CN101780043B - Preparation method of sanguinarine liposome with acid sensitivity - Google Patents
Preparation method of sanguinarine liposome with acid sensitivity Download PDFInfo
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- CN101780043B CN101780043B CN2010101355883A CN201010135588A CN101780043B CN 101780043 B CN101780043 B CN 101780043B CN 2010101355883 A CN2010101355883 A CN 2010101355883A CN 201010135588 A CN201010135588 A CN 201010135588A CN 101780043 B CN101780043 B CN 101780043B
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Abstract
The invention relates to the field of pharmaceutical preparation, in particular to a preparation method of sanguinarine liposome with acid sensitivity, which is characterized by selecting citric acid ammonium salt for preparing the sanguinarine liposome when an ammonium salt gradient method is adopted for preparation. The sanguinarine liposome prepared by the method of the invention has acid sensitivity and is favorable to the antitumor effect.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to a kind of method for preparing of Sanguinarine liposome, adopt the Sanguinarine liposome of the inventive method preparation to have acid-sensitive.
Background technology
Sanguinarine was found in for 19 beginnings of the century, and molecular formula is C
20H
14NO
4, relative molecular mass is 332.As a kind of Bian Ji isoquinoline alkaloid, have a series of antibacteriums widely, antifungal, anti-infective characteristic.Recent research shows; Sanguinarine has good inhibition activity to the multiple cancer cell of the mankind; It can reduce cancerous cell peripheral vessels hypertrophy through suppressing ECGF; Micro-molar concentration with regard to can anticancer growth and do not influence normal cell, and can block most tumors cell MDR (multidrug resistance effect) effectively, therefore be expected to aspect clinical cancer therapy, play a role.See (Mackraj, ThirumalaGovender, Prem Gathiram.Sanguinarine [J] .Cardiovascular Therapeutics for details; 2008; 26:75-83) (Haseeb Ahsan, Shannon Reagan-Shaw, Jorien Breur; Nihal Ahmad; Sanguinarine induces apoptosisof human pancreaticcarcinoma AsPC-1and BxPC-3cells via modulations in Bcl-2family proteins [J] .Cancer Letters, 2007,249 (2): 198-208.)
This medicine is the same with most of tumour medicines to have toxicity, and the human body untoward reaction has nausea and vomiting, the limb swelling erythema, and heart failure etc., the drug-supplying system that therefore is necessary to select to be fit to improves its interior curative effect to reduce its toxicity.Liposome is the first-selected a kind of drug-supplying system of cancer therapy drug as a kind of drug-loading system with biological degradability and biocompatibility.
Though liposome has series of advantages such as the cancer therapy drug of reduction whole body toxic and side effects, raising curative effect, also exists to be prone to by great number of issues such as RES System Cleaning, targeting property deficiency, immunogenicities.One of them is: most of conventional liposomes are to get into cell with the endocytosis mode; At first be present in the endosome (endosome); Under the mediation of microtubule system, be transported to lysosome (lysosome) then; In lysosome, liposome and the active ingredient that is comprised thereof are degraded, thereby directly cause the loss of cancer therapy drug.
The pH value of blood of human body is 7.4; The pH value of tumor tissues is about 6.5, and the pH value of endosome is about 5.5, if the lipid physical ability is triggered by the lower pH of endosome; The active ingredient that it comprised is discharged; Escape in the Cytoplasm, just can avoid medicine to be destroyed, thereby improve curative effect by lysosome.
Acid-sensitive liposome is exactly a difference of utilizing above-mentioned pH, triggers the interior active ingredient of liposome and is discharged in the Cytoplasm, avoids by a kind of functional liposome of lysosome degraded.At present, the acid-sensitive liposome mainly contains two kinds of principles, and a kind of is to use pH sensitivity lipoid, like DOPE, oleic acid, hemisuccinic acid cholesterol etc.; Another kind is that the polyelectrolyte of using pH sensitivity is incorporated into surface of liposome, as gathers (2-ethylacrylic acid) etc.The conformation of these materials changes along with pH, causes the liposome membrane instability, assembles, merges, discharges content.
Summary of the invention
The invention discloses a kind of method for preparing with Sanguinarine liposome of acid-sensitive.
We find adopting the ammonium salt gradient method to prepare in the process of Sanguinarine liposome: adopt conventional ammonium sulfate, resulting Sanguinarine liposome does not have acid-sensitive; And adopt the citric acid ammonium salt, and resulting Sanguinarine liposome but has acid-sensitive, and this obviously helps improving the antitumor action of Sanguinarine.
Method for preparing of the present invention comprises: phospholipid, cholesterol are dissolved in organic solvent, and the evaporation under reduced pressure removed organic solvent adds the hydration of Diammonium citrate aqueous solution and forms suspension, homogenize, and dialysis promptly gets with the hatching of Sanguinarine aqueous solution again.In the preferred chloroform of wherein said organic solvent, dichloromethane, methanol, ethanol, ether, the acetone one or more.More preferably chloroform, methanol, dichloromethane or ethanol.
Method for preparing of the present invention can also be: phospholipid, cholesterol are dissolved in organic solvent, splash into the Diammonium citrate aqueous solution under the stirring condition, reduction vaporization is removed organic solvent, homogenize, and dialysis promptly gets with the hatching of Sanguinarine aqueous solution again.Organic solvent preferred alcohol or ether.
The preferred soybean phospholipid of phospholipid described in the present invention.
Ratio involved in the present invention is mol ratio.
Among the present invention, the proportioning of Sanguinarine and phospholipid, cholesterol directly has influence on the quality of liposome, and the concentration of the Diammonium citrate that uses in the preparation process is also influential to its quality.
Other parameter constants in fixed prescription and preparation process, when only investigating the ratio of medicine and phospholipid, the mean diameter and the envelop rate of Sanguinarine liposome are as shown in table 1.
The ratio of table 1. Sanguinarine/phospholipid is to the influence (n=3) of liposome particle diameter and envelop rate
Can find out that from table 1 molar ratio of Sanguinarine and phospholipid is in 1: 1～5 scopes, envelop rate is lower than 80%; When both mol ratio in 1: 6～20 scopes, envelop rate meets the requirements greater than 80%; But after both ratios surpass 1: 15,, cause the liquid thickness, and layering easily because phospholipid concentration is higher in the liposome.Therefore among the present invention the ratio of Sanguinarine/phospholipid preferably 1: 6～15.
Ceteris paribus in fixed prescription, when only changing the consumption of cholesterol, the mean diameter of Sanguinarine liposome is also different with envelop rate.The result sees table 2.
The ratio of table 2. Sanguinarine/cholesterol is to the influence (n=3) of liposome particle diameter and envelop rate
Can find out that from table 2 when the molar ratio of medicine and cholesterol during less than 1: 0.1, envelop rate is lower than 80%; When both ratio in 1: 0.5～2.5 scopes, envelop rate is more than 80%; When both mol ratio in 1: 5～15 scopes, envelop rate increases with cholesterol and descends, particle diameter also increases gradually, and the liposome of preparation is unstable, layering easily.Therefore the molar ratio of Chinese medicine/cholesterol of the present invention is preferably 1: 0.5～2.5.
Ceteris paribus in fixed prescription, when only changing the concentration of the Diammonium citrate that uses in the preparation process, the mean diameter of Sanguinarine liposome is also different with envelop rate, and the result sees table 3.
Table 3. Diammonium citrate concentration is to the influence (n=3) of Sanguinarine liposome particle diameter and envelop rate
Can find out that from table 3 different Diammonium citrate concentration of aqueous solution is less to liposome grain diameter influence, but to the envelop rate influence significantly.Along with Diammonium citrate concentration increases, envelop rate raises gradually.When Diammonium citrate concentration during at 0～200mmol/L, envelop rate is lower than 80%; When Diammonium citrate concentration during at 250～500mmol/L, envelop rate is higher than 80%, wherein concentration when 400mmol/L envelop rate near 100%.But when Diammonium citrate concentration when 500mmol/L is above, prepared liposome is unstable, layering easily.Therefore the preferred concentration range for of Diammonium citrate is 250～500mmol/L among the present invention.
When adopting the ammonium salt gradient method to prepare the Sanguinarine liposome; This area uses ammonium sulfate as ammonium salt more; But this test is found: when adopting the ammonium salt gradient method to prepare the Sanguinarine liposome; Use Diammonium citrate and the prepared Sanguinarine liposome of ammonium sulfate to have certain difference, wherein the Sanguinarine liposome of Diammonium citrate preparation has tangible acid-sensitive, can obtain proof by extracorporeal releasing test.
One, extracorporeal releasing experiment:
Configuration HEPES buffer (0.14mol/LNaCl, 0.01mol/L HEPES) is as release medium, and using NaOH solution to regulate pH is 7.4,6.5,5.5.These three pH simulate physiological fluid (pH7.4), tumor tissues (pH6.5), endosome picked-up back environment (pH5.5) respectively.
Precision pipettes Sanguinarine liposome 1.5mL, places bag filter, and tighten at two ends, put in the 40mL HEPES buffer, and 37 ℃ of constant temperature magnetic agitation, timing sampling 0.5mL, and in time replenish fresh release medium.Sample is drawn supernatant behind high speed centrifugation, HPLC measures medicament contg, calculates the accumulative total release rate, and draws the time release profiles.
Two kinds of liposomees being examined or check are respectively by the Sanguinarine liposome of ammonium sulphate gradient preparation and the Sanguinarine liposome that is prepared by the Diammonium citrate gradient method.See Fig. 1 and Fig. 2.Wherein, the ammonium sulfate group shows acid-sensitive hardly, under three kinds of pH environment, discharges no significant difference; But adopt Diammonium citrate group liposome to show tangible acid-sensitive, along with the reduction of pH value of solution, the release of liposome Chinese medicine is significantly accelerated.
Two, adopt the human cervical carcinoma Hela cell that two kinds of liposomees are carried out anticancer experiment in vitro relatively
Be in the human cervical carcinoma Hela cell of exponential phase, with 0.02%EDTA digestion, the trypan blue living cell counting is processed cell suspension, the direct centrifugal collection of H22 cell.With 0.5 * 10
4/ mL cell concentration adds in 96 well culture plates, and every hole 100 μ L establish three multiple holes, put 37 ℃ of 5%CO
2Incubated overnight in the incubator adds 3,5,7,9 μ gmL respectively
-1Sanguinarine solution, adopt Sanguinarine liposome, the Sanguinarine liposome of the present invention of ammonium sulfate preparation; Do not have other positive controls, negative control group adds isopyknic blank liposome, with equal-volume simple cell suspension as blank; 100 μ L/ holes, 37 ℃ of 5%CO
2Incubator is hatched 44h, and every hole adds 5mgmL
-1MTT solution 20 μ L continue to cultivate 4h, and the tumor cell attached cell directly discards whole supernatants, and the H22 suspension cell is in the centrifugal 10min of board-like centrifuge 1000rpm, and back-off is inhaled and removed supernatant in absorbent paper.Add DMSO 100 μ L/ holes respectively, vibration is 5 minutes on the microoscillator, and crystallization is dissolved fully, joins appearance 570nm wavelength in enzyme and measures absorbance (A), and the high more viable count of A value is also many more.Can calculate the growth inhibition ratio of medicine pair cell according to A, the result is as shown in table 4.
Table 4 Sanguinarine solution and liposome are to human cervical carcinoma Hela cell 24h tumor-inhibiting action
* P＜0.05, the liposome group of * * P＜0.01 liposome of the present invention and ammonium sulphate gradient preparation relatively
After two groups of liposomees act on human cervical carcinoma Hela cell 24h, obvious tumor-inhibiting action is all arranged, and concentration dependent is arranged.The tumor-inhibiting action of liposome wherein of the present invention under equal administration concentration is significantly higher than the Sanguinarine liposome of ammonium sulfate preparation, has significant difference.
Analyze reason, liposome is after endocytosis gets into cell, because the liposome of Diammonium citrate gradient method preparation has acid-sensitive; Under the triggering of the low pH of endosome, the film of liposome membrane and endosome merges, and Sanguinarine is discharged; Get into Cytoplasm, thus the performance tumor-inhibiting action; And the Sanguinarine liposome of ammonium sulphate gradient preparation is not had an acid-sensitive, changes lysosome over to by endosome more, and medicine is degraded by lysosome, so tumor killing effect is relatively poor.
Three, adopt the anti-tumor in vivo effect of two kinds of liposomees of mice evaluation of lotus Heps tumor.
Get 50 of ICR mices, 18-22g, male and female half and half.Press the transplanted tumor organon, inoculation Heps solid type tumor (is got the tumor piece, is weighed, grind with the glass Potter-Elvehjem Tissue Grinders under the sterile working; Put in people's sterile chamber after mill is even, add the cell suspension that normal saline is diluted to 1: 3, container is put on the ice cube, aspirates with empty needle; Each suction is preceding with the cell mixing, every mice right fore axillary fossa subcutaneous vaccination 0.2mL), inoculate back 24 hours and claim that Mus is heavy; And being divided into 5 groups at random, blank group, cyclophosphamide solution group (20mg/kg) are respectively the positive and negative matched group, Sanguinarine solution group; Adopt the Sanguinarine liposome of ammonium sulfate preparation, Sanguinarine liposome of the present invention (dosage is 14mg/kg) is in inoculation tail vein injection administration after 24 hours; Once a day, administration is 6 times altogether, the 2nd day execution tumor-bearing mice after drug withdrawal; Weigh, and separate the tumor piece and weigh, the gained data are carried out statistical procedures (t check).The result is as shown in table 5.
Table 5 Sanguinarine solution and liposome i.v. are to the inhibitory action (
) of mice-transplanted tumor Heps (n=10)
* P＜0.05, * * P＜0.01 and blank control group comparison
Compare with the solution group, two kinds of liposomees all have the effect (P＜0.01) of remarkable inhibition Heps tumor growth.But tumour inhibiting rate obviously is superior to the non-acid-sensitive Sanguinarine liposome of ammonium sulfate preparation in the body of liposome of the present invention.
This further specifies: adopt the Sanguinarine liposome of citric acid gradient method preparation, significantly improve its curative effect in vivo owing to having acid-sensitive.
The Sanguinarine liposome of the present invention's preparation, in optimizing the prescription scope, envelop rate is greater than 80%, and particle diameter is in 100～300nm scope.
The invention has the advantages that: adopt the citric acid gradient method to prepare the Sanguinarine liposome, preparation technology is simple, not only can make liposome have high envelop rate, but also makes liposome have the characteristics of acid-sensitive, thereby significantly improves its inside and outside tumour inhibiting rate.
Description of drawings
Fig. 1 is the release conditions of Sanguinarine liposome under three kinds of pH conditions that adopts the ammonium sulfate preparation
Fig. 2 is the release conditions of Sanguinarine liposome under three kinds of pH conditions of the inventive method preparation
Fig. 3 is Sanguinarine liposome particle size distribution figure of the present invention
Fig. 4 is a Sanguinarine liposome transmission electron microscope photo of the present invention
The specific embodiment
Embodiment 1
Take by weighing 1.6g soybean phospholipid (purity is greater than 99% phosphatidylcholine), the 160mg cholesterol is dissolved in the 50mL ethanol, and is ultrasonic, the dissolving; Under 300rpm magnetic agitation condition, above-mentioned solution is slowly injected the Diammonium citrate solution (300mmol/L) of 30mL.50 ℃ of rotary evaporation 2h of mixed liquor volatilize ethanol fully, and high pressure homogenize obtains the preceding blank liposome of medicine carrying to reduce particle diameter (5000psi, 3 times).Then blank liposome is placed bag filter, tighten at two ends, put into the 500mL normal saline 2 hours, per hour changes normal saline one time.After the 90mg Sanguinarine is dissolved in the 90mL distilled water, again with above-mentioned dialysis after liposome mix, 30 ℃ of water-baths hatching 5min after the aseptic filtration (membrane filter aperture 0.2 μ m), are sub-packed in subsequent filtrate in the cillin bottle and get final product.Sanguinarine wherein: soybean phospholipid: the molar ratio of cholesterol is 1: 7.5: 1.5.
Prepared liposome encapsulation is 94.45%, and mean diameter is 110.5nm, and polydispersity coefficient is 0.18.
The finished product character: these article are orange red suspendible liquid.
Particle size determination: these article as retarder thinner, with PCS method are measured particle diameter (MalvernZetasizer3000HS) after the dilution several times with normal saline, and particle size distribution figure sees shown in Figure 3,
Morphological observation: these article ooze normal saline as retarder thinner with waiting, dilute tens of times after observation under transmission electron microscope.As shown in Figure 4, liposome is the spheroid of rule, and the outward appearance roundness is good, lipid film rule homogeneous.
Embodiment 2
Basic identical with embodiment 1, but following change is arranged: early stage, operating process was when preparing blank liposome: take by weighing 1g soybean phospholipid (purity is greater than 99% phosphatidylcholine), the 160mg cholesterol is dissolved in the 50mL ether, and is ultrasonic, dissolving; Under 300rpm magnetic agitation condition, above-mentioned solution is slowly injected the Diammonium citrate solution (300mmol/L) of 30mL, 50 ℃ of rotary evaporation 2h of mixed liquor volatilize ether fully, and water-bath is ultrasonic to reduce particle diameter, obtains blank liposome before the medicine carrying.Then blank liposome is placed bag filter, tighten at two ends, put into the 500mL normal saline 2 hours, per hour changes normal saline one time.After the Sanguinarine aqueous solution of preparation will be mixed with above-mentioned solution again, 5min are hatched in 30 ℃ of water-baths, after the aseptic filtration (membrane filter aperture 0.2 μ m), subsequent filtrate is sub-packed in the cillin bottle gets final product.Sanguinarine wherein: soybean phospholipid: the molar ratio of cholesterol is 1: 7.5: 1.5.
Prepared Sanguinarine liposome encapsulation is 92.71%, and mean diameter is 104.3nm, and polydispersity coefficient is 0.15.
Embodiment 3
Take by weighing 1.6g soybean phospholipid (purity is greater than 99%), the 160mg cholesterol is dissolved in the dichloromethane; This solution is placed the ground eggplant-shape bottle; Reduction vaporization is removed organic solvent in 30 ℃ of waters bath with thermostatic control; Make phospholipid, cholesterol at the bottom of bottle, form uniform films, be placed on that evacuation spends the night in the vacuum desiccator, subsequent use.Other adds the Diammonium citrate solution of the 300mmol/L of 30mL in the above-mentioned eggplant-shape bottle, under 30 ℃ of conditions, rotates and washes film, and until forming the milky liposome turbid liquor, the high pressure homogenize reduces particle diameter (5000psi, 3 times), obtains the preceding blank liposome of medicine carrying.Then blank liposome is placed bag filter, tighten at two ends, put into the 500mL normal saline 2 hours, per hour changes normal saline one time.Sanguinarine aqueous solution among the embodiment 1 is mixed with above-mentioned blank liposome suspension, 30 ℃ of water-bath hatching 5min, (membrane filter aperture 0.2 μ m) gets final product after the aseptic filtration.Sanguinarine wherein: soybean phospholipid: the molar ratio of cholesterol is 1: 7.5: 1.5.
The envelop rate of prepared Sanguinarine liposome is 93.78%, and particle diameter is 113.2nm, and polydispersity coefficient is 0.174.
Take by weighing 1.5g soybean phospholipid (purity is greater than 99%), the 200mg cholesterol is dissolved in the dichloromethane; This solution is placed the ground eggplant-shape bottle; Reduction vaporization is removed organic solvent in 30 ℃ of waters bath with thermostatic control; Make phospholipid, cholesterol at the bottom of bottle, form uniform films, be placed on that evacuation spends the night in the vacuum desiccator, subsequent use.Other adds the Diammonium citrate solution of the 300mmol/L of 30mL in the above-mentioned eggplant-shape bottle, under 30 ℃ of conditions, rotates and washes film, and until forming the milky liposome turbid liquor, the high pressure homogenize reduces particle diameter (5000psi, 3 times), obtains the preceding blank liposome of medicine carrying.Then blank liposome is placed bag filter, tighten at two ends, put into the 500mL normal saline 2 hours, per hour changes normal saline one time.Sanguinarine aqueous solution among the embodiment 1 is mixed with above-mentioned blank liposome suspension, 30 ℃ of water-bath hatching 5min, (membrane filter aperture 0.2 μ m) gets final product after the aseptic filtration.Sanguinarine wherein: soybean phospholipid: the molar ratio of cholesterol is 1: 7.0: 1.9.
Prepared Sanguinarine liposome, envelop rate is 91.37%, and polydispersity coefficient is 0.174, and particle diameter is 105.1nm.
Take by weighing 2g soybean phospholipid (purity is greater than 99%), the 150mg cholesterol is dissolved in the dichloromethane; This solution is placed the ground eggplant-shape bottle; Reduction vaporization is removed organic solvent in 30 ℃ of waters bath with thermostatic control; Make phospholipid, cholesterol at the bottom of bottle, form uniform films, be placed on that evacuation spends the night in the vacuum desiccator, subsequent use.Other adds the Diammonium citrate solution of the 300mmol/L of 30mL in the above-mentioned eggplant-shape bottle, under 30 ℃ of conditions, rotates and washes film, and until forming the milky liposome turbid liquor, the high pressure homogenize reduces particle diameter (5000psi, 3 times), obtains the preceding blank liposome of medicine carrying.Then blank liposome is placed bag filter, tighten at two ends, put into the 500mL normal saline 2 hours, per hour changes normal saline one time.Sanguinarine aqueous solution among the embodiment 1 is mixed with above-mentioned blank liposome suspension, 30 ℃ of water-bath hatching 5min, (membrane filter aperture 0.2 μ m) gets final product after the aseptic filtration.Sanguinarine wherein: soybean phospholipid: the molar ratio of cholesterol is 1: 9.4: 1.4.
Prepared Sanguinarine liposome, envelop rate is 97.47%, and polydispersity coefficient is 0.174, and particle diameter is 117.2nm.
Claims (4)
1. the method for preparing of a Sanguinarine liposome adopts the preparation of ammonium salt gradient method, it is characterized in that comprising: phospholipid, cholesterol are dissolved in organic solvent; The evaporation under reduced pressure removed organic solvent adds the hydration of Diammonium citrate aqueous solution and forms suspension, homogenize; Dialysis promptly gets with the hatching of Sanguinarine aqueous solution again; Wherein the mol ratio of Sanguinarine, phospholipid, cholesterol is 1: 6～15: 0.5～2.5; The concentration of Diammonium citrate aqueous solution is 250～500mmol/L.
2. the method for preparing of claim 1, wherein said organic solvent is selected from one or more in chloroform, dichloromethane, methanol, ethanol, ether, the acetone.
3. the method for preparing of a Sanguinarine liposome adopts the preparation of ammonium salt gradient method, it is characterized in that comprising: phospholipid, cholesterol are dissolved in organic solvent; Splash into the Diammonium citrate aqueous solution under the stirring condition, reduction vaporization is removed organic solvent, homogenize; Dialysis promptly gets with the hatching of Sanguinarine aqueous solution again; Wherein the mol ratio of Sanguinarine, phospholipid, cholesterol is 1: 6～15: 0.5～2.5; The concentration of Diammonium citrate aqueous solution is 250～500mmol/L.
4. the method for preparing of claim 3, wherein organic solvent is ethanol or ether.
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