CN111789866A - Enhancer of antitumor effect of polymer-type anticancer drug - Google Patents

Enhancer of antitumor effect of polymer-type anticancer drug Download PDF

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CN111789866A
CN111789866A CN202010209784.4A CN202010209784A CN111789866A CN 111789866 A CN111789866 A CN 111789866A CN 202010209784 A CN202010209784 A CN 202010209784A CN 111789866 A CN111789866 A CN 111789866A
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anticancer drug
polymer
drug
apatite
enhancer
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吴鑫
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Nano Surpass Co ltd
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Abstract

A dual-drug cancer therapeutic agent, its drug kit, and the use of the related drugs of anti-tumor effect enhancer are provided. By administering an enhancer containing carbonic apatite but not containing a polymer type anticancer drug before, after or simultaneously with the administration of the polymer type anticancer drug, the polymer type anticancer drug can be efficiently accumulated in the tumor tissue, and the antitumor effect thereof can be drastically enhanced.

Description

Enhancer of antitumor effect of polymer-type anticancer drug
Technical Field
The present invention relates to an enhancer for enhancing the antitumor effect of a polymer type anticancer drug. The present invention also relates to a cancer therapeutic agent using the enhancer.
Background
In recent years, the survival rate of cancer patients has been on the rise due to the progress of cancer therapeutic drugs, therapeutic methods, and the like, but cancer still accounts for the 1 st cause of death in japan, and even at present, over 30 ten thousand of japanese people die each year due to cancer.
Cancer treatment methods are largely classified into surgical therapy, radiotherapy, and chemotherapy. Among them, chemotherapy is a therapy in which an anticancer drug is administered to a cancer patient, and is applied to preoperative/postoperative adjuvant chemotherapy for eradicating a lesion thereof to improve the curative effect before and after surgery or radiotherapy, or to the treatment of cancer of systemic metastasis which cannot be treated with surgery or radiotherapy. In the past, various anticancer drugs such as metabolic antagonists, alkylating drugs, platinum preparations, topoisomerase inhibitors, molecular targeting drugs, antitumor antibiotics, and the like have been practically used in the clinic, and some cancers have been expected to be cured.
However, although conventional anticancer drugs have confirmed a certain therapeutic effect, the therapeutic effect is insufficient or the effect varies depending on the case, and it is also true that the therapeutic effect achieved by chemotherapy is limited. Therefore, in recent years, various techniques for enhancing the antitumor effect of anticancer drugs have been studied and proposed in order to improve the therapeutic effect of chemotherapy. For example, patent document 1 reports that isosorbide dinitrate can enhance the antitumor effect of a platinum preparation. In addition, patent document 2 reports that the antitumor effect of an anticancer drug can be enhanced by an aldoketoreductase 1C family inhibitor. Further, patent document 3 reports that the antitumor effect of cisplatin can be enhanced by a phosphodiesterase III B inhibitor.
On the other hand, polymer-bound anticancer drugs, nucleic acid preparations (including nucleic acid monomers and nucleic acids encapsulated in DDS (drug delivery system) such as liposomes), antibodies, and the like have been developed in recent years. The polymeric anticancer drugs have limited permeability to the capillary wall and the like, and exhibit different in vivo kinetics from low-molecular-weight anticancer drugs having a molecular weight of 1000 daltons or less. Therefore, in order to improve the therapeutic effect of a polymeric anticancer drug, separate technical development is required.
Documents of the prior art
Patent document
Patent document 1: japanese patent laid-open publication No. 2011-144190
Patent document 2: japanese patent laid-open publication No. 2011-102255
Patent document 3: japanese patent laid-open No. 2009-242378
Disclosure of Invention
Technical problem to be solved by the invention
The purpose of the present invention is to provide an enhancer for enhancing the antitumor effect of a polymer-type anticancer drug. In addition, the present invention also aims to provide a cancer therapeutic agent for treating cancer using the enhancer.
Means for solving the technical problem
The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that the administration of an enhancer comprising apatite carbonate and not comprising a polymeric anticancer agent before, after or simultaneously with the administration of the polymeric anticancer agent can increase the expression of vascular permeability factors, increase the vascular permeability in tumor tissues, effectively accumulate the polymeric anticancer agent in the tumor tissues, and drastically enhance the antitumor effect. The present invention has been completed based on this finding and through further continuing studies.
That is, the present invention relates to an enhancer for enhancing the antitumor effect of a polymeric anticancer drug, which comprises carbonic acid apatite and does not contain a polymeric anticancer drug. Preferably, the polymeric anticancer drug is a polymer-bound anticancer drug. Preferably, the enhancer further comprises albumin.
The invention provides a double-drug preparation type cancer therapeutic drug, which comprises a first drug preparation and a second drug preparation, wherein the first drug preparation contains carbonic apatite and does not contain a high molecular type anticancer drug; the second pharmaceutical preparation contains a polymeric anticancer drug. Preferably, the polymeric anticancer drug is a polymer-bound anticancer drug. Preferably, the first pharmaceutical preparation further comprises albumin.
The invention also provides a pharmaceutical kit which contains the dual-pharmaceutical preparation type cancer treatment drug.
The present invention also provides use of the carbonated apatite for producing an enhancer for enhancing an antitumor effect of a polymer-based anticancer drug, the enhancer being free from the polymer-based anticancer drug. Preferably, the polymeric anticancer drug is a polymer-bound anticancer drug. Preferably, the enhancer further comprises albumin.
The present invention also provides use of a first pharmaceutical preparation and a second pharmaceutical preparation in the manufacture of a dual drug formulation type cancer therapeutic drug, wherein the first pharmaceutical preparation contains apatite carbonate and does not contain a polymeric anticancer drug; the second pharmaceutical preparation contains a polymeric anticancer drug. Preferably, the polymeric anticancer drug is a polymer-bound anticancer drug. Preferably, the first pharmaceutical preparation further comprises albumin.
The invention also provides the use of apatite carbonate for the preparation of a medicament for increasing vascular permeability in tumour tissue, wherein the medicament comprises apatite carbonate. Preferably, the medicament further comprises albumin.
The invention also provides the use of carbonate apatite in the preparation of an agent for up-regulating the expression of vascular permeability factor, wherein the agent comprises carbonate apatite. Preferably, the reagent further comprises albumin. Preferably, the vascular permeability factor comprises a factor selected from the group consisting of IFN- γ, H2O2, and TNF.
Effects of the invention
According to the present invention, the expression of vascular permeability factor can be up-regulated, vascular permeability in tumor tissue can be improved, polymer-bound anticancer drugs, nucleic acid preparations (including nucleic acid monomers and nucleic acids encapsulated in DDS such as liposomes), antibodies, and other high molecular anticancer drugs can be effectively accumulated in tumor tissue, and the antitumor effect of the high molecular anticancer drugs can be remarkably enhanced.
Drawings
FIG. 1 is a graph showing the IVIS assay protocol when measuring P-THP accumulation produced by the combined use of carbonate apatite (iNaD).
FIG. 2 is a graph showing the results of tumor imaging after 1 and 27 hours from the administration of P-THP in the IVIS assay protocol shown in FIG. 1. The graph shown on the right is a graph in which the imaging result is quantified.
FIG. 3 is a graph showing the results of imaging normal tissue after 1 and 27 hours from the administration of P-THP in the IVIS assay protocol shown in FIG. 1.
FIG. 4 is a graph showing the results of an examination of the antitumor effects of P-THP produced by the combined use of iNaD.
FIG. 5 is a graph showing an IVIS measurement protocol when L-OHP accumulation generated by the combined use of carbonate apatite (iNaD) is measured.
FIG. 6 is a graph showing the results of L-OHP accumulation measurements in tumors and liver in the IVIS assay protocol shown in FIG. 5.
FIG. 7 is a graph showing the results of an examination of the antitumor effect of L-OHP produced by the combined use of iNaD.
FIG. 8 is a graph showing the results of in-tumor angiography performed and the results of quantification of vascular permeability in tumors using fluorescence intensity.
FIG. 9 shows the microarray analysis and IPA protocol (top left), results of a heatmap analysis by staining the values of the microarray analysis with log2 transformation of signal values (bottom left), IFN-. gamma.H.by pathway analysis using IPA2O2And the network (network) in which TNF is involved (upper right), and the factor (Z-score above 2.0) for increased expression by administration of ina indicated by IPA results (lower right).
Detailed Description
1. Reinforcing agent
The enhancer of the present invention is used for the purpose of enhancing the antitumor effect of a polymer-type anticancer drug, and is characterized by comprising a carbonic apatite as an active ingredient and not containing a polymer-type anticancer drug. Next, the reinforcing agent of the present invention will be described in detail.
[ Carbonic apatite ]
The enhancer of the invention contains carbonate apatite and does not contain a high-molecular anticancer drug. In particular, the present invention uses a carbonate apatite without a polymer type anticancer agent. "Carbonic apatite without a polymer type anticancer drug" means carbonic apatite without a polymer type anticancer drug in the interior of particles. In the method for producing a carbonic acid apatite described later, since a carbonic acid apatite containing a polymer type anticancer drug is produced when the polymer type anticancer drug is contained in an aqueous solution containing a raw material for producing carbonic acid apatite, carbonic acid apatite obtained without adding a polymer type anticancer drug in the production process is used in the present invention.
The carbonate apatite has a carbon atom of CO3Group-substituted hydroxyapatite (Ca)10(PO4)6(OH)2) A part of the hydroxyl groups of (A) is represented by the general formula Ca10-mXm(PO4)6(CO3)1-nYnThe compound shown in the specification. Wherein X is an element capable of partially substituting Ca in the apatite carbonate, and examples thereof include Sr, Mn, rare earth elements, and the like. m is usually a number of 0 to 1, for example, a positive number of 0 to 1, preferably 0 to 0.1, more preferably 0 to 0.01, and still more preferably 0 to 0.001. Y is CO in partly substitutable apatite carbonate3Examples of the group or element(s) include OH, F, and Cl. n is usually a number of 0 to 0.1, for example, a positive number of 0 to 0.1, preferably 0 to 0.01, more preferably 0 to 0.001, and still more preferably 0 to 0.0001.
The average particle size of the carbonate apatite particles used in the present invention is not particularly limited as long as the particles are of a size that allows migration into cells when administered into a living body. Specifically, the average particle diameter of the apatite carbonate particles used in the present invention is usually 30nm or more, for example, more than 30nm, preferably 30 to 3000nm, more preferably 30 to 2000nm, and particularly preferably 30 to 1500 nm.
The average particle diameter of the apatite carbonate is a value measured by particle measurement (DLS) using a dynamic light scattering method. When there are giant particles (for example, particles having a particle diameter of 5 μm or more) which are not suitable for measurement using DLS, these giant particles are removed from the range to be measured. In the present specification, the particle diameter refers to the particle diameter of an individual particle that can be recognized as a single particle when measured by a scanning probe microscope. Therefore, in the case where a plurality of particles are aggregated, the aggregate of these particles is determined as one particle.
The formulation form of the enhancer of the present invention is not particularly limited, and a dispersion liquid is preferable from the viewpoint of suppressing reaggregation of the carbonate apatite particles to maintain the above-mentioned average particle diameter, and effectively enhancing the antitumor effect of the polymer type anticancer drug.
The concentration of the apatite carbonate in the reinforcing agent of the present invention is not particularly limited, and may be appropriately set in consideration of the administration method and the like so as to satisfy the administration amount described below. For example, in the case where the reinforcing agent of the present invention is a dispersion, the concentration of the apatite carbonate is 1X 108～1×1012One/ml, preferably 1X 109～1×1011One/ml, more preferably 1X 109～5×1010More preferably 3X 10/ml, in particular9～3×1010One/ml, more preferably 6X 109～1.5×1010One per ml.
When the reinforcing agent of the present invention is a dispersion, the solvent in which the apatite carbonate is dispersed is not particularly limited as long as it is a pharmaceutically acceptable solvent in which the apatite carbonate can be dispersed, and specific examples thereof include physiological saline and other buffer solutions.
The method for producing the apatite having the average particle size is not particularly limited, and specifically, a method including a step of preparing a dispersion in which apatite carbonate particles are dispersed in a pharmaceutically acceptable solvent and a step of adding ultrasonic vibration treatment to the dispersion as necessary can be exemplified.
The carbonate apatite particles can be obtained by a known method. For example, it can be produced by allowing calcium ions, phosphate ions, and bicarbonate ions to coexist in an aqueous solution. The concentration of each ion in the aqueous solution is not particularly limited as long as it can form carbonate apatite particles, and can be appropriately set with reference to the following.
The concentration of calcium ions in the aqueous solution is usually 0.1 to 1000mM, preferably 0.5 to 100mM, and more preferably 1 to 10 mM.
The concentration of the phosphate ion in the aqueous solution is usually 0.1 to 1000mM, preferably 0.5 to 100mM, and more preferably 1 to 10 mM.
The bicarbonate ion concentration in the aqueous solution is usually 1.0 to 10000mM, preferably 5 to 1000mM, and more preferably 10 to 100 mM.
The supply source of the calcium ion, phosphate ion and bicarbonate ion is not particularly limited as long as these ions can be supplied in the aqueous solution, and examples thereof include water-soluble salts of these ions. Specifically, CaCl may be used2As the calcium ion source, NaH can be used2PO4·2H2O as the phosphate ion source, NaHCO may be used3As a source of carbonate ions.
The aqueous solution for producing the carbonic acid apatite particles may contain the above-mentioned ion supply sources and other components as long as the carbonic acid apatite particles can be formed. For example, in the aqueous solution, Ca or CO in apatite carbonate may be partially substituted by adding fluoride ion, chloride ion, Sr, Mn, polyethylene glycol (PEG), or the like to the composition3Etc. or modified. However, the amount of fluorine ions, chlorine ions, Sr, Mn, PEG, and the like to be added is preferably within a range that does not significantly affect the pH solubility and particle size range of the formed composite particles. The aqueous solution for producing the apatite carbonate particles may be water as a base, and various culture solutions or buffers for culturing cells may be used.
In the production of the carbonic acid apatite particles used in the present invention, the order of mixing the ion sources and other substances into the aqueous solution is not particularly limited, and the aqueous solution may be produced in any mixing order as long as the desired carbonic acid apatite particles can be obtained. For example, a first solution containing calcium ions and other substances may be prepared, a second solution containing phosphate ions and bicarbonate ions may be prepared separately, and the first solution and the second solution may be mixed to prepare an aqueous solution.
The apatite carbonate particles can be obtained by adjusting the pH of an aqueous solution containing the above ions to a range of 6.0 to 9.0 and allowing the aqueous solution to stand for a certain period of time (incubation). The pH of the aqueous solution for forming apatite carbonate particles is, for example, 6.5 to 9.0, preferably 6.7 to 8.8, more preferably 6.7 to 8.6, still more preferably 6.8 to 8.5, particularly preferably 7.0 to 8.5, and most preferably 7.1 to 8.0.
The temperature condition of the aqueous solution in forming the apatite carbonate particles is not particularly limited as long as the apatite carbonate particles can be formed, but is usually 0 ℃ or higher, and examples thereof include 4 ℃ or higher, or 37 ℃.
The incubation time of the aqueous solution for forming the apatite particles is not particularly limited as long as the apatite particles can be formed, but it is usually 1 minute to 24 hours, preferably 5 minutes to 1 hour. The presence or absence of particle formation can be confirmed, for example, by observation under a microscope.
The method for controlling the average particle size of the apatite carbonate particles to the above range is not particularly limited, and for example, a dispersant may be mixed in the course of producing the particles, or the dispersant may be added after forming the particles. The type of the dispersant is not particularly limited as long as it can disperse the carbonate apatite particles, and any dispersant can be used as long as it is generally added to a pharmaceutical product. The dispersant may be used alone or in combination of two or more. The concentration of the dispersant in the aqueous solution containing apatite carbonate particles is not particularly limited as long as the effect of suppressing the micronization and/or reaggregation can be obtained, and may be, for example, about 0.1 to 500mg/ml, preferably about 1 to 100mg/ml, and more preferably about 1 to 10 mg/ml; or about 0.001 to 10 wt%. As another example of the method of controlling the particle size, there is a method of subjecting apatite carbonate particles formed in the above-mentioned aqueous solution to ultrasonic oscillation treatment. Specific examples of the ultrasonic oscillation treatment include: a treatment of applying ultrasonic waves to a sample by bringing an ultrasonic transducer such as an ultrasonic crusher into direct contact with the sample; an ultrasonic cleaner having an ultrasonic transducer and a water tank (cleaning tank) is used, and a liquid (e.g., water) is added to the water tank, a container (e.g., a plastic tube) containing the apatite carbonate particles is floated thereon, and ultrasonic waves are applied to an aqueous solution containing the apatite carbonate particles through the liquid. By such ultrasonic oscillation treatment, the particle size of the apatite carbonate particles can be reduced to the above range easily and efficiently.
The conditions of the ultrasonic oscillation treatment are not particularly limited as long as the particle size can be controlled within a predetermined range. For example, when the treatment is performed using an ultrasonic cleaner having an ultrasonic transducer and a water tank (cleaning tank), the following conditions are listed.
Temperature of the water tank: for example, the temperature is 5 to 45 ℃, preferably 10 to 35 ℃, and more preferably 20 to 30 ℃.
High-frequency output: for example, 10 to 500W, preferably 20 to 400W, more preferably 30 to 300W, and still more preferably 40 to 100W.
Oscillation frequency: for example, 10 to 60Hz, preferably 20 to 50Hz, and more preferably 30 to 40 Hz.
Treatment time: for example, 30 seconds to 30 minutes, preferably 1 to 20 minutes, and more preferably 3 to 10 minutes.
The type of the container for containing the apatite carbonate particles used in the ultrasonic oscillation treatment is not particularly limited as long as the particles can be made finer to a predetermined particle size range, and may be appropriately selected depending on the volume of the aqueous solution, the purpose of use, and the like. For example, a plastic tube having a volume of 1 to 1000ml can be used.
The ultrasonic oscillation treatment is preferably performed in the presence of a dispersant (i.e., in a state where the dispersant is added to an aqueous solution containing apatite carbonate particles). This is because carbonate apatite nanoparticles having a finer particle size can be obtained by performing ultrasonic oscillation treatment in an environment in which a dispersant and carbonate apatite particles coexist, and reaggregation of the particles can be suppressed.
[ use/method of use ]
The enhancer of the present invention is used for the purpose of enhancing the antitumor effect of a polymer-type anticancer drug.
The term "polymeric anticancer agent" refers to an anticancer agent having a molecular weight greater than 1000 daltons. Specific examples of the polymer-type anticancer agent include polymer-bound anticancer agents, nucleic acid preparations having an antitumor effect (including nucleic acid monomers and nucleic acids encapsulated in DDS such as liposomes), antibodies having an antitumor effect, and substances sensitive to photodynamic therapy (albumin-bound ICG and polymeric zinc protoporphyrin (P-ZnPP)).
The term "polymer-bound anticancer drug" refers to a high-molecular drug in which a water-soluble polymer is bonded to a low-molecular anticancer drug (having a molecular weight of 1000 daltons or less) via a chemical bond, either directly or via hydrazone or the like.
The type of the low molecular weight anticancer drug constituting the polymer-bound anticancer drug is not particularly limited, and examples thereof include metabolic antagonists, platinum agents, alkylating agents, microtubule-acting agents, anticancer antibiotics, topoisomerase inhibitors and the like. Specific examples of the metabolic antagonist include 5-fluorouracil, methotrexate, doxifluridine, tegafur, arabinoside, and gemcitabine. Specific examples of the platinum preparation include cisplatin, oxaliplatin, carboplatin, and nedaplatin. Specific examples of alkylating agents include cyclophosphamide, ifosfamide, thiotepa, carboquone, and nimustine hydrochloride. Examples of microtubule agents include docetaxel, paclitaxel, vincristine, vindesine, and vinorelbine. Specific examples of the antitumor antibiotics include doxorubicin hydrochloride, mitomycin, amrubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, aclarubicin hydrochloride, mitoxantrone hydrochloride, bleomycin hydrochloride, and pellomycin sulfate. Specific examples of the topoisomerase inhibitor include irinotecan, irinotecan hydrochloride, topotecan hydrochloride, and the like.
The type of water-soluble polymer constituting the polymer-bound anticancer drug is not particularly limited, and examples thereof include Poly (N- (2-hydroxypropyl) methacrylamide (PHPMA), styrene-maleic acid copolymer, and the like.
The average molecular weight of the polymer-bound anticancer drug is, for example, about 1000 to several hundred thousand, preferably about several thousand to 300,000, more preferably about 5,000 to 250,000, and still more preferably about 10,000 to 200,000. In the present specification, the average molecular weight of the polymer-bound anticancer drug is a weight average molecular weight measured by GPC using polyethylene as a standard.
As the polymer-bound anticancer drug, known polymer-bound anticancer drugs can be used. Specific examples of the polymer-bound anticancer agent include pirarubicin (P-THP) to which PHPMA is linked and zinc protoporphyrin (P-ZnPP) to which PHPMA is linked.
The nucleic acid having an antitumor effect may be any nucleic acid that can be used as a nucleic acid drug having an antitumor effect, and examples thereof include siRNA, shRNA, dsRNA, microRNA, antisense nucleic acid (antisense DNA, antisense RNA), stabilized artificial nucleic acid BNA, ribozyme, decoy nucleic acid, and aptamer. As the nucleic acid having an antitumor effect, known nucleic acids can be used. In the case where such nucleic acids require a DDS such as liposome for exerting an antitumor effect, the nucleic acids encapsulated in the DDS can be regarded as a polymer-type anticancer drug.
The antibody having an anti-tumor effect may be any antibody having an anti-tumor effect, and examples thereof include an anti-EGFR antibody, an anti-CD 40 antibody, an anti-CD 33 antibody, an anti-HER 2 antibody, an anti-VEGF antibody, an anti-CTLA-4 antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CD 20 antibody.
Examples of the sensitive substance targeted for photodynamic therapy include polymeric zinc protoporphyrin (P-ZnPP) and albumin-bound indocyanine green (ICG). ICG is a low molecular substance, but binds to albumin in serum to become a polymer.
These polymeric anticancer drugs can be used alone or in combination of two or more kinds thereof as the potentiator of the present invention to enhance the antitumor effect. Among these high molecular weight anticancer drugs, polymer-bound anticancer drugs and nucleic acid pharmaceutical preparations are preferred.
The type of cancer to be treated with the potentiator of the present invention is not particularly limited as long as it is a cancer to be treated with chemotherapy, and specific examples thereof include solid cancers such as colorectal cancer, colon cancer, gastric cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, bladder cancer, prostate cancer, cervical cancer, head and neck cancer, bile duct cancer, gallbladder cancer, and oral cancer; hematological cancers such as leukemia and malignant lymphoma. Among them, solid cancer is preferable as a treatment target of the enhancer of the present invention.
The method of administering the enhancer of the present invention is not particularly limited, and the enhancer may be administered systemically or locally. The enhancer of the present invention has an excellent effect of specifically accumulating a high-molecular weight anticancer drug in a tumor tissue even when administered systemically, and a preferable administration method includes systemic administration. Systemic administration includes intravascular (intraarterial or intravenous), subcutaneous, intraperitoneal and the like, and intravascular administration is preferable, and arteriovenous administration is more preferable. In addition, intravascular administration includes not only intravascular injections but also continuous drops. The method of administering the potentiator of the present invention may be the same as or different from the method of administering a polymer-type anticancer drug to be enhanced in antitumor effect.
The administration amount of the enhancer of the present invention is appropriately determined depending on the kind of the polymer type anticancer drug to be enhanced in the antitumor effect, sex, age, symptom and the like of the patient, and cannot be determined in any way, but may be, for example, about 10mg to 1g/kg (body weight) per time in terms of the amount of the apatite carbonate. The administration frequency of the enhancer of the present invention may be 1 time per 1 time of administration of the polymer type anticancer drug, and the administration of the enhancer of the present invention may be about 2 to 3 times per 1 time of administration of the polymer type anticancer drug.
The timing of administration of the enhancer of the present invention is not particularly limited, and for example, it may be administered simultaneously with or within 24 hours before or after the administration of the polymer type anticancer drug to be enhanced in the antitumor effect, preferably within 12 hours before or after the administration of the polymer type anticancer drug, and more preferably within 8 hours before or simultaneously with the administration of the polymer type anticancer drug. The enhancer of the present invention is preferably used in a form of administration without mixing with a polymeric anticancer drug.
2. Cancer therapeutic agent
The cancer therapeutic agent of the present invention is a dual drug formulation type cancer therapeutic agent comprising a first drug preparation and a second drug preparation, wherein the first drug preparation contains the enhancer and the second drug preparation contains a polymer type anticancer drug. In the present invention, the dual pharmaceutical preparation type cancer therapeutic agent is a cancer therapeutic agent composed of two preparations containing the first pharmaceutical preparation and the second pharmaceutical preparation as separate preparations.
The constitution, the mode of use, and the like of the first pharmaceutical preparation of the therapeutic agent for cancer of the present invention are as shown in the column of the above [1. enhancer ]. The type and the like of the polymer type anticancer agent contained in the second pharmaceutical preparation of the therapeutic agent for cancer of the present invention may be appropriately determined according to the type of the polymer type anticancer agent, as shown in the column of [1. enhancer ], and the method of administration, the amount of administration and the like thereof.
[ examples ]
The present invention will be described below with reference to examples. However, the present invention is not to be construed as being limited to the following examples.
1. Test materials and methods
1-1. cell culture
In the experiments shown below, two human colon cancer cell lines, HCT116 and HT29, were used. The HCT116 was cultured using DMEM (Dulbecco's Modified Eagle Medium) (Seimer Feishell science, Waltham, Mass.) and the HT29 was cultured using RPMI1640 (Rosverv Park Memori Institute Medium, Saisha) (Seimer Feishell science). Both media were supplemented with 10% FBS (Fetal Bovine Serum: Total Bovine Serum) (BIO-WEST, St. Makes, Tex., USA) at 5% CO2The culture was carried out in a 37 ℃ incubator.
1-2 preparation of Carbonic apatite particles
0.37g of NaHCO390. mu.l of NaH2PO4·2H2O (1M) and 180. mu.l of CaCl2(1M) was added to 100ml of distilled water to dissolve it completely, and adjusted to pH7.5 with 1N HCl, thereby preparing a buffer. The resulting buffer was sterilized by filtration through a filter having a diameter of 0.2 μm and dispensed in 25ml portions. Then, 100. mu.l of CaCl was added to 25ml of the buffer2(1M), after 3 seconds of vortex stirring, incubate at 37 ℃ for 30 minutes. Then, the resulting mixture was centrifuged at 12,000rpm at 4 ℃ for 3After that, the supernatant was discarded, and the precipitate obtained from 50ml of the buffer solution was collected with physiological saline (200 to 400. mu.l). Subsequently, albumin was added to the solution so as to be 0.5% of the solution, and the solution was gently stirred to prepare a dispersion of apatite carbonate particles (hereinafter referred to as iNaD (inorganic nanoparticle drug)). Before tail vein injection, ultrasonic treatment (38kHz, 80W) was carried out for 10 minutes by an ultrasonic machine, and tail vein injection was carried out within 10 minutes.
1-3 preparation of mouse with cancer of the lotus
7 weeks old/female BALB/cAJcl nude mice (CLEA Japan K.K., Osaka, Japan) were injected subcutaneously at two sites on the back of each mouse at 3X 10 times6HT29 or HCT116, to prepare cancer-bearing mice.
1-4. imaging system
Images were taken under anesthesia with isoflurane (pfeiry, new york, usa) using an IVIS spectral CT apparatus (perkin elmer, waltham, massachusetts, usa). The image was taken in the fluorescence mode at an excitation wavelength of P-THP 500 nm. The Relative fluorescence unit (Relative fluorescence unit) is calculated by setting an ROI (Region of interest) and subtracting the ROI value of the background from the obtained ROI value.
1-5 study on the accumulation of Polymer-type anticancer drugs produced by Combined use of iNaD
In this experiment, P-THP was used as a high molecular weight anticancer drug. P-THP is a high molecular weight anticancer drug (average molecular weight 39,000) in which a water-soluble polymer, Poly (N- (2-hydroxypropyl) methacrylamide (PHPMA), is covalently bonded via hydrazone to the low molecular weight anticancer drug, pirarubicin (THP).
HT29 cancer-bearing mice were divided into three groups: the treatment-free group (n ═ 1), the P-THP (i.v.) group with P-THP injected into the tail vein (i.v.) and (n ═ 3), and the ina (i.v.) + P-THP (i.v.) group with P-THP injected into the tail vein after 1 hour after the injection of the ina into the tail vein (n ═ 3). Tail vein injection of 20mg/kg P-THP. 120mg/kg of iNaD was injected into the tail vein based on the amount of apatite carbonate. 1 and 27 hours after the start of P-THP administration, mice were euthanized, tumor and normal tissues (heart, lung, liver, spleen, pancreas, kidney) were harvested, and the amount of P-THP accumulation was determined by IVIS.
1-6 study of antitumor Effect of Polymer-type anticancer drug (P-THP) produced by Combined use of iNaD
HT29 tumor volume of HT 29-bearing cancer-bearing mice reaches about 80mm3Then, the method is divided into the following three groups: a treatment-free group (n ═ 7), a P-THP (i.v.) group (n ═ 5), and an ina (i.v.) + P-THP (i.v.) group (n ═ 3). P-THP (i.v.) group and iNaD (i.v.) + P-THP (i.v.) group, 10mg/kg of P-THP was injected in tail vein on day 0, and 20mg/kg of P-THP was injected in tail vein on days 5 and 13. In addition, group iNaD (i.v.) + P-THP (i.v.), iNaD was injected caudally on days 0, 5, and 13 at a dose of 120mg/kg based on carbonate apatite. Tumor size was determined on days 0, 5, 13, 16 and 21. Tumor volume is calculated according to the equation [ tumor volume (mm)3)＝a×b2/2 (a: long diameter mm, b: short diameter mm)]And (4) calculating.
1-7 study on accumulation of Low molecular anticancer drugs produced by Combined use of iNaD
In this experiment, Oxaliplatin (Oxaliplatinum: L-OHP, molecular weight 397) (Yakult, Tokyo, Japan) was used as a low-molecular-weight anticancer drug. HCT116 cancer-bearing mice were divided into two groups: L-OHP (i.v.) group injected via caudal vein with L-OHP and iNaD (i.v.) + L-OHP (i.v.) group injected via caudal vein with L-OHP after 1 hour after iNaD injection via caudal vein. L-OHP tail vein injection 0.15 mg/kg. The iNaD tail was injected intravenously at 120mg/kg based on the amount of apatite carbonate. After 1 and 4 hours from the start of L-OHP administration, mice were euthanized, tumors (n 4-6) and livers (n 3) were harvested, and the amount of platinum was determined by inductively coupled plasma mass spectrometry (ICP-MS). The ICP-MS was measured as follows.
Transferring the tumor mass and liver into semi-sealed glass container, and suspending in 2ml of HNO3(Kanto chemical Co., Ltd., Tokyo, Japan). Each sample was heated on a heating plate (70-100 ℃ C.) for 12 hours or more. With HNO3The acid decomposition product was diluted to 10ml in total, and purified by centrifugation. Supernatant with 2% (v/v) HNO3Diluted 100-fold and used as a sample for ICP-MS assay. Platinum (II)The amount was measured by ICP-MS (7500CX) (Agilent technologies, Tokyo, Japan). The processing of the measured data was performed using analytical software 7500series ICP-MS MassHunter Workstation (G7200A) (Agilent technologies). The setting of the measurement conditions was optimized based on platinum (atomic weight 195) (Wako pure chemical industries, Ltd.) as an object to be measured and thallium (atomic weight 205) (Wako pure chemical industries, Ltd.) as an internal standard. The results are expressed as the amount of platinum (μ g/g) in 1g of tumor mass (n ═ 4 to 6) or liver (n ═ 3). The measurement value obtained by subtracting the blank control value was used.
1-8 study of antitumor Effect of Low-molecular anticancer drug (L-OHP) produced by Combined use of iNaD
When HCT116 tumor volume of HCT116 in mice with HCT116 cancer reached about 80mm3Then, the method is divided into the following three groups: a treatment-free group (n-6), an L-OHP (i.v.) group (n-6), and an ina (i.v.) + L-OHP (i.v.) group (n-6). L-OHP (i.v.) and iNaD (i.v.) + L-OHP (i.v.) groups were injected into the tail vein on days 0, 4, 8, 12, 15, 19 and 22 at 0.15mg/kg of L-OHP, and the tumor size was determined on the same day. In addition, the iNaD (i.v.) + L-OHP (i.v.) group was subjected to tail vein injection of iNaD in an amount of 120mg/kg on days 0, 4, 8, 12, 15, 19 and 22 in terms of carbonate apatite amount.
1-9 intravascular angiography in tumors
HCT116 cancer-bearing mice were divided into a treatment-free group (n ═ 3) and an ina (i.v.) group (n ═ 3), respectively, and the ina (i.v.) group was injected with the iNaD in a tail vein at a dose of 120mg/kg based on the amount of apatite carbonate. After 4 hours, two groups of tail veins were injected with OTN Ceramic probe y (OTN Ceramic probe y) as an imaging agent (kayama chemical industries co., osaka, japan), and intra-tumor angiography was performed using an in vivo fluorescence imaging system (SAI-1000, shimadzu corporation, kyoto, japan). In addition, the fluorescence intensity in the angiographic image was used for comparison.
1-10 microarray Analysis and Ingenity Path Analysis (IPA)
HT29 cancer-bearing mice were divided into a treatment-free group (n ═ 3) and an iand (i.v.) group (n ═ 3), and the iand (i.v.) group was subjected to caudal vein injection of inand at a dose of 120mg/kg based on the amount of apatite carbonate, and was euthanized 4 hours later. Tumors were excised from both groups, immersed in RNAlater (Saimer Feishell science) and stored at-80 ℃. Then, microarray analysis and IPA were performed. Genes with Z scores of 2 or more and 2 or less were judged as significantly different genes.
1-11 statistical analysis
Statistical values are expressed as mean ± standard deviation. Statistical evaluation using Student-T test, if P <0.05, then it was judged as significant.
2. Results of the experiment
2-1 study of antitumor Effect of P-THP produced by Combined use of iNaD
The enhancement of the antitumor effect of the combined use of iNaD in animal experiments was investigated. In this experiment, measurement of the amount of P-THP accumulation and study of antitumor effect using IVIS were carried out using a polymer anticancer drug (P-THP).
In the measurement of P-THP accumulation amount, the P-THP accumulation amount of tumor and normal tissue after 1 and 27 hours from the administration of P-THP was measured by IVIS (FIG. 1). As a result, it was found that the accumulation of P-THP into tumors was significantly increased in the irad (i.v.) + P-THP (i.v.) group after 1 and 27 hours from the start of administration, compared to the P-THP (i.v.) group and the treatment-free group (fig. 2). In addition, with respect to normal tissues (heart, lung, liver, spleen, pancreas, kidney), no significant difference was found between the iand (i.v.) + P-THP (i.v.) group and the P-THP (i.v.) (fig. 3). In fig. 2 and 3, the numbers in the imaging graphs are relative to the fluorescence intensity.
Further, regarding the antitumor effect, the tumor volume was significantly decreased in the irad (i.v.) + P-THP (i.v.) group on days 13, 16 and 21 from the start of administration as compared with the P-THP (i.v.) group, and it was found that the antitumor effect by the irad, P-THP was enhanced (fig. 4).
2-2 study of antitumor Effect of oxaliplatin with combination of iNaD
In this experiment, measurement of the amount of accumulation of L-OHP and study of antitumor effect were carried out by mass spectrometry using oxaliplatin (L-OHP) as a low-molecular-weight anticancer drug.
In the measurement of the accumulation amount of L-OHP, the accumulation of tumor and liver was measured 1 and 4 hours after the start of L-OHP administration (FIG. 5). The accumulation of L-OHP into tumors was significantly improved in the ina (i.v.) + L-OHP (i.v.) group 1 and 4 hours after the start of administration compared to the L-OHP (i.v.) group (p <0.05, fig. 6). On the other hand, accumulation of L-OHP to liver no significant difference was found between the two groups (fig. 6).
Further, regarding the antitumor effect, although the antitumor effect was enhanced in the iand (i.v.) + L-OHP (i.v.) group compared with the L-OHP (i.v.) group, no particularly significant difference was found between the two groups as in the case of using P-THP (fig. 7).
2-3 intravascular angiography in tumors
In this experiment, angiography was performed to elucidate the mechanism of enhancement of the antitumor effect of the polymer-type anticancer drug produced by ina, and the change in the vascular permeability in tumors produced by ina was studied.
By comparing the treatment-free group with the ina (i.v.) group, it was found that the blood vessel running in the tumor of the HCT116 cancer-bearing mouse was not clearly confirmed in the treatment-free group. On the other hand, clearer vessel navigation was confirmed in the ina (i.v.) group compared to the treatment-free group (fig. 8). Further, the fluorescence intensity was measured, and it was found that the ina (i.v.) group had a significantly improved fluorescence intensity as compared with the treatment-free group (fig. 8).
2-4. microarray Analysis and Ingenity Path Analysis (IPA)
From the results of angiography, it was found that administration of iNaD improved vascular permeability in tumors, and thus the effect of iNaD on the expression level of vascular permeability factors was examined.
Specifically, microarray analysis and IPA analysis were performed on two groups of HT29 tumors (ina (i.v.) group) and HT29 tumors (no treatment group) after 4 hours after tail vein injection of ina (fig. 9 upper left).
As a result of the microarray analysis, it was confirmed that genes that were low-expressed in the non-treatment group became high-expressed in the ina (i.v.) group, and conversely, genes that were high-expressed in the non-treatment group became low-expressed in the ina (i.v.) group, indicating the presence of a genome whose expression was greatly changed by administration of ina (fig. 9, bottom left).
Further, from the results of IPA, it was found that IFN-. gamma.and H as vascular permeability factors were present upstream of the gene whose expression was changed2O2And TNF, the expression of these factors was increased by ina (fig. 9 right).
These results strongly suggest that IFN-. gamma.H is expressed by iNaD2O2The three factors, TNF, are involved in enhancing the antitumor effect of the polymeric antitumor agent.

Claims (15)

1. A dual pharmaceutical formulation type cancer therapeutic agent comprising a first pharmaceutical formulation and a second pharmaceutical formulation, wherein the first pharmaceutical formulation comprises apatite carbonate and does not contain a polymeric anticancer agent; the second pharmaceutical preparation contains a polymeric anticancer drug.
2. The dual pharmaceutical preparation type cancer therapeutic agent of claim 1, wherein the polymeric anticancer drug is a polymer-bound anticancer drug.
3. The dual drug formulation type cancer therapeutic according to claim 1 or 2, wherein the first drug formulation further comprises albumin.
4. A pharmaceutical kit comprising the dual pharmaceutical dosage form of cancer treatment drug of any one of claims 1-3.
5. Use of apatite carbonate for producing an enhancer for enhancing an antitumor effect of a polymer-based anticancer drug, wherein the enhancer is free from the polymer-based anticancer drug.
6. The use according to claim 5, wherein the polymeric anticancer drug is a polymer-bound anticancer drug.
7. The use according to claim 5 or 6, wherein the enhancer further comprises albumin.
8. Use of a first pharmaceutical preparation and a second pharmaceutical preparation in the manufacture of a dual drug formulation cancer treatment, wherein the first pharmaceutical preparation comprises apatite carbonate and does not comprise a polymeric anti-cancer agent; the second pharmaceutical preparation contains a polymeric anticancer drug.
9. The use according to claim 8, wherein the polymeric anticancer drug is a polymer-bound anticancer drug.
10. Use according to claim 8 or 9, wherein the first pharmaceutical preparation further comprises albumin.
11. Use of apatite carbonate for the manufacture of a medicament for increasing vascular permeability in tumour tissue, wherein the medicament comprises apatite carbonate.
12. The use of claim 11, wherein the medicament further comprises albumin.
13. Use of apatite carbonate for the preparation of an agent for up-regulating the expression of vascular permeability factor, wherein the agent comprises apatite carbonate.
14. The use of claim 13, wherein the agent further comprises albumin.
15. Use according to claim 13 or 14, wherein the vascular permeability factor comprises a factor selected from IFN- γ, H2O2 and TNF.
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RU2765465C2 (en) * 2021-04-28 2022-01-31 Федеральное государственное бюджетное учреждение "Национальный медицинский исследовательский центр радиологии" Министерства здравоохранения Российской Федерации (ФГБУ "НМИЦ радиологии" Минздрава России) Method for functionalisation of calcium phosphate material with cisplatin preparation in aqueous solution

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WO2022071496A1 (en) * 2020-09-30 2022-04-07 株式会社ナノビヨンド Efficacy enhancing agent for inflammatory disease treatment drug, and accumulation-promoting agent for promoting accumulation of contrast medium in inflammation site

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140302145A1 (en) * 2012-11-28 2014-10-09 Toshihiro Akaike Pharmaceutical composition for treating cancer using carbonate apatite nanoparticles
JP2015155392A (en) * 2014-02-20 2015-08-27 弘幸 中西 Anticancer agent using glucose and apatite carbonate
US20170128487A1 (en) * 2014-02-20 2017-05-11 Osaka University Enhancer of anti-tumor effect of anti-cancer agent

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3453390B1 (en) * 2016-05-06 2024-02-14 Biodynamic Research Foundation Polymerized drug-containing pharmaceutical composition

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140302145A1 (en) * 2012-11-28 2014-10-09 Toshihiro Akaike Pharmaceutical composition for treating cancer using carbonate apatite nanoparticles
JP2015155392A (en) * 2014-02-20 2015-08-27 弘幸 中西 Anticancer agent using glucose and apatite carbonate
US20170128487A1 (en) * 2014-02-20 2017-05-11 Osaka University Enhancer of anti-tumor effect of anti-cancer agent

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2765465C2 (en) * 2021-04-28 2022-01-31 Федеральное государственное бюджетное учреждение "Национальный медицинский исследовательский центр радиологии" Министерства здравоохранения Российской Федерации (ФГБУ "НМИЦ радиологии" Минздрава России) Method for functionalisation of calcium phosphate material with cisplatin preparation in aqueous solution

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