CN105709227A - Anti-tumor medicine composition - Google Patents
Anti-tumor medicine composition Download PDFInfo
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- CN105709227A CN105709227A CN201610079038.1A CN201610079038A CN105709227A CN 105709227 A CN105709227 A CN 105709227A CN 201610079038 A CN201610079038 A CN 201610079038A CN 105709227 A CN105709227 A CN 105709227A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/49—Urokinase; Tissue plasminogen activator
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
Abstract
The invention discloses an anti-tumor medicine composition comprising a fiber protein regulation medicine with a two-week dosage and a tumor inhibitor.The fiber protein regulation medicine and the tumor inhibitor are combined, the use amount of the fiber protein regulation medicine is controlled, and accordingly the delivery effect of the tumor inhibitor is improved.On the premise that normal functions of vessels are maintained, targeted administration is achieved as much as possible, and therefore a good anti-tumor effect is good.
Description
Technical field
The invention belongs to biomedicine field, more particularly, to a kind of antineoplastic pharmaceutical compositions.
Background technology
Tumor be body under various tumorigenesis factor effects, the cell of local organization loses the normal regulation to its growth on gene level and causes paraplasm and differentiation and the neoplasm that formed.Neoplasm, once be formed, does not stop growing because the cause of disease eliminates, and his growth is not by normal body physiological regulation, but destroys normal structure and organ, and this point is especially apparent in malignant tumor.Compared with benign tumor, malignant growth speed is fast, in infiltrative growth, easily there is hemorrhage, downright bad, ulcer etc., and often have metastasis, cause human body to become thin, unable, anemia, inappetence, heating and serious organ function impaired etc., ultimately cause death.
Current antitumor drug is study hotspot, more effective antitumor drug, still has yet-to-be developed.
Summary of the invention
Disadvantages described above or Improvement requirement for prior art, the invention provides a kind of antineoplastic pharmaceutical compositions, its object is to the combination by fibrin regulating medicine and tumor inhibitor, a kind of anti-tumor compositions with excellent antitumor effect and preferably targeting is thus provided.
For achieving the above object, according to one aspect of the present invention, it is provided that a kind of antineoplastic pharmaceutical compositions, including fibrin regulating medicine and the tumor inhibitor of two weeks dosages.
Preferably, described antineoplastic pharmaceutical compositions, its fibrin regulating medicine is thrombolytic drug and/or anticoagulant.
Preferably; described antineoplastic pharmaceutical compositions, its thrombolytic drug is that agent is lived or acetylation fibrinolysin is fainted-streptokinase activator complex in streptokinase, urokinase, tissue-type plasminogen activator, rt-PA, single chain urokinase type plasminogen activator fiber type plasmin emblem of fainting.
Preferably, described antineoplastic pharmaceutical compositions, its anticoagulant is injection anticoagulant, oral anticoagulation thing or thrombin inhibitor；The described preferred heparin of injection anticoagulant, low molecular weight；The described preferred warfarin of oral anticoagulation thing, dicoumarol, nitric acid coumarin；The preferred hirudin of described thrombin inhibitor or argatroban.
Preferably, described antineoplastic pharmaceutical compositions, its tumor inhibitor is free tumor inhibitor and/or tumor inhibitor nanometer formulation.
Preferably, described antineoplastic pharmaceutical compositions, its tumor inhibitor is paclitaxel, amycin, doxorubicin or genomic medicine.
Preferably, described antineoplastic pharmaceutical compositions, its nanometer formulation is Polyethylene Glycol-macromolecular material nano-emulsion.
Preferably, described antineoplastic pharmaceutical compositions, its macromolecular material is polylactic acid, polyglycolic-polylactic acid, polycaprolactone or DSPE.
In general, by the contemplated above technical scheme of the present invention compared with prior art, it is possible to obtain following beneficial effect:
The present invention adopts fibrin regulating medicine and tumor inhibitor to combine, and control the consumption of fibrin regulating medicine, thus improving the delivery effect of tumor inhibitor, by increasing the blood vessel number with normal function, increase the delivery of antitumor drug, thus reaching good antitumous effect.
Accompanying drawing explanation
Fig. 1 is the subcutaneous tumor model that embodiment 1 sets up lotus A549 pulmonary carcinoma, and tumor inner fibrin is expressed the experimental result of impact by detection rtPA administration；Wherein Figure 1A is immunofluorescence experiment result, and Figure 1B is Elisa result.
Fig. 2 is that in embodiment 2, rtPA, on the impact of blood perfusion in tumor, and compares with normal saline group；Wherein Fig. 2 A is immunofluorescence experiment result, and Fig. 2 B is the semi-quantitative results of ImageJ statistics.
Fig. 3 is the characterization result of embodiment 2 nanoparticle, and figure A is Electronic Speculum result, and figure B is particle instrument test result.
Fig. 4 is the subcutaneous tumor model that embodiment 3 sets up lotus A549 pulmonary carcinoma, with nir dye DiR marking nano grain, observes nanoparticle distributional difference in rtPA process group and normal saline group tumor.
Fig. 5 is the subcutaneous tumor model that embodiment 4 sets up lotus A549 pulmonary carcinoma, with Coumarin-6 marking nano grain, observes nanoparticle distributional difference in rtPA process group and normal saline group tumor biopsy.
Fig. 6 is embodiment 5 and embodiment 6 sets up lotus A549 lung carcinoma subcutaneous tumors animal model, evaluates rtPA and combines the Nano medication treatment situation to cancer of pancreas.Being divided into four groups: normal saline group, rtPA group, normal saline+NP-PTX organizes and rtPA+NP-PTX group；Fig. 6 A is the change in volume of tumor, Fig. 6 B is the weight of animals change, Fig. 6 C is the tumor peeled off after putting to death animal, and Fig. 6 D is the weight peeling off tumor, and Fig. 6 E is TUNEI apoptosis dyeing (amplification respectively 100 times) after the tumor row specimens paraffin embedding slices of above-mentioned stripping.
Detailed description of the invention
In order to make the purpose of the present invention, technical scheme and advantage clearly understand, below in conjunction with drawings and Examples, the present invention is further elaborated.Should be appreciated that specific embodiment described herein is only in order to explain the present invention, is not intended to limit the present invention.As long as just can be mutually combined additionally, technical characteristic involved in each embodiment of invention described below does not constitute conflict each other.
Antineoplastic pharmaceutical compositions provided by the invention, including fibrin regulating medicine and the tumor inhibitor of two weeks dosages.
Described fibrin regulating medicine is thrombolytic drug and/or anticoagulant.Described thrombolytic drug is that agent (SCUPA) is lived or acetylation fibrinolysin is fainted-streptokinase activator complex (APSAC) in streptokinase, urokinase, tissue-type plasminogen activator (tPA), rt-PA (rtPA), single chain urokinase type plasminogen activator fiber type plasmin emblem of fainting.Described anticoagulant is injection anticoagulant, oral anticoagulation thing or thrombin inhibitor；The described preferred heparin of injection anticoagulant, low molecular weight；The described preferred warfarin of oral anticoagulation thing, dicoumarol, nitric acid coumarin；The preferred hirudin of described thrombin inhibitor or argatroban.
Described tumor inhibitor is free tumor inhibitor and/or tumor inhibitor nanometer formulation.Described tumor inhibitor is paclitaxel, amycin, doxorubicin or genomic medicine.Institute
The nanometer formulation of described tumor inhibitor, it is preferred to the polyethyleneglycol modified liposome in surface, nanoparticle, polymer waterfloocling, polymer micelle, solid lipid nanoparticle.Tumor inhibitor is combined with nano-carrier in the way of wrapping up or be covalently bound, and described nanometer formulation particle diameter is 10-300nm.
State nanometer formulation more preferably Polyethylene Glycol-macromolecular material nano-emulsion.Described macromolecular material is polylactic acid, polyglycolic-polylactic acid, polycaprolactone or DSPE.Molecular weight polyethylene glycol is 1000-20000Da, it is preferable that 2000-5000Da, and polylactic acid molecule amount is 5000-50000Da, it is preferable that 20000-4000Da.
The antitumous effect of anti-tumor compositions of the present invention measures as follows:
With PEG-PLA for carrier, mon-galacta method is adopted to prepare nanoparticle.Zeta/ laser particle analyzer measures mean diameter and current potential, its form of transmission electron microscope observing of nanoparticle.
Set up subcutaneous lotus A549 lung cancer animal models, after the formation of modulate tumor inner fibrin, by the situation of change of immunofluorescence and Elisa technology assessment tumor inner fibrin.
After adopting immunofluorescence to evaluate modulate tumor inner fibrin, the situation of change of inside tumor perfusion.
After IR dyes DiR marking nano grain, after evaluating modulate tumor inner fibrin by small animal living body imager, nano-carrier is enriched with difference in the tumor of experimental group and matched group.
After green fluorescence probe Coumarin-6 marking nano grain, observed after after modulate tumor inner fibrin by frozen section, nano-carrier distributional difference in the tumor of experimental group and matched group.
Tested by Tumor growth inhibition, evaluate the anti-tumor compositions provided by the invention inhibition to A549 tumor.
Compositions provided by the invention has good antitumous effect, it may be possible to due to the fact, that
Effective hemoperfusion of inside tumor is the basis that tumor passs medicine.The new vessels of tumor lacks due to pericyte, basement membrane is imperfect and function imperfection, extrude blood vessel in tumor to a certain extent plus extracellular matrix, the blood perfusion in tumor is often below normal surrounding tissue, thus stoping medicine effectively to arrive tumor thus the medicine affecting tumor delivers.Its strategy of tumor in order to increase the perfusion in tumor, rich blood vessel and substrate abundant is different.For euangiotic tumor, previously study general adopts the means of blood vessel normalization.Owing to the means of this promotion blood vessel normalization decrease the space between vascular endothelial cell to a certain extent; generally can only increase small-molecule drug or the delivery of particle diameter Nano medication (10-40nm) less than normal, it is impossible to increase the delivery of the Nano medication of about 100nm.
Fibrin is as the end-product of blood coagulation waterfall, except being enriched with at endothelial injury position, it is also possible to as one of the composition of tumor stroma at tumor cell external sediment, and in cross-linked state, similar with the fibrin structure of thrombosis, damage location.In tumor stroma, fibrin is formed mainly due to the tissue factor combined effect of tumor vascular leakage and tumor cell surface.Normal structure is owing to the integrity of blood vessel endothelium is without there being fibrinous expression.Fibrin is except possessing the tumour-specific of height, and in its tumor, distribution also exists certain location specific.For the blood vessel tumor compared with horn of plenty, the fibrin in tumor is distributed mainly near vessels, and this is that the blood coagulation waterfall namely started by the tissue factor of process LAN in tumor after penetrating into blood vessel due to Fibrinogen is converted into caused by fibrin.Intratumoral vasculature may be caused a degree of extruding by substantial amounts of fibrin, thus the blood perfusion reduced in tumor and weaken further tumor medicine deliver.
The present invention adopts fibrin regulating medicine and tumor inhibitor to combine, and control the consumption of fibrin regulating medicine, thus improving the delivery effect of tumor inhibitor, by increasing the number of blood vessel with normal function, increase medicine to deliver, thus reaching good antitumous effect.
It is below embodiment:
Embodiment 1
Lotus A549 lung cancer model mice, after continuous two weeks (dosage is 25mg/kg/d) lumbar injections of rtPA, prepares frozen section.Immunofluorescence dyeing result shows, normal saline group fibrin is streak being distributed in around blood vessel, and away from the distribution of blood vessel place seldom (Figure 1A, B).And after rtPA processes, the fracture of tumor inner fibrin in being dispersed in distribution (Fig. 1 C, D), illustrates that rtPA can effectively degrade tumor inner fibrin.Find that fibrinous selective degradation product DDi is about 2.3 times of matched group in rtPA process group by Elisa quantitative analysis further, demonstrate again that the rtPA effective destruction to tumor inner fibrin.
Embodiment 2
RtPA administration terminates rear tail vein and givesThe agglutinin of 488 labellings (488-lectin), dosage is that after 5mg/kg, 1h, carbon dioxide suffocates rapid PBS and 4% paraformaldehyde solution perfusion after execution animal, and prepares frozen section.After CD31 immunofluorescence dyeing, Laser Scanning Confocal Microscope analytic function blood vessel (488+CD31+) account for the ratio of all blood vessels (CD31+), result shows, after rtPA processes, and the blood vessel showed increased of inside tumor functionalization, increase 75.5 ± 7.0% from the 38.3 ± 3.9% of normal saline group, be greatly improved the blood perfusion (Fig. 2) in tumor.It is presumed that be primarily due to rtPA to destroy the fibrin near tumor vessel, relieve fibrin to tumor vascular extruding, make the original extruded blood vessel of part regain perfusion after extruding releases, become the blood vessel having function, establish condition for effectively delivering of Nano medication.
Embodiment 3
Nanoparticle adopts single emulsion process to prepare.The polyethylene glycol-polylactic acid (MPEG-PLA) of 24mg, joins after dissolving with 1mL dichloromethane in the sodium cholate solution of 5mL0.6%, and ice-water bath 5s/5s impulse ultrasound 15 times afterwards, power is 200W.Rotary evaporation is concentrated into suitable concn after removing dichloromethane and namely obtains unmodified nanoparticle (NP).Granularity/potential measurement instrument result display nanoparticle particle diameter is 115.5 ± 0.7nm (Fig. 3 A), and current potential is 11.5 ± 0.6mv, and under Electronic Speculum, Nanoparticle Size is homogeneous, good dispersion, and smooth surface is in rule spheroidal (Fig. 3 B).
Embodiment 4
After rtPA administration terminates, with nir dye DiR marking nano grain, adopt small animal living body imager detection nanoparticle at the aggregation extent of tumor locus by 24h after 10 μ g/kg dosage tail intravenously administrables, result prompting rtPA process is more beneficial for nanoparticle at cohesion (Fig. 4 A left side: the rtPA of tumor, the right: normal saline group), in vitro tissue imaging and semi-quantitative results confirm, in the tumor tissues of rtPA process group, average fluorescent strength is about 2.0 times (Fig. 4 B and C) of normal saline group tumor tissues, and experimental group is compared with matched group, Mean Fluorescence in normal organ does not have significant difference (Fig. 4 D and E).Illustrate that the process of rtPA can be effectively increased nanoparticle distribution in tumor tissues, but on normal intraorganic nanoparticle distribution not impact.
Embodiment 5
After rtPA administration terminates, with green fluorescence probe Coumarin-6 marking nano grain, by 4h after 0.05mg/kg dosage tail intravenously administrable, perfusion also prepares frozen section.Confocal microscopy result shows, rtPA process group nanoparticle can be widely distributed in inside tumor, and arrives distance blood vessel tumor locus (Fig. 5, C, D) remotely.And in normal saline, nanoparticle major part is near vessels, and fluorescence more weak compared with rtPA group (Fig. 5, A, B).It is presumed that be the action breaks down fibrin of near vessels due to rtPA, relieve vascular compression and reduce Nano medication penetration resistance that may be present, it is possible to Nano medication be effectively delivered to tumor tissues and be comparatively uniformly distributed in whole tumor tissues.
Embodiment 6
When diameter of tumor reaches 4-5mm, 24 model of nude mice bearing tumor are divided into four groups, often group 6.A, matched group (two weeks normal saline lumbar injections start tail vein from second week and give normal saline)；B, rtPA group (two weeks rtPA lumbar injections start tail vein from second week and give normal saline)；C, NP-PTX group (two weeks normal saline lumbar injections start tail vein from second week and give NP-PTX)；D, rtPA+NP-PTX group (two weeks rtPA lumbar injections start tail vein from second week and give NP-PTX).Tail intravenously administrable starts to be calculated as the 0th day, and PTX dosage is 8mg/kg, within every two days, is administered once, the body weight of the every two days sizes recording a tumor and tumor-bearing mice during experiment.It is administered carbon dioxide smother play after continuation after terminating is monitored 4 days and puts to death animal, take tumor tissues, weigh and prepare frozen section, description with reference to TUNEL test kit carries out apoptosis dyeing, the Hochest33342 room temperature dyeing 5min, the PBS that adopt 1 μ g/ml wash the situation being placed on fluorescence microscopy Microscopic observation different disposal group tumor tissues inner tumour cell apoptosis three times.The weight of the nude mice according to record draws Mouse Weight change curve, calculates inhibition rate of tumor growth.Gross tumor volume change curve shows, normal saline group tumor sustainable growth, the tumor growth pattern being given only rtPA group is similar with normal saline group.And be given only NP-PTX group and can to a certain degree suppress the growth of tumor.On the basis giving rtPA, NP-PTX can more singly be administered NP-PTX group and suppress the growth (Fig. 6 A, C, D) of tumor more significantly.The tumor weight suppression ratio of tumor growth is respectively as follows: 35.7% and 73.7% by NP-PTX and rtPA+NP-PTX group, to gross tumor volume suppression ratio respectively 42.8% and 71.7%.During whole experiment, each body weight no significant difference (Fig. 6 B) organizing tumor-bearing mice, illustrate that PTX dosage in tolerance range, can not cause obvious toxic-side effects mice.TUNEL coloration result display normal saline group only has, with rtPA group, the individual cells apoptosis being dispersed in, and NP-PTX group can cause slightly many apoptosis of tumor cells, rtPA+NP-PTX group then can cause in tumor tissues apoptosis (Fig. 6 E) widely (to be followed successively by matched group from left to right, rtPA group, NP-PTX group and rtPA+NP-PTX group), this result is consistent with the gross tumor volume change curve of reaction tumor growth situation.
Those skilled in the art will readily understand; the foregoing is only presently preferred embodiments of the present invention; not in order to limit the present invention, all any amendment, equivalent replacement and improvement etc. made within the spirit and principles in the present invention, should be included within protection scope of the present invention.
Claims (8)
1. an antineoplastic pharmaceutical compositions, it is characterised in that include fibrin regulating medicine and the tumor inhibitor of two weeks dosages.
2. antineoplastic pharmaceutical compositions as claimed in claim 1, it is characterised in that described fibrin regulating medicine is thrombolytic drug and/or anticoagulant.
3. antineoplastic pharmaceutical compositions as claimed in claim 2; it is characterized in that, described thrombolytic drug is that agent is lived or acetylation fibrinolysin is fainted-streptokinase activator complex in streptokinase, urokinase, tissue-type plasminogen activator, rt-PA, single chain urokinase type plasminogen activator fiber type plasmin emblem of fainting.
4. antineoplastic pharmaceutical compositions as claimed in claim 2, it is characterised in that described anticoagulant is injection anticoagulant, oral anticoagulation thing or thrombin inhibitor；The described preferred heparin of injection anticoagulant, low molecular weight；The described preferred warfarin of oral anticoagulation thing, dicoumarol, nitric acid coumarin；The preferred hirudin of described thrombin inhibitor or argatroban.
5. antineoplastic pharmaceutical compositions as claimed in claim 1, it is characterised in that described tumor inhibitor is free tumor inhibitor and/or tumor inhibitor nanometer formulation.
6. antineoplastic pharmaceutical compositions as claimed in claim 5, it is characterised in that described tumor inhibitor is paclitaxel, amycin, doxorubicin or genomic medicine.
7. antineoplastic pharmaceutical compositions as claimed in claim 5, it is characterised in that described nanometer formulation is Polyethylene Glycol-macromolecular material nano-emulsion.
8. antineoplastic pharmaceutical compositions as claimed in claim 7, it is characterised in that described macromolecular material is polylactic acid, polyglycolic-polylactic acid, polycaprolactone or DSPE.
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| Publication number | Priority date | Publication date | Assignee | Title |
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