ME: G5.NHAc-FI-FA mol ratio=10-12: 1 wherein.
2. a kind of method based on multi-functional polyamide-amide PAMAM dendrimer load cancer therapy drug according to claim 1, it is characterized in that: the dialysis in said step (1) or (2) or (3) is dialysed in deionized water in the PBS buffer, to dialyse again.
3. a kind of method based on multi-functional polyamide-amide PAMAM dendrimer load cancer therapy drug according to claim 1 is characterized in that: the molecule number of FITC and FA all is 5 among each G5.NHAc-FI-FA of said step (3) preparation.
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