CN105287383A - Application of novel liposome-entrapped mitoxantrone combined chemotherapeutic drug in antineoplastic treatment - Google Patents
Application of novel liposome-entrapped mitoxantrone combined chemotherapeutic drug in antineoplastic treatment Download PDFInfo
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Abstract
The invention discloses an application of a novel liposome-entrapped mitoxantrone combined chemotherapeutic drug in antineoplastic treatment. According to the invention, a new liposome-entrapped mitoxantrone preparation containing components such as cardiolipin is prepared internationally, and is used for being combined with other clinical routine first-line chemotherapeutics for antineoplastic treatment. The invention expounds the preparation method and symptom research of the novel liposome preparation, the preparation has the characteristics of high entrapment rate, uniform particle size distribution, good stability, prolongation of chemotherapeutics half life, and reduction of toxic and side effect; compared with other treatment methods, in breast cancer and leukemia tumor animal models, antineoplastic curative effect of the new liposome-entrapped mitoxantrone preparation and other chemotherapeutics is more obvious.
Description
Technical field
The invention discloses the application of novel mitoxantrone liposome combined chemotherapy medicine in antineoplaston.Relate to the application of mitoxantrone Liposomal formulation and other routine clinical front-line chemotherapeutic agents therapeutic alliance tumors, also relate to the preparation method of mitoxantrone liposome and relevant characterization research thereof.
Background technology
In China, the health burden of cancer increases year by year, surpasses 1,600,000 people every year and is diagnosed as cancer, and 1,200,000 people are dead because of cancer.It is worth noting, there is the new cancer patient of 20% in the whole world in China, and the cancer mortality patient of 24% is in China.Current China is dead 5 people often, namely have 1 people to die from cancer; And in 0 ~ 64 years old population, often dead 4 people, namely have 1 people to die from cancer, cancer presents the high trend of rejuvenation, M & M " three lines ".World Health Organization (WHO) (WHO) has delivered " global cancer report 2014 " for 2014, global cancer patients in 2012 and death is claimed all to increase disturbingly, newly-increased cases of cancer has nearly half to appear at Asia, wherein major part is in China, and the newly-increased cases of cancer of China is in first.Within 2012, the whole world increases 1,400 ten thousand cases of cancers newly altogether and has 8,200,000 people dead.Wherein, newly-increased 3,070,000 cancer patients of China also cause about 2,200,000 people dead, account for 21.9% and 26.8% of global total amount respectively.Address prediction whole world cases of cancer will present swift and violent growing trend, and by 1,400 ten thousand people of 2012,1,900 ten thousand people of cumulative year after year to 2025 year, will reach 2,400 ten thousand people by 2035.
At present, the Therapeutic Method of tumor remains surgical operation therapy, radiotherapy and chemotherapy.Tumor patient after being in patient that middle and advanced stage staged tumors shifted, undergoing surgery and cannot carrying out is performed the operation or the tumor patient of radiotherapy, chemotherapeutics directly can kill tumor cell or control tumor cell, in the treatment of tumor, occupy very important status.Although antineoplastic chemotherapy achieves huge advance, the toxic and side effects that medicine produces while treatment tumor seriously reduces quality of life and the compliance of patient.The performance of pharmaceutical dosage form to the release of medicine, distribution in vivo and curative effect of medication plays an important role, select suitable pharmaceutical carrier to improve the release of medicine and distribution thus to reduce the toxic and side effects of medicine, ceiling effect ground plays curative effect becomes the focus that people pay close attention to.
Liposome has protection medicine as pharmaceutical carrier and is not degraded in blood circulation, makes drug targeting in reticuloendothelial system, extends drug effect, reduces drug toxicity, improves curative effect, avoids Drug tolerance, changes the advantages such as route of administration; the preparation raw material that Liposomal formulation is applied simultaneously has biodegradability; immunoreation and various toxic and side effects can not be produced to body; therefore be a kind of good medicament carrier system; there is the advantage that viral vector is incomparable, be thus subject to the extensive concern of the world of medicine.
Mitoxantrone (MitoxantroneHydrochloride, MTO) (molecular formula: C22H28N4O62HCl, molecular weight: 517.41) be a kind of Anthraquinone, its structure and antitumaous effect close with amycin, because it is without amino sugar structure, do not produce free radical, and have anti-lipid peroxidation effect, thus lower to cardiac toxicity.Its main mechanism is Topoisomerase II inhibitors, can the intercalation of DNA and form cross key chain, and suppressing nucleic acid synthesis and cause cell death, is cell cycle nonspecific agent (CCNSA).Because it can kill the cancerous cell of any cell cycle, propagation and non-proliferative cell are all suppressed.Somatoblast is more responsive to this product than resting cell, and the S later stage is the most responsive to this product.Be mainly used in acute nonlymphocytic leukemia and advanced breast cancer and non-Hodgkin lymphoma clinically and have very high anti-tumor activity, malignant tumor planted to pulmonary carcinoma etc. more than 10 also effective in cure.In 2000, U.S. food Drug Administration (FDA) have approved again the treatment of MTO for multiple sclerosis (MS).Although MTO has good antitumous effect clinically, its serious untoward reaction (bone marrow depression, dose-limiting cardiac toxicity, gastrointestinal toxicity, weak etc.) limits its Clinical practice.
At present, the dosage forms such as mitoxantrone lipid nanoparticle all have research at home and abroad, but effect is all undesirable.Domesticly also be in the stage at the early-stage at this area research, application yet there are no other reports containing the Liposomal formulation of the liposomal encapsulated mitoxantrone of cuorin except this seminar related ends, and not yet has the relevant report that mitoxantrone liposome and other chemotherapy drugs in combination are applied.
The object of this project research is intended to solve the limitation of mitoxantrone in process of clinical application, namely this pharmaceutical carrier of liposome is utilized, first Application is wrapped up mitoxantrone containing the liposome of cuorin in the world, prepare a kind of novel mitoxantrone Liposomal formulation, from reduction medicine clearance rate in vivo, change the metabolic pathway of medicine, reduce medicine to the toxic and side effects of body, and improve its antitumor curative effect.
Clinically, compared with single drug, combined chemotherapy has obvious superiority.The chemotherapeutics of the different mechanism of action of conbined usage, is intended to killing off tumor cells aspect and produces synergism or potentiation, thus improve antitumor curative effect.Meanwhile, by using multiple medications, avoid the probability being used alone a kind of drug dose is excessive, overlong time causes this poisonous side effect of medicine and obviously increasing; For a long time, Reusability same medicine still one of factor causing tumor drug resistance.Combined chemotherapy can remove drug resistance factor, thus decreases the probability that cancerous cell produces drug resistance; Most of chemotherapeutics can not or seldom enter in brain, and thus cannot play the effect of prevention or treatment brain metastes, a kind of chemotherapeutics that can enter in brain of conbined usage, then can make up the defect of many medicines in this.
Summary of the invention
The invention discloses the novel mitoxantrone liposome nanometer formulation of a kind of high encapsulation rate, high stability.Said preparation should meet that envelop rate is high, good stability, uniform particle diameter, clinical administration are simple to operate, can repeat to amplify the requirements such as production.
Above-mentioned mitoxantrone Liposomal formulation can reduce the drug toxicity of mitoxantrone further, improves drug therapeutic indices.
The present invention not only can solve the limitation of mitoxantrone in process of clinical application, provides the novelty teabag that other chemotherapeutics of associating reach better antitumor curative effect simultaneously.
The associable chemotherapeutics of above-mentioned mitoxantrone liposome comprises alkylating agent, as nimustine, carmustine, lomustine, cyclophosphamide, ifosfamide, glyforfin etc.; Antimetabolite, as deoxidation fluorine guanosine, the pyridine of how western fluorine bird, 5-fluorouracil, mercaptopurine, thioguanine, fluorine guanosine, ftorafur, gemcitabine, carmofur, hydroxyurea, methotrexate, UFT, ancitabine etc.; Antitumor antibiotics, as actinomycin D, doxorubicin, daunorubicin, epirubicin, mitomycin, peplomycin, Bleomycin A5, pirarubicin etc.; Plant anticarcinogen, as irinotecan, harringtonine, hydroxy camptothecin, vinorelbine, paclitaxel, Docetaxel, topotecan, vincristine, vindesine, vindesine, vinblastine, teniposide, etoposide, elemene etc.; Hormone and endocrine class medicine, as atamestane, Anastrozole, aminoglutethimide, tamoxifen, formestane etc.; Miscellany, as asparaginase, cisplatin, carboplatin, dacarbazine, oxaliplatin, OXA, procarbazine etc.; Biological response modifier, as interferon, lentinan, thymosin etc.
The associable chemotherapeutics of above-mentioned mitoxantrone liposome is one or more of above chemotherapeutics.
The preparation method of above-mentioned mitoxantrone liposome can select the method for preparing lipidosome commonly used, any means, as long as involved preparation method does not affect liposome to the envelop rate of mitoxantrone medicine and relevant characterization, the present invention mainly adopts thin film aquation method and ammonium sulphate gradient to prepare mitoxantrone liposome, and carries out enlarged experiment research by lyophilization.
Above-mentioned thin film aquation method, mixes according to a certain percentage by phospholipid and cholesterol, is dissolved in chloroform-ethanol solution, is utilized by mixture Rotary Evaporators dry under vacuum, continues dry 10min again after forming lipid membrane.Secondly certain density mitoxantrone saline solution is joined on lipid film and make lipid film aquation 1 ~ 3h, carry out vortex oscillation afterwards and be in homogeneous state to suspension, again supersound process is carried out to obtain the mitoxantrone of liposome to sample, i.e. mitoxantrone Liposomal formulation.
Above-mentioned ammonium sulphate gradient, is dissolved according to a certain percentage in organic solvent by phospholipid and cholesterol, under the effect of nitrogen current, forms thin film, removing organic solvent.Ammonium sulfate is utilized to carry out aquation 1 ~ 3h to lipid film.Blank liposome can be obtained to mixture is ultrasonic.Secondly, blank liposome is loaded in bag filter, is placed in the conical flask filling normal saline and dialyses, to set up ammonium sulphate gradient.Finally, after dialysis, in liposome, add mitoxantrone sodium chloride solution carry out medicine loading, regulate mitoxantrone concentration with normal saline.
Above-mentioned lyophilization refers to and adopts cold drying technology, by repeatedly encapsulating, lyophilizing and again merge and realize higher envelop rate.Lyophilization process stabilizing, be suitable for suitability for industrialized production, quality be easy to control and product stability good.Be dissolved in chloroform by phospholipid and cholesterol with certain proportion, add containing 2% polyvidon after logical nitrogen rotary evaporated to dryness, the phosphate buffer of pH7.4 soaks 2h.Shake under turbine mixer after 10min makes it complete miscibility and be distributed into bottle, after freeze dryer Program lyophilization 24h, take out bottle, sealing is stored in room temperature or 4 DEG C of refrigerators.When preparing mitoxantrone liposome, by the mitoxantrone saline solution of 1mg/ml, mix with the lipid of lyophilizing, medicine fat mol ratio controls at 1:15.Mixture is aquation 2h at room temperature, and namely supersound process obtains mitoxantrone Liposomal formulation in 10 minutes afterwards.
Above-mentioned mitoxantrone liposome phospholipid material used of preparing comprises natural, synthetic and semisynthetic biocompatible materials.Material can be hydrophilic or hydrophobic.Can select and prepare material with positive charge or with negative charge and electroneutral material as liposome.Suitable liposomal preparation material comprises: phospholipid, fatty acid, sterols etc.If optimize further liposome, optional cuorin, phosphatidylcholine, cholesterol, Phosphatidylserine, phosphatidylinositols, tocopherol etc., are more preferably electronegative phospholipid as cuorin, Phosphatidylserine, phosphatidylinositols etc.
The selection formula of above-mentioned liposome can comprise lecithin, cholesterol, cuorin, phosphatidylinositols, Phosphatidylserine, stearylamine etc.The Material selec-tion of the liposomal preparation scheme more optimized can comprise cuorin, lecithin, cholesterol.
In above-mentioned mitoxantrone liposomal preparation process required solvent can be polarity, low pole, neutral or nonpolar.Such as can select: acetic acid, propanoic acid, chloroform, acetone, triethylamine etc., also can comprise sterile water for injection.The choice criteria of solvent should be the easy evaporative removal of solvent and not produce residual, or its residual quantity is within permission limit.
In above-mentioned liposome, the relative molar mass of mitoxantrone and lipid is than there being a suitable scope, preferred scope in the more preferred scope of 1:1-30 in 1:1-25, preferred scope in 1:1-20, most preferred ratio at 1:15.
Can carry out the formation of the operation inducing lipids bodies such as the aquation of adipose membrane in liposomal preparation process, the solution of aquation can select polar solvent, specifically can comprise normal saline solution and PBS solution, and solution can be dissolved with mitoxantrone further.Multiple hybrid mode can be selected after solution adds to carry out the parcel of adipose membrane to medicine.The formation that DL oscillatory process should be liposome provides enough shearing forces, such as, can adopt magnetic agitation, and the mode such as vortex oscillation, supersound process carries out the preparation of liposome.Preferred method can adopt the mode of vortex oscillation, and the liposomal form obtained is multilamellar liposome, if expect, unilamellar liposome is by membrane filtration or the mode such as ultrasonic further.
Above-mentioned gained mitoxantrone liposome by observing the uniform particle sizes of visible lipid body under light microscopic, and without lumps thing, can see liposome particle of uniform size through electron microscopic observation more clearly.Adopt ultramicroscope and particle size analyzer to carry out particle size determination, liposomal particle size scope should at below 150nm, and preferred scope is 100 ~ 120nm.
Above-mentioned gained mitoxantrone liposome can utilize multiple method to measure its envelop rate, such as, can adopt supercentrifugal process, dialysis etc.The computational methods of envelop rate are: dosage × 100% being wrapped in the mitoxantrone amount/mitoxantrone in liposome after envelop rate (the %)=dialysis of mitoxantrone liposome.In the present invention, the envelop rate of mitoxantrone liposome should control on 80%, can bring up on 85% further, further can bring up on 90%.
Above-mentioned gained mitoxantrone liposome has good stability at duration of storage, keeps certain size and integrity before playing its slow releasing function in vivo.Investigated the stability of mitoxantrone novel form in the present invention, its envelop rate in 8 hours is in steady statue, has good stability.
Above-mentioned gained mitoxantrone liposome is little compared with conventional mitoxantrone preparation toxic and side effects, to be mainly reflected in single-dose toxicity test mitoxantrone liposome compared with free mitoxantrone medicine, higher dosage can be used, the long-term survival rate of mice can reach 100%, and under same dose, mitoxantrone liposome to leukocytic lethality and all more conventional mitoxantrone of bone marrow depression toxicity less; In multiple dosing toxicity test, the more conventional mitoxantrone group of mitoxantrone liposome group mouse survival rate of same dose significantly rises.
The above-mentioned gained mitoxantrone Liposomal formulation half-life can reach 0.96h, more conventional mitoxantrone (half-life: 0.11h) significant prolongation, and reach peak concentration and significantly improve, clearance rate significantly reduces, distribution specific ionization mitoxantrone in heart is low 3 times, show that the pharmacokinetics behavior of mitoxantrone Liposomal formulation is well improved, and it significantly reduces to the toxic and side effects of cardiac muscle.
Above-mentioned gained mitoxantrone Liposomal formulation possesses better antitumor curative effect compared with free mitoxantrone, and the inhibition that mitoxantrone liposome increases gross tumor volume is more remarkable.In addition utilize Liposomal formulation can reduce mitoxantrone toxic and side effects, when mitoxantrone dosage is identical, Lipidosome better can reduce the laboratory animal mortality rate because drug toxicity causes.
The using method of above-mentioned gained mitoxantrone Liposomal formulation treats with one or more use in conjunction of other front-line chemotherapeutic agents the innocent and malignant tumour comprising leukemia or breast carcinoma, and the antitumor action of drug combination is better than single drug and is better than free MTO and other drug joins and uses.In the present invention, LEM can significantly improve the survival rate of Leukemia Model mice with cytosine arabinoside, cyclophosphamide or vincristine conbined usage respectively; LEM uses with paclitaxel, cisplatin or cyclophosphamide combined respectively, compared with other experimental grouies, more remarkable to the inhibitory action of breast cancer model mice tumors grew, illustrates that other chemotherapy drugs in combination of LEM use the therapeutic effect that can significantly improve tumor.
The route of administration of above-mentioned gained mitoxantrone Liposomal formulation is varied, can select oral administration, intravenously administrable, topical, Intraperitoneal medication etc., but first-selected parenteral administration, more preferably administering mode is intravenously administrable.
In sum, the Liposomal formulation of mitoxantrone disclosed in the present invention substantially increases the picked-up of mitoxantrone medicine; Improve survival rate that is acute and long term toxicity test small mouse, and reduce MTO bone marrow depression toxicity and myocardial toxicity, illustrate that LEM reduces medicine toxic and side effects; Mice Half-life in vivo is 8.7 times of MTO, substantially prolongs the action time of medicine; Inside and outside anti-tumor activity is all better than MTO, has better played the curative effect of medicine; And when applying with chemotherapy drugs in combination such as cytosine arabinoside, cyclophosphamide, vincristine, paclitaxel, cisplatin, its antitumor action is significantly better than the antitumor curative effect of simple mitoxantrone Liposomal formulation.
Accompanying drawing explanation
Fig. 1: LEM grain size distribution.
Fig. 2: variable concentrations MTO and LEM is to HL-60 cytotoxic effect.
Fig. 3: variable concentrations MTO and LEM is to MCF-7 cytotoxic effect.
Fig. 4: MTO and LEM blood plasma Drug-time curve.
Fig. 5: LEM associating cytosine arabinoside is to L1210 model mice survival rate result.
Fig. 6: LEM commissural arch phosphamide is to L1210 model mice survival rate result.
Fig. 7: LEM associating vincristine is to L1210 model mice survival rate result.
Fig. 8: LEM associating cytosine arabinoside is to HL-60 model mice survival rate result.
Fig. 9: LEM commissural arch phosphamide is to HL-60 model mice survival rate result.
Figure 10: LEM associating vincristine is to HL-60 model mice survival rate result.
Figure 11: LEM associating cytosine arabinoside is to P388 model mice survival rate result.
Figure 12: LEM commissural arch phosphamide is to P388 model mice survival rate result.
Figure 13: LEM associating vincristine is to P388 model mice survival rate result.
Figure 14: LEM associating paclitaxel is to 4T1 model mice gross tumor volume result.
Figure 15: LEM associating paclitaxel respectively organizes body weight change result to 4T1 model mice.
Figure 16: LEM combination with cisplatin is to 4T1 model mice gross tumor volume result.
Figure 17: LEM combination with cisplatin anti-4T1 mouse tumor photo.
Figure 18: LEM commissural arch phosphamide is to 4T1 model mice gross tumor volume result.
Figure 19: LEM associating paclitaxel is to MCF-7 model mice gross tumor volume result.
Figure 20: LEM combination with cisplatin chemotherapy MCF-7 model mice gross tumor volume result.
Figure 21: LEM associating Treated with Chemotherapy with Cyclophosphamide MCF-7 model mice gross tumor volume result.
Figure 22: LEM associating Paclitaxel Chemotherapy MDA-MB-231 model mice gross tumor volume result.
Figure 23: LEM combination with cisplatin chemotherapy MDA-MB-231 model mice gross tumor volume result.
Figure 24: LEM associating Treated with Chemotherapy with Cyclophosphamide MDA-MB-231 model mice gross tumor volume result.
Detailed description of the invention
The present invention is described further now to utilize embodiment, and embodiment only for explaining goal of the invention, instead of is used for limiting the present invention.
Embodiment 1: prepare mitoxantrone liposome (LEM) preparation
1,1 ', 2,2 '-4 myristoyl cuorin, lecithin and cholesterol are that the ratio of 1:5:10 is lyophilized into powder type with mol ratio.Be that the aseptic mitoxantrone normal saline solution of 1.0mg/ml joins in the middle of dry lipid by concentration.The molar ratio of medicine and lipid is 1:15.By above mixture aquation 2h at ambient temperature, then by the supersound process 10min in bath formula ultrasonic device of the suspension after aquation, obtain LEM.
The envelop rate of gained liposome of the present invention is 89.41 ± 1.26%.The liposome mean diameter 100-120nm (Fig. 1) that the method is obtained, 8h lactone liposome stability reaches 94%.
Embodiment 2: prepare mitoxantrone liposome (LEM) preparation
Be that the ratio of 1:7:12 is lyophilized into powder with mol ratio by cuorin, phosphatidylcholine, cholesterol.0.5mg/ml mitoxantrone normal saline solution mixes with dried lipid.Medicine fat mol ratio is 1:12.5.Mixture is aquation 2h under room temperature, ultrasonic 10min.The liposome of parcel mitoxantrone can be obtained.In liposome, the amount of mitoxantrone is measured in 658nm place by spectrophotometer.Entrapment efficiency is by following formulae discovery: envelop rate=(drug level before the drug level/dialysis after dialysis) × 100%.
The envelop rate of the preparation-obtained mitoxantrone liposome of said method is 94.62 ± 3.19%, and the particle diameter of gained liposome is 57.63 ± 1.24nm, and has good stability, under room temperature, mitoxantrone liposome having good stability within 8 hours, percolation ratio lower than 5%, in table 1.
Table 1LEM tri-batch sample percolation ratio detects
The cell in vitro poison experiment of embodiment 3:LEM
(cell divides into groups: normal saline group, blank liposome group, LEM group the HL60 leukaemia of exponential phase to be inoculated into 96 porocyte culture plates, MTO group) cultivate, add LEM or MTO of variable concentrations afterwards, the multiple hole of each concentration 3, at 5%CO
2, cultivate 72 hours in 37 DEG C of cell culture incubators, adopt mtt assay to evaluate LEM and MTO to the cytotoxicity of different cell line, with the action intensity of preliminary forecasting LEM and the sensitivity to dissimilar tumor cell.Negative control is normal saline or blank liposome contrast.The cytotoxicity of mtt assay to two kinds of preparations is adopted to study.
Ask cell survival rate by following formula, ask IC50 according to linear equation.
Cell survival rate={ processed group D (570) value/matched group D (570) value } × 100%
Cell inhibitory rate=1-cell survival rate.
Shown in result, MTO with LEM of same concentrations compares, and LEM treatment group has stronger cytotoxicity (Fig. 2).
The cell in vitro poison experiment of embodiment 4:LEM
The MCF-7 breast cancer cell of exponential phase is inoculated into 96 porocyte culture plates, in 37 DEG C and 5%CO
2cell culture incubator in cultivate, remove culture medium after adherent, every hole add variable concentrations containing the culture medium of LEM or MTO, zeroing hole and matched group add the culture medium of respective volume.The cytotoxicity of mtt assay to two kinds of preparations is adopted to study.
Result shows that LEM and MTO all demonstrates the growth inhibited effect to MCF-7 cell, and along with the increase of drug level, strengthens the inhibitory action of tumor cell.After LEM and MTO and MCF-7 cell hatches 72h altogether, when the concentration of LEM and MTO is 1000ng/ml, tumor cell survival is respectively (17 ± 0.41) % and (11 ± 0.72) %.(Fig. 3).
The toxicity in vivo test of embodiment 5:LEM
Adopt CD2F1 mice single or multiple injection MTO and LEM to compare two kinds of formulations toxic.
In single-dose experiment, get male CD2F1 mice single tail vein injection MTO5.0mg/kg, 25.0mg/kg or LEM5.0-35.0mg/kg respectively.Matched group is injecting normal saline or blank liposomes liquid solution (Lipid Concentration is equivalent to Lipid Concentration in 35.0mg/kgLEM) respectively, and every day observes mice, weighs Mouse Weight 2 times weekly.Experiment carries out 67 days.After administration, the 3rd day and experiment are got mice and are carried out histopathology each group of last day.Experimental result shows, LEM shows the toxicity lower compared with MTO, and the mice of injection LEM35.0mg/kg is without death, and long-term survival rate is 100%, in table 2; Numeration of leukocyte and spleen and the display of marrow protection testing result, the toxic and side effects of LEM is lower, in table 3.
The survival rate result of study (single-dose) of table 2MTO and LEM in Mice Body
NA:MTO dosage does not detect; * compared with MTO group, P<0.001;
median survival interval is 9.5 days;
median survival interval is 6.5 days.
Table 3MTO and LEM single-dose respectively organizes the numeration of leukocyte of mice and spleen and marrow protection situation
§ blank liposome (BL) dosage is equivalent to the LEM of 35.0mg/kg; * MTO group compared with normal saline group or LEM group compared with BL, P<0.01;
mTO group compared with normal saline group or LEM group compared with BL, P<0.001; Without survivor; ++ mild toxicity; +++ moderate toxicity; N is normal; NA does not detect.
In multiple dosing experiment, get the female CD2F1 mice every 5 days same dose drug (MTO:2.5-7.5mg/kg of difference tail vein injection; LEM:2.5-10.0mg/kg).Matched group is injecting normal saline or blank liposomes liquid solution (Lipid Concentration is equivalent to Lipid Concentration in 7.5mg/kgLEM) respectively, and every day observes mice, weighs Mouse Weight 2 times weekly.Within 64 days after first time administration, stop experiment.After administration, the 7th day and experiment are got mice and are carried out histopathology each group of last day.Result shows, and LEM respectively organizes mouse survival rate significantly to be increased, in table 4.
Table 4MTO and LEM multiple dosing respectively organizes mouse survival rate
NA:MTO dosage group does not detect; * compared with MTO group, P<0.001;
median survival interval is 7.5 days;
median survival interval is 6.5 days;
median survival interval is 7.5 days.
Pharmacokinetic in embodiment 6:LEM Mice Body
Get male CD2F1 mice, respectively MTO or LEM of tail vein injection 5.0mg/kg.5min after administration, 15min, 30min, 1h, 2h, 4h, 8h, 24h and 48h often group carries out heart puncturing extracting blood and is placed in the calparine pipe of the citrate buffer (pH3.0) containing 20 μ l100mg/ml ascorbic acid after getting 4 mouse anesthesias, the centrifugal 10min separated plasma of 2000rpm at 4 DEG C.Core, liver, spleen, lung, kidney ice normal saline flushing.Tissue and blood plasma-20 DEG C store in order to detecting.Adopt the mitoxantrone in reversed phase high-performance liquid chromatography analysed for plasma and tissue sample.Mitoxantrone adopts reversed phase chromatographic column to be separated, and use mobile phase is for acetonitrile (33%) and 0.16M and the mixed solution of the Ammonium formate buffer of pH2.7 (67%), and flow velocity is 1.0ml/min.Mitoxantrone determined wavelength is 600nm.The retention time of internal standard substance and mitoxantrone is respectively 3.7 and 4.3min.Within the scope of mitoxantrone treatment, the method is linear, reproducible.Sensitivity is 10ng/ml.Plasma pharmacokinetics parameter carries out analysis and assessment by practical pharmacokinetic program (3P87).
Result shows that LEM has longer circulation time and the peak concentration of Geng Gao compared with MTO, and tissue distribution results shows that LEM more conventional MTO of (in heart) distribution in important organ significantly reduces.MTO and LEM mice plasma concentration curve is shown in Fig. 4, and pharmacokinetic parameter is in table 5, and tissue distribution concentration is in table 6.
Plasma pharmacokinetics parameter (dosage: 5.0mg/kg, i.v.) (n=4) of table 5MTO and LEM in CD2F1 Mice Body
*P<0.001；**P<0.03；***P<0.002。
Distribution (dosage: 5.0mg/kg, i.v.) (n=4) of table 6MTO and LEM vitals in CD2F1 Mice Body
*P<0.02；**P<0.001
Embodiment 7:LEM combines the antitumor curative effect research of other chemotherapeutics in leukemia animal model
Get Balb/c male mice 2, lumbar injection L1210 Cell sap, 1 × 10
6cell/0.2ml.Extract the centrifugal removing erythrocyte of ascites after ascites to be formed under aseptic condition, carrying out L1210 cell counting and adjusting cell concentration is 5 × 10
6individual/ml.The animal raising that conforms is divided into 12 groups after one week at random, often organizes 6.In d0 lumbar injection L1210 ascites dilutions, 1 × 10
6individual/only.Start vein in the rear 24h of inoculation and give medicine.Specific as follows:
Model group: tail vein injection saline, 0.2ml/ only.
MTO group: tail vein injection MTO, 5mg/kg.
LEM group: tail vein injection LEM, 5mg/kg.
Cytosine arabinoside group: tail vein injection cytosine arabinoside 19.5mg/kg, once a day, continuous 5 days.
MTO combines cytosine arabinoside group: tail vein injection MTO1mg/kg, once a day, for three days on end; Cytosine arabinoside 19.5mg/kg, once a day, continuous 5 days.
LEM combines cytosine arabinoside group: tail vein injection LEM1mg/kg, once a day, for three days on end; Cytosine arabinoside 19.5mg/kg, once a day, continuous 5 days.
Cyclophosphamide group: tail vein injection cyclophosphamide 126mg/kg.
MTO commissural arch phosphamide group: d1 tail vein injection MTO1mg/kg, once a day, for three days on end; D2 tail vein injection cyclophosphamide 126mg/kg.
LEM commissural arch phosphamide group: d1 tail vein injection LEM1mg/kg, once a day, for three days on end; D2 tail vein injection cyclophosphamide 126mg/kg.
Vincristine group: tail vein injection vincristine 0.26mg/kg/w.
MTO combines vincristine group: d1 tail vein injection MTO1mg/kg, once a day, for three days on end; Vincristine 0.26mg/kg/w.
LEM combines vincristine group: d1 tail vein injection LEM1mg/kg, once a day, for three days on end; Vincristine 0.26mg/kg/w.
This experiment shows, comparatively MTO is better for the antitumor action of LEM, effectively extends life span, improves animal survival rate.And LEM and each chemotherapy drugs in combination can play better antitumor action.Wherein, in LEM commissural arch phosphamide group mice 60 days, survival rate can reach 50%, LEM and combines cytosine arabinoside group mouse survival rate and reach 20%, sees Fig. 5-7.
Embodiment 8:LEM combines the antitumor curative effect research of other chemotherapeutics in leukemia animal model
Get SCID mice 60,4-6 week age, body weight (16.5 ~ 20.5) g, gnotobasis raise.Tail vein injection HL-60 cell 1 × 10
7individual/only.Model mice is divided into 12 groups at random, often organizes 6.Administering mode, with embodiment 7, observes each group of mouse survival time.
Result shows, LEM comparatively can better improve model mice survival rate by MTO, and acquired by combining with clinical conventional front-line chemotherapeutic agents, therapeutic effect is better, sees Fig. 8-10.
Embodiment 9:LEM combines the antitumor curative effect research of other chemotherapeutics in leukemia animal model
Get DBA mice 60,4-6 week age, body weight (18 ~ 22) g, gnotobasis raise.Lumbar injection exponential phase P388 cell 5 × 10
6individual/only.Model mice is divided into 12 groups at random, often organizes 6.Administering mode, with embodiment 7, observes each group of mouse survival time.
This experiment shows, comparatively MTO is better for the antitumor action of LEM, effectively extends life span, improves animal survival rate.And LEM and each chemotherapy drugs in combination can play better antitumor action.Wherein, LEM commissural arch phosphamide group and LEM combine survival rate in cytosine arabinoside group mice 60 days can reach 30%, the results are shown in Figure 11-13.
Embodiment 10:LEM combines the antitumor curative effect research of other chemotherapeutics in breast cancer animal model
Abandon supernatant by centrifugal after the trypsinization of 4T1 breast cancer cell, with the resuspended rear counting of 4ml physiological saline solution, after recentrifuge, be configured to 4 × 10 with physiological saline solution
6the cell suspension of/ml, under being inoculated in mice second mammary fat pad, inoculation volume is 0.05ml that is 2 × 10
5individual cell.Treat that tumor average diameter is that 4-5mm and mean tumour volume are about 50mm
3for model is set up.Tumor is less than 50mm
3rejecting, all the other mices are divided into 12 groups at random, often organize 8.Give medicine respectively.Give medicine respectively.Specific as follows:
Blank group: tail vein injection saline, 0.2ml/ only.
Model group: tail vein injection saline, 0.2ml/ only.
MTO group: tail vein injection mitoxantrone normal saline solution, 5mg/kg.
LEM group: tail vein injection mitoxantrone liposome solutions, 5mg/kg.
Paclitaxel group: tail vein injection paclitaxel glucose solution 36.8mg/kg.
MTO combines paclitaxel group: tail vein injection mitoxantrone normal saline solution 2.5mg/kg after tail vein injection paclitaxel glucose solution 36.8mg/kg.
LEM combines paclitaxel group: tail vein injection mitoxantrone liposome solutions 2.5mg/kg after tail vein injection paclitaxel glucose solution 36.8mg/kg.
Cisplatin group: tail vein injection cisplatin normal saline solution 6.31mg/kg, continuous 2 days.
MTO combination with cisplatin group: tail vein injection mitoxantrone normal saline solution 2.1mg/kg, injection cisplatin normal saline solution 6.31mg/kg, continuous 2 days.
LEM combination with cisplatin group: tail vein injection mitoxantrone liposome solutions 2.1mg/kg, injection cisplatin normal saline solution 6.31mg/kg, continuous 2 days.
Cyclophosphamide group: tail vein injection cyclophosphamide 105mg/kg.
MTO commissural arch phosphamide group: tail vein injection mitoxantrone normal saline solution 2.1mg/kg and cyclophosphamide 105mg/kg.
LEM commissural arch phosphamide group: tail vein injection mitoxantrone liposome solutions 2.1mg/kg and cyclophosphamide 105mg/kg.
Often organize tumor animal within the 1st day, to rise after inoculation, use vernier caliper measurement tumor size, measure 2 times weekly, and calculate gross tumor volume.The computing formula of gross tumor volume (tumorvolume, TV) is: V=1/2 × a × b
2.Wherein: a and b represents long and wide respectively.
The antitumaous effect experiment of different dosing group in Balb/c mouse model has carried out 29 days, and result shows the mouse tumor volume of each treatment group obviously less than the gross tumor volume of normal saline group (p < 0.05); LEM comparatively MTO has better antitumor activity, significantly limit the growth of model mice tumor tissues, and with other front-line chemotherapeutic agents use in conjunction better effects if, and each group Mouse Weight curve shows LEM, and comparatively MTO toxicity is lower, the results are shown in Figure 14-18.
Embodiment 11:LEM combines the antitumor curative effect research of other chemotherapeutics in breast cancer animal model
Breast cancer model is set up: the MCF-7 (2 × 10 of trophophase of taking the logarithm in Balb/c nude mouse
6individual cell/0.2ml), subcutaneous injection is mammary region on the left of Balb/c nude mice.Treat that tumor growth is approximately 50mm to average external volume
3after, start treatment.Lotus MCF-7 mice with tumor is divided into 13 groups (n=8) at random.Each group of administering mode is with embodiment 10, and periodic measurement respectively organizes mouse tumor volume.
Result shows that LEM and MTO compares and has better anti-tumor activity, and best with other chemotherapy drugs in combination effects, the results are shown in Figure 19-21.
Embodiment 12:LEM combines the antitumor curative effect research of other chemotherapeutics in breast cancer animal model
Breast cancer model is set up: the MDA-MB-231 (1 × 10 of trophophase of taking the logarithm in Balb/c nude mouse
6individual cell/0.1ml), subcutaneous injection is mammary region on the left of Balb/c nude mice.Treat that tumor growth is approximately 50mm to average external volume
3after, start treatment.Lotus MDA-MB-231 mice with tumor is divided into 13 groups (n=8) at random.Each group of administering mode is with embodiment 10, and periodic measurement respectively organizes mouse tumor volume.
Result shows that LEM and MTO compares and has better anti-tumor activity, and best with other chemotherapy drugs in combination effects, sees Figure 22-24.
Claims (10)
1. the invention discloses the application of novel mitoxantrone liposome combined chemotherapy medicine in antineoplaston, it is characterized in that: itself and other chemotherapy drugs in combination application has better antitumor curative effect.
2. the Liposomal formulation described in right 1 is mitoxantrone liposome, also can be the Liposomal formulation of other chemotherapeutics, it is characterized in that: described Liposomal formulation constituent phospholipid material can be natural, synthetic and semisynthetic; Can be hydrophilic or hydrophobic; Can be with positive charge or with negative charge and electroneutral, be more preferably electronegative phospholipid as cuorin, Phosphatidylserine, phosphatidylinositols etc., the envelop rate as mitoxantrone can be increased under electrostatic attraction effect.
3. the Liposomal formulation preparation method described in claim 1 and 2 can be membrane process, ultrasonic method, ammonium sulphate gradient and lyophilization, removal of surfactant method, high pressure homogenization method etc., and more conventional is membrane process, ammonium sulphate gradient and lyophilization; The present invention's preparation method used can select from above numerous method and prepared Liposomal formulation envelop rate at least more than 85%, particle size range should within the scope of 10nm-0.5 μm.
4. the Liposomal formulation route of administration described in claim 1,2,3 can be oral administration, intravenously administrable, topical, Intraperitoneal medication etc.; Drug safety is higher than mitoxantrone, and after can comprising medication, the weight of animals alleviates less, mortality of animals is low, Leukocyte Killing is low in body, myocardial toxicity is low, bone marrow and spleen hemopoietic function suppress the aspect such as low.
5. the comparatively free mitoxantrone of the Liposomal formulation pharmacokinetics behavior described in claim 1,2,3 has clear improvement, and is embodied in drug half-life and extends, in main organs distributed density reductions etc. such as cardiac muscles.
6. the Liposomal formulation described in claim 1,2,3 can be applied with other chemotherapy drugs in combination, and described the second therapeutic agent comprises antineoplastic agent, antifungal agent, antibiotic and other active medicine.
7. the antineoplastic agent described in claim 6 can be alkylating agent, comprises cyclophosphamide, nimustine etc.; Also can be antimetabolite, comprise 5-fluorouracil, gemcitabine, methotrexate etc.; Can also be antitumor antibiotics, comprise cytosine arabinoside, doxorubicin, actinomycin D, mitomycin etc.; Can also be plant anticarcinogen, comprise irinotecan, paclitaxel, vincristine etc.; Can also be hormone and endocrine class medicine, comprise tamoxifen, atamestane etc.; Can also be miscellany, comprise cisplatin, dacarbazine etc.; All right biological response modifier, as interferon, lentinan, thymosin etc.
8. the malignant tumor of the treatment described in claim 1 can be malignant lymphoma, breast carcinoma, acute leukemia, pulmonary carcinoma, melanoma, soft tissue sarcoma, multiple myeloma, hepatocarcinoma, colorectal cancer, renal carcinoma, carcinoma of prostate, carcinoma of endometrium, tumor of testis, ovarian cancer and incidence cancer etc.
9., as described in claim 2 and 7, mitoxantrone Liposomal formulation comparatively mitoxantrone free drug has better curative effect to leukemia; Mitoxantrone Liposomal formulation and cytosine arabinoside, cyclophosphamide and vincristine respectively conbined usage to treat leukemic curative effect better.
10., as described in claim 2 and 7, mitoxantrone Liposomal formulation comparatively mitoxantrone free drug has better curative effect to breast carcinoma; The curative effect that mitoxantrone Liposomal formulation and paclitaxel, cisplatin and cyclophosphamide difference conbined usage treat breast carcinoma is better.
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