CN109908356B - Cyanoacrylate material loaded with antitumor drug - Google Patents

Cyanoacrylate material loaded with antitumor drug Download PDF

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CN109908356B
CN109908356B CN201711326225.6A CN201711326225A CN109908356B CN 109908356 B CN109908356 B CN 109908356B CN 201711326225 A CN201711326225 A CN 201711326225A CN 109908356 B CN109908356 B CN 109908356B
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cyanoacrylate
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drug
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CN109908356A (en
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徐亮
张涛
张伟
刘克良
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Institute of Pharmacology and Toxicology of AMMS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract

The invention relates to the field of biomedicine and materials, in particular to a cyanoacrylate material loaded with an anti-tumor drug. In particular, the invention relates to a composition containing an antitumor drug and cyanoacrylate, and a pharmaceutical preparation containing the composition, such as a pharmaceutical preparation which can be used for intratumoral injection.

Description

Cyanoacrylate material loaded with antitumor drug
Technical Field
The invention relates to the field of biomedicine and materials, in particular to a cyanoacrylate material loaded with an anti-tumor drug.
Background
The tumor intratumoral injection treatment is a new tumor treatment scheme developed in recent years, and the medicine is directly injected into the tumor to play a role in site-specific treatment, so that the first-pass effect and systemic toxic and side effects and the like required by means of oral administration, intravenous injection and the like can be avoided or alleviated to a certain extent. Treatment regimens employing intratumoral injection of drugs have unique advantages in sites that are accessible without open surgical instrumentation, as well as sites that are not conducive to surgical resection, or in view of post-operative aesthetics, among other things.
The approved marketed virus therapy for the polyoma virus, such as IMLYGIC from Anjin, domestic new drugs from today and Ankeri, all adopt the intratumoral injection method. In addition, many drug development studies have also adopted intratumoral injection, such as the MultiVir company used intratumoral injection to deliver the drug Ad-IL-24 for the treatment of head and neck tumors. Furthermore, the existing clinical related technical means are mature, can realize the intratumoral injection of multiple parts, for example, can realize the minimally invasive treatment of tumor puncture under the guidance of B ultrasonic, CT, magnetic resonance and other images, and the clinical means such as argon-nitrogen knife freezing, radio frequency heating and the like can be used.
However, in the scheme of intratumoral injection, two risks need to be particularly concerned, one is that the intratumoral pressure is higher than that of normal tissues, so that liquid medicines are easy to overflow after being injected into tumors, and the other is that blood vessels in the tumors are rich, so that the medicines are easy to diffuse to other tissues from the tumor part quickly after being administered, and the purpose of long-acting administration cannot be achieved.
Therefore, a new preparation or a new material for intratumoral injection is provided, the risk of drug overflow is avoided, and the long-time intratumoral fixed-point slow-release drug delivery is realized, so that the method has practical application value.
Disclosure of Invention
Cyanoacrylate is a compound capable of being cured quickly and generating adhesive property, the alkene double bond in the structure is very active, and the monomer can be polymerized between molecules quickly under the condition of anion to form a polymer. The cyanoacrylate monomer is generally in a liquid state and has fluidity, and therefore, can satisfy application methods such as coating and injection. The polymerized high polymer can be a solid glue block or a glue film according to different use modes. In addition to domestic and industrial adhesive applications, cyanoacrylates may also be used as biomedical materials, for example as medical glues for wound adhesion, hemostasis, embolization, etc., or as nano-drug carriers for drug delivery.
Through a great deal of research work, the inventors creatively found that: the drug-loaded adhesive with good anti-tumor effect can be prepared by selectively mixing cyanoacrylate with a certain structure with an anti-tumor drug, thereby providing the following invention:
in one aspect, the present invention provides a composition comprising an antineoplastic drug and a cyanoacrylate, wherein the cyanoacrylate is a mono- α -cyanoacrylate, or a bis- α -cyanoacrylate diester, or a combination of a plurality (e.g., 2 or 3) of mono- α -cyanoacrylates, or a combination of a plurality (e.g., 2 or 3) of bis- α -cyanoacrylate diesters, or a combination of mono- α -cyanoacrylate and bis- α -cyanoacrylate diesters (e.g., a combination of a mono- α -cyanoacrylate and a bis- α -cyanoacrylate diester, a combination of a mono- α -cyanoacrylate and a plurality of bis- α -cyanoacrylate diesters, a combination of a plurality of mono- α -cyanoacrylate and a bis- α -cyanoacrylate diesters, or a combination of a plurality of mono-alpha-cyanoacrylates with a plurality of bis-alpha-cyanoacrylate diesters).
In certain embodiments, the mono α -cyanoacrylate has the structure shown in formula (I):
Figure BDA0001505698170000021
wherein R is selected from:
(1)C1-30straight or branched alkyl, acyloxy, halogeno C1-4Alkyl radical, C1-4Alkoxy, halogen, or cyano-substituted C1-30Straight or branched alkyl, C2-30Straight-chain or branched alkenyl radical, C2-30Straight-chain or branched alkynyl, 5-to 10-membered cycloalkyl, C6-10aryl-C1-4Alkyl radical, C1-4alkyl-C6-10Aryl radical, C6-10An aryl group;
(2)-R1-O-R2-O-R3wherein R is1、R2Each independently selected from C1-6Alkylene radical, R3Is C1-6An alkyl group;
(3)-(C2H4O)nCH3、-(C2H4O)nC2H5、-(C2H4O)nh, wherein n is independently selected from an integer of 1-500 (e.g. 1-10, 10-100, 100-200, 200-300, 300-400 or 400-500).
In certain embodiments, said C1-30The linear or branched alkyl group is selected from: c1-4Straight or branched alkyl, C4-8Straight or branched alkyl, C1-8Straight or branched alkyl, C1-10Straight or branched alkyl, C1-20Straight or branched chain alkyl.
In certain embodiments, said C2-30Straight or branched alkenyl is selected from: c2-4Straight-chain or branched alkenyl, C4-8Straight-chain or branched alkenyl, C2-8Straight-chain or branched alkenyl, C2-10Straight-chain or branched alkenyl, C2-20Straight or branched alkenyl.
In certain embodiments, said C2-30Straight or branched alkynyl is selected from: c2-4Straight-chain or branched alkynyl, C4-8Straight-chain or branched alkynyl, C2-8Straight-chain or branched alkynyl, C2-10Straight-chain or branched alkynyl, C2-20Straight or branched alkynyl.
In certain embodiments, the halogen atom is selected from: fluorine, chlorine, bromine, iodine.
In certain embodiments, the halo C1-4Alkyl is selected from fluoro C1-4Alkyl or chloro C1-4An alkyl group.
In certain embodiments, R is selected from: methyl, ethyl, n-butyl, n-octyl, 2-isooctyl, -C2H4-O-CH3、-C2H4-O-C2H4-O-CH3。
In certain embodiments, R is selected from: n-butyl, n-octyl, 2-isooctyl, -C2H4-O-CH3、-C2H4-O-C2H4-O-CH3。
In certain embodiments, the bis- α -cyanoacrylate diester has the structure shown in formula (II):
Figure BDA0001505698170000031
wherein W is selected from:
(1)C1-30straight-chain or branched alkylene, acyloxy, halogeno C1-4Alkyl radical, C1-4Alkoxy, halogen, or cyano-substituted C1-30Straight-chain or branched alkylene, C2-30Straight-chain or branched alkenylene radical, C2-30Straight-chain or branched alkynylene, 5-to 10-membered cycloalkylene, C6-10aryl-C1-4Alkylene radical, C1-4alkyl-C6-10Arylene radical, C6-10An arylene group;
(2) segments of the following polymers: polyethylene glycol (PEG), polylactic acid (PLA), polyglycolic acid (PGA), poly (lactic-co-glycolic acid) (PLGA), copolymers containing polyhydroxy acids and polyalkylene glycol compounds (e.g., PLA-PEG-PLA block copolymers, PGA-PEG-PGA block copolymers).
In certain embodiments, theC1-30Linear or branched alkylene is selected from: c1-4Straight or branched alkylene, C4-8Straight or branched alkylene, C1-8Straight or branched alkylene, C1-10Straight or branched alkylene, C1-20Straight or branched chain alkylene.
In certain embodiments, said C2-30Linear or branched alkenylene is selected from: c2-4Linear or branched alkenylene, C4-8Linear or branched alkenylene, C2-8Linear or branched alkenylene, C2-10Linear or branched alkenylene, C2-20Straight or branched alkenylene.
In certain embodiments, said C2-30Straight or branched alkynylene groups selected from: c2-4Straight-chain or branched alkynylene, C4-8Straight-chain or branched alkynylene, C2-8Straight-chain or branched alkynylene, C2-10Straight-chain or branched alkynylene, C2-20Straight or branched alkynylene.
In certain embodiments, the halogen atom is selected from: fluorine, chlorine, bromine, iodine.
In certain embodiments, the halo C1-4Alkyl is selected from fluoro C1-4Alkyl or chloro C1-4An alkyl group.
In certain embodiments, W is selected from: ethylene, n-butylene, n-octylene and polyethylene glycol chain segments, wherein the polyethylene glycol chain segments are shown as a formula (III)
Figure BDA0001505698170000041
Wherein p is selected from integers between 0 and 100, preferably between 1 and 50 (e.g. 1 and 10, 10 and 20, 20 and 30, 30 and 40 or 40 and 50).
In certain embodiments, the composition comprises: (1) a mono- α -cyanoacrylate, (2) a plurality (e.g., 2 or 3) of mono- α -cyanoacrylates, (3) a bis- α -cyanoacrylate diester, or, (4) an α -monocyanoacrylate and a bis- α -cyanoacrylate diester.
In certain embodiments, the mono α -cyanoacrylate is selected from: n-butyl α -cyanoacrylate (BCA), methoxyethyl α -cyanoacrylate (MOE-CA), and methoxy diethylene glycol α -cyanoacrylate (MOEOE-CA).
In certain embodiments, the bis- α -cyanoacrylate diester is selected from: triethylene glycol bis-alpha-cyanoacrylate (CA-TEG-CA) and PEG bis-alpha-cyanoacrylate600Esters (CA-PEG)600-CA), PEG bis-alpha-cyanoacrylate2000Esters (CA-PEG)2000-CA)。
In the present invention, PEG600And PEG2000The lower subscripts in (a) indicate the number average molecular weight of the polyethylene glycol segment, which corresponds to a number of repeat units of about 14 and about 45, respectively.
In certain embodiments, the compositions comprise mono-and bis-alpha-cyanoacrylate esters in a molar ratio of from 2 to 150:1 (e.g., 2:1, 2.3:1, 5:1, 5.3:1, 10:1, 13:1, 13.9:1, 30:1, 32.5:1, 40:1, 44:1, 100:1, 125.3:1, or 150: 1).
In certain embodiments, the composition comprises a mono-alpha-cyanoacrylate and a bis-alpha-cyanoacrylate in a mass ratio of 99:1 to 50:50 (e.g., 99:1, 98:2, 97:3, 96:4, 95:5, 94:6, 93:7, 92:8, 91:9, 90:10, 89:11, 88:12, 87:13, 86:14, 85:15, 84:16, 83:17, 82:18, 81:19, 80:20, 79:21, 78:22, 77:23, 76:24, 75:25, 74:26, 73:27, 72:28, 71:29, 70:30, 69:31, 68:32, 67:33, 66:34, 65:35, 64:36, 63:37, 62:38, 61:39, 60:40, 59:41, 58:42, 57:43, 56:44, 55:45, 54:46, 53:47, 52:48, 51: 50, 49: 50).
In certain embodiments, the composition comprises a mono- α -cyanoacrylate and a bis- α -cyanoacrylate diester, the mono- α -cyanoacrylate being selected from: BCA, MOE-CA, said bis-alpha-cyanoacrylate diester being selected from: CA-TEG-CA, CA-PEG600-CA、CA-PEG2000-CA。
In certain embodiments, the composition comprises MOE-CA and CA-TEG-CA.
In certain embodiments, the composition comprises BCA and CA-TEG-CA.
In certain embodiments, the composition comprises MOE-CA and CA-PEG600-CA。
In certain embodiments, the composition comprises BCA and CA-PEG600-CA。
In certain embodiments, the composition comprises MOE-CA and CA-PEG2000-CA。
In certain embodiments, the composition comprises BCA and CA-PEG2000-CA。
In certain embodiments, the composition comprises two mono- α -cyanoacrylates in a molar ratio of 2 to 150:1 (e.g., 2:1, 2.3:1, 5:1, 5.3:1, 10:1, 13:1, 13.9:1, 30:1, 32.5:1, 40:1, 44:1, 100:1, 125.3:1, or 150: 1).
In certain embodiments, the composition comprises a mass ratio of 99:1 to 50:50 (e.g., 99:1, 98:2, 97:3, 96:4, 95:5, 94:6, 93:7, 92:8, 91:9, 90:10, 89:11, 88:12, 87:13, 86:14, 85:15, 84:16, 83:17, 82:18, 81:19, 80:20, 79:21, 78:22, 77:23, 76:24, 75:25, 74:26, 73:27, 72:28, 71:29, 70:30, 69:31, 68:32, 67:33, 66:34, 65:35, 64:36, 63:37, 62:38, 61:39, 60:40, 59:41, 58:42, 57:43, 56:44, 55:45, 54:46, 53:47, 52:48, 51: 50, or 50:50) mono-alpha acrylate.
In certain embodiments, the composition comprises two mono- α -cyanoacrylates selected from the group consisting of: BCA, MOE-CA, MOEOE-CA.
In certain embodiments, the composition comprises BCA and MOE-CA.
In certain embodiments, the composition comprises BCA and MOEOE-CA.
In certain embodiments, the composition comprises MOE-CA and MOEOE-CA.
In the invention, the same loading material may have different drug release rates for different drugs, and different loading materials may also have different drug release rates for the same drug. The rate of drug release may be related to factors such as the microstructure of the material, degradation of the material, and interaction of the material with the drug. The invention can adjust the degradation rate of the material and the drug release rate by selecting the cyanoacrylate monomer so as to meet different treatment requirements.
In the present invention, the antitumor drug is preferably a drug molecule having a structure that does not contain a functional group capable of causing anionic polymerization of cyanoacrylate, such as an amino group, or the like. In addition, the drug used in the composition of the present invention preferably has a suitable solubility in cyanoacrylate and a suitable interaction force with cyanoacrylate, so that the composition of the present invention has an effective drug release meeting the clinical therapeutic requirements, thereby producing a practical therapeutic effect.
In certain embodiments, the anti-neoplastic agent is selected from: mesylate derivatives, polyols, anthracycline derivatives, pyrimidine derivatives, taxane derivatives, and any combination thereof.
In certain embodiments, the anti-neoplastic agent is selected from: busulfan (Busulfan, Myleran, Marylan 17-24), dibromomannitol, dibromodulcitol, fluorouracil, paclitaxel, docetaxel, oxaliplatin, docetaxel, epirubicin, gemcitabine, vinblastine, doxorubicin, pirarubicin, capecitabine, hydroxycamptothecin, and any combination thereof.
In certain embodiments, the anti-neoplastic agent is selected from: fluorouracil, curcumin, doxorubicin, paclitaxel, docetaxel, and any combination thereof.
In certain embodiments, the anti-neoplastic drug is present in the composition in an amount of 0.001% to 20%, preferably 0.1% to 10% (e.g., 0.1% to 5%, e.g., 0.1%, 0.25%, 0.3125%, 0.5%, 0.625%, 0.75%, 1%, 1.25%, 1.5%, 2%, or 2.5%) by mass.
The compositions of the invention may also contain auxiliaries, such as synthesis auxiliaries, reactive auxiliaries, functional auxiliaries, process auxiliaries and/or stabilizing auxiliaries.
The antineoplastic medicine can be directly dissolved in the cyanoacrylate liquid in a monomer state to obtain the composition of the invention. In certain embodiments, using a plurality of cyanoacrylate monomers, the corresponding monomer components may be mixed under nitrogen protection to obtain a clear and transparent formulation glue; the clear and transparent drug-loaded glue solution can be obtained by mixing the formula glue and the drug. Optionally, stirring, shaking, heating, and the like may be used to facilitate mixing of the components.
The invention also relates to a drug-loaded polymer gel block obtained by polymerization reaction of any one of the compositions. Accordingly, the present invention provides a composition comprising an antineoplastic agent and a polycyanoacrylate, wherein the polycyanoacrylate is selected from the group consisting of: homopolymers of mono- α -cyanoacrylate, homopolymers of bis- α -cyanoacrylate diesters, copolymers of a plurality (e.g., 2 or 3) of mono- α -cyanoacrylate, copolymers of a plurality (e.g., 2 or 3) of bis- α -cyanoacrylate, or copolymers of mono- α -cyanoacrylate with bis- α -cyanoacrylate diesters (e.g., a copolymer of an α -mono-cyanoacrylate and a bis- α -cyanoacrylate diester, a copolymer of a mono- α -cyanoacrylate with a plurality of bis- α -cyanoacrylate diesters, a copolymer of a plurality of mono- α -cyanoacrylate with a bis- α -cyanoacrylate, or a copolymer of a plurality of mono- α -cyanoacrylate with a plurality of bis- α -cyanoacrylate diesters).
In certain embodiments, the mono α -cyanoacrylate has the structure shown in formula (I). In certain embodiments, the bis- α -cyanoacrylate diester has the structure shown in formula (II). In certain embodiments, the mono α -cyanoacrylate is selected from: n-butyl α -cyanoacrylate (BCA), methoxyethyl α -cyanoacrylate (MOE-CA), and methoxy diethylene glycol α -cyanoacrylate (MOEOE-CA). In certain embodiments, the bis- α -cyanoacrylate diester is selected from: triethylene glycol bis-alpha-cyanoacrylate (CA-TEG-CA) and PEG bis-alpha-cyanoacrylate600Esters (CA-PEG)600-CA), PEG bis-alpha-cyanoacrylate2000Esters (CA-PEG)2000-CA)。
In certain embodiments, the polycyanoacrylate comprises mono- α -cyanoacrylate monomer units and bis- α -cyanoacrylate diester monomer units in a molar ratio of 2 to 150:1 (e.g., 2:1, 2.3:1, 5:1, 5.3:1, 10:1, 13:1, 13.9:1, 30:1, 32.5:1, 40:1, 44:1, 100:1, 125.3:1, or 150: 1).
In certain embodiments, the polycyanoacrylate comprises mono- α -cyanoacrylate monomer units and bis- α -cyanoacrylate diester monomer units in a mass ratio of 99:1 to 50:50 (e.g., 99:1, 98:2, 97:3, 96:4, 95:5, 94:6, 93:7, 92:8, 91:9, 90:10, 89:11, 88:12, 87:13, 86:14, 85:15, 84:16, 83:17, 82:18, 81:19, 80:20, 79:21, 78:22, 77:23, 76:24, 75:25, 74:26, 73:27, 72:28, 71:29, 70:30, 69:31, 68:32, 67:33, 66:34, 65:35, 64:36, 63:37, 62:38, 61:39, 60:40, 59:41, 58:42, 57:43, 56:44, 55: 44, 54: 47, 47: 23: 22, 47: 23, 23: 24, and 75:25, respectively, 52:48, 51:49 or 50: 50).
In certain embodiments, the composition comprises a copolymer of a mono- α -cyanoacrylate and a bis- α -cyanoacrylate diester, the mono- α -cyanoacrylate being selected from the group consisting of: BCA, MOE-CA, said bis-alpha-cyanoacrylate diester being selected from: CA-TEG-CA, CA-PEG600-CA、CA-PEG2000-CA。
In certain embodiments, the polycyanoacrylate comprises two mono α -cyanoacrylate monomer units in a molar ratio of 2 to 150:1 (e.g., 2:1, 2.3:1, 5:1, 5.3:1, 10:1, 13:1, 13.9:1, 30:1, 32.5:1, 40:1, 44:1, 100:1, 125.3:1, or 150: 1).
In certain embodiments, the polycyanoacrylate comprises two mono- α -cyanoacrylate monomer units in a mass ratio of 99:1 to 50:50 (e.g., 99:1, 98:2, 97:3, 96:4, 95:5, 94:6, 93:7, 92:8, 91:9, 90:10, 89:11, 88:12, 87:13, 86:14, 85:15, 84:16, 83:17, 82:18, 81:19, 80:20, 79:21, 78:22, 77:23, 76:24, 75:25, 74:26, 73:27, 72:28, 71:29, 70:30, 69:31, 68:32, 67:33, 66:34, 65:35, 64:36, 63:37, 62:38, 61:39, 60:40, 59:41, 58:42, 57:43, 56:44, 55:45, 54:46, 54: 48, 47: 48, 49: 50, or 49: 50).
In certain embodiments, the polycyanoacrylate comprises two mono- α -cyanoacrylate monomer units selected from the group consisting of: BCA, MOE-CA, MOEOE-CA.
In certain embodiments, the anti-neoplastic agent is selected from: mesylate derivatives, polyols, anthracycline derivatives, pyrimidine derivatives, taxane derivatives, and any combination thereof.
In certain embodiments, the anti-neoplastic agent is selected from: busulfan (Busulfan, Myleran, Marylan 17-24), dibromomannitol, dibromodulcitol, fluorouracil, paclitaxel, docetaxel, oxaliplatin, docetaxel, epirubicin, gemcitabine, vinblastine, doxorubicin, pirarubicin, capecitabine, hydroxycamptothecin, and any combination thereof.
In certain embodiments, the anti-neoplastic agent is selected from: fluorouracil, curcumin, doxorubicin, paclitaxel, docetaxel, and any combination thereof.
In certain embodiments, the anti-neoplastic drug is present in the composition in an amount of 0.001% to 20%, preferably 0.1% to 10% (e.g., 0.1% to 5%, e.g., 0.1%, 0.25%, 0.3125%, 0.5%, 0.625%, 0.75%, 1%, 1.25%, 1.5%, 2%, or 2.5%) by mass.
In certain embodiments, the composition further comprises an auxiliary, such as a synthesis auxiliary, a reactive auxiliary, a functional auxiliary, a process auxiliary, and/or a stabilizing auxiliary.
In certain embodiments, the composition is prepared from a composition comprising an anti-tumor drug and a cyanoacrylate as any of the above.
The invention also relates to a pharmaceutical preparation containing the composition as described in any one of the above.
In the present invention, the composition containing the antitumor agent and the cyanoacrylate is usually in a liquid state, and is suitable for injection (e.g., injection solution or concentrated solution for injection), and in particular, for intratumoral injection. Cyanoacrylate is polymerized in tumors to form a solid drug-loaded rubber block, on one hand, the polymer plays a role of a drug storage, can release the drug loaded in the polymer in a fixed amount and slowly within a certain time according to treatment needs, and plays a role of fixed-point treatment; on the other hand, the polymerization of cyanoacrylate itself may destroy the micro blood supply in the tumor and may make the tumor produce sensitization and synergy effect on the drug; on the other hand, due to the bonding property generated by cyanoacrylate polymerization, the polymer can be well fixed and adhered in a tumor or on a corresponding tissue, and the risk of falling, displacement and the like is avoided.
The invention also relates to the use of the composition as defined in any one of the above for the preparation of a medicament for the treatment of a tumor-associated disease in a subject, said tumor-associated disease being a disease treatable by an anti-tumor drug contained in said composition.
The present invention also relates to a method for treating a tumor-related disease, which comprises administering an effective amount of the composition as described above to a subject in need thereof, wherein the tumor-related disease can be treated by an anti-tumor drug contained in the composition.
In the present invention, a tumor refers to a neoplasm (neoglowth) formed by local histiocyte proliferation of an organism under the action of various tumorigenic factors. Tumors of the invention include benign tumors and malignant tumors, as well as neoplastic polyps.
In the present invention, the tumor-related diseases include, but are not limited to: brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, cancer of the female genital tract, carcinoma in situ, lymphoma, neurofibroma, thyroid cancer, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, glioma, or sarcoma.
In the present invention, the subject is preferably a mammal, such as a bovine, equine, porcine, canine, feline, rodent, primate; for example, the subject is a human.
In the present invention, unless otherwise specified, scientific and technical terms used herein have the meanings that are commonly understood by those skilled in the art. Also, the laboratory procedures referred to herein are all conventional procedures widely used in the corresponding field. Meanwhile, in order to better understand the present invention, the definitions and explanations of related terms are provided below.
"C" according to the invention1-30Straight-chain or branched alkyl "denotes straight-chain or branched alkyl having 1 to 30 carbon atoms, including for example" C1-4Straight or branched alkyl group "," C4-8Straight or branched alkyl group "," C1-8Straight or branched alkyl group "," C1-10Straight or branched alkyl group "," C1-20Straight or branched alkyl group "," C10-20Straight or branched alkyl group "," C20-30Straight or branched chain alkyl "and the like, and specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, 2-isooctyl and the like.
"C" according to the invention1-4Alkoxy "means" C1-4alkyl-O- ", said" C1-4Alkyl "means a straight or branched chain alkyl group containing 1 to 4 carbon atoms.
"C" according to the invention2-30Straight-chain or branched alkenyl "means straight-chain or branched alkenyl containing at least one carbon-carbon double bond and having 2 to 30 carbon atoms, and includes, for example," C2-4Straight-chain or branched alkenyl group "," C4-8Straight-chain or branched alkenyl group "," C2-8Straight-chain or branched alkenyl group "," C2-10Straight-chain or branched alkenyl group "," C2-20Straight-chain or branched alkenyl group "," C10-20Straight-chain or branched alkenyl group "," C20-30Straight or branched alkenyl "and the like. Examples include, but are not limited to: vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1, 3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1, 3-pentadienyl, 1, 4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1, 4-hexadienyl and the like.
According to the invention“C2-30Straight-chain or branched alkynyl refers to straight-chain or branched alkynyl containing at least one carbon-carbon triple bond and having 2 to 30 carbon atoms, including, for example, "C2-4Straight or branched alkynyl "," C4-8Straight or branched alkynyl "," C2-8Straight or branched alkynyl "," C2-10Straight or branched alkynyl "," C2-20Straight or branched alkynyl "," C10-20Straight or branched alkynyl "," C20-30Straight or branched alkynyl "and the like. Examples include, but are not limited to: ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1, 4-pentynyl, 1-hexynyl, 2-hexynyl and 3-hexynyl.
"C" according to the invention1-30Straight or branched chain alkylene "refers to a straight or branched chain alkane containing 1 to 30 carbon atoms, derived from the removal of two hydrogens not on the same carbon atom, and includes" C1-4Straight-chain or branched alkylene group "," C4-8Straight-chain or branched alkylene group "," C1-8Straight-chain or branched alkylene group "," C1-10Straight-chain or branched alkylene group "," C1-20Straight-chain or branched alkylene group "," C10-20Straight-chain or branched alkylene group "," C20-30Straight or branched chain alkylene "and the like, and specific examples include, but are not limited to: -CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-、-CH2CH2CH2CH2CH2-、-CH2CH2CH2CH2CH2CH2-and the like.
"C" according to the invention2-30Straight or branched alkenylene refers to a straight or branched alkene of 2 to 30 carbon atoms derived from the removal of two hydrogens not on the same carbon atom, and includes "C2-4Straight-chain or branched alkenylene group "," C4-8Straight-chain or branched alkenylene group "," C2-8Straight-chain or branched alkenylene group "," C2-10Straight-chain or branched alkenylene group "," C2-20Straight-chain or branched alkenylene group "," C10-20Straight-chain or branched alkenylene group "," C20-30Straight-chain or branched alkenylene ", and the like, and specific examples include, but are not limited to, -CH ═ CH-, -CH ═ CHCH2-、-CH2CH＝CHCH2-、-CH＝CHCH＝CH-、-CH2CH2CH＝CHCH2-and the like.
"C" according to the invention2-30Straight or branched alkynylene "refers to a straight or branched alkyne of 2 to 30 carbon atoms derived from the removal of two hydrogens not on the same carbon atom, and includes" C2-4Straight or branched alkynylene group "," C4-8Straight or branched alkynylene group "," C2-8Straight or branched alkynylene group "," C2-10Straight or branched alkynylene group "," C2-20Straight or branched alkynylene group "," C10-20Straight or branched alkynylene group "," C20-30Straight or branched alkynylene ", and the like, and specific examples include, but are not limited to: -C.ident.C-, -C.ident.CCH2-、-H2CC≡CCH2-、-C≡CCH2CH、-H2CC≡CCH2CH-、-H2CC≡CCH2C ≡ C-, etc.
The "halogen atom" as referred to herein means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
The term "halo" as used herein means substituted by a "halogen atom".
The auxiliary agent refers to auxiliary raw materials in the production process and/or the use process of the adhesive. Adhesive aids include, but are not limited to: synthesis aids, reactive aids, functional aids, process aids and stabilizing aids.
As used herein, the term "synthesis aid" includes primarily emulsifiers, initiators, inhibitors, catalysts, solvents, oxidants, dispersants, chain extenders, regulators, neutralizers, terminators, and the like used during the synthesis and/or formulation of adhesives or other materials having adhesive properties.
As used herein, the term "reactive auxiliary agent" refers to a compound having a reactive group that can react with a matrix polymer in an adhesive or other substance having adhesive properties to form a network or cross-linked structure, and mainly includes a toughening agent, a curing agent, a cross-linking agent, a photoinitiator, an accelerator, a reactive flame retardant, and the like.
As used herein, the term "functional adjuvant" also referred to as "modification adjuvant" refers to an adjuvant capable of improving the original performance of an adhesive or other substance having adhesive properties, or imparting a new function thereto, and mainly includes plasticizers, coupling agents, tackifiers, foaming agents, colorants, reinforcing agents, fillers, flame retardants, softeners, antistatic agents, odor-masking agents, toughening agents, accelerators, chelating agents, and the like.
As used herein, the term "process aid" refers to an aid used for the convenience of formulation and use of an adhesive or other substance having adhesive properties and to ensure its intended performance, and mainly includes thickeners, defoamers, antifreeze, detackifiers, diluents, thixotropic agents, scorch retarders, and the like.
As used herein, the term "stabilizing additive" refers to an additive capable of preventing aging and deterioration of an adhesive or other substances having adhesive properties during synthetic preparation, storage and transportation, and use, prolonging the service life, and/or improving the storage stability, and mainly includes antioxidants, heat stabilizers, light stabilizers, bactericides, preservatives, metal ion deactivators, and the like.
Advantageous effects of the invention
The invention provides a composition containing cyanoacrylate monomers and an anti-tumor drug, wherein the cyanoacrylate monomers are in a liquid state before polymerization, have good solubility and compatibility with the anti-tumor drug and play a role in loading the drug; the composition has good fluidity, and can be injected into tumor by site-specific injection. The polymerizable property of the cyanoacrylate monomer enables the composition to form a solid drug-loaded gel block inside a tumor or at a corresponding applicable tissue within a few seconds of contacting human tissues. On one hand, the cyanoacrylate polymer formed by polymerization can play a role of drug storage, and can release the loaded drug in a fixed amount and slowly within a certain time according to the treatment requirement, so as to play a role of fixed-point treatment; on the other hand, the polymerization of cyanoacrylate monomers can destroy the micro blood supply in the tumor and can lead the tumor to generate sensitization and synergism on the medicine; on the other hand, due to the bonding property generated by cyanoacrylate polymerization, the medicine-carrying rubber block can be well fixed and adhered in a tumor or on a corresponding tissue, and the risk of falling, displacement and the like is avoided.
In the composition of the present invention, the drug and the loading material (cyanoacrylate monomer and/or polymer) have a synergistic (accelerating) therapeutic effect, and have a better therapeutic effect than a single drug group or blank material group.
Embodiments of the present invention will be described in detail below with reference to the drawings and examples, but those skilled in the art will understand that the following drawings and examples are only for illustrating the present invention and are not to be construed as limiting the scope of the present invention. Various objects and advantageous aspects of the present invention will become apparent to those skilled in the art from the accompanying drawings and the following detailed description of the preferred embodiments.
Drawings
FIG. 1 is a peak area-concentration standard curve of fluorouracil content in example 3.
FIG. 2 shows exemplary drug release profiles of drug loaded gel blocks (J-Fu-0.3125, J-Fu-0.625, J-Fu-1.25) loaded with different concentrations of drug.
FIG. 3 shows the cell viability of each group in the in vitro cytotoxicity assay.
Fig. 4 exemplarily shows cell morphology observed microscopically in an in vitro cytotoxicity assay, wherein a: group J, B: J-Fu-1.25 group, C: J-Fu-0.625 group, D: J-Fu-0.3125 group, E: normal group, F: and (4) Fu group.
FIG. 5 shows the change in tumor volume of each group of mice in the in vivo antitumor assay of example 6.
FIG. 6 shows the survival rate of each group of mice in the in vivo antitumor assay of example 6.
FIG. 7 shows the body weight change of each group of mice in the in vivo antitumor test of example 6.
Fig. 8 exemplarily shows the tumor status of each group of mice at day 14 of the in vivo anti-tumor test, wherein a: PBS group, B: fu group, C: group J, D: group J-Fu-1.25.
FIG. 9 is a photograph showing H & E staining of the major organs of J-Fu-1.25 group of mice on day 36 of in vivo antitumor test administration.
FIG. 10 is a photograph showing the H & E staining of the skin, muscle and major organs of the J-Fu-1.25 group of rats at day 30 of the subcutaneous dorsal implant test in SD rats.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to the drawings and examples, but those skilled in the art will understand that the following drawings and examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention. Those not indicated in the drawings and examples were carried out under the conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available. The anhydrous solvents used are all commercially available.
EXAMPLE 1 preparation of formulation glue
Using cyanoacrylate monomers BCA, MOE-CA, CA-TEG-CA, CA-PEG600-CA、CA-PEG2000-CA, formulated glue prepared according to the formulation in table 1. Under the protection of nitrogen, corresponding monomer components are mixed in modes of stirring, oscillation and the like, and clear and transparent formula glue can be obtained. The glue in the formula is polymerized in the air at normal temperature and pressure to form a glue block. The degradation rate and the adhesive strength of the gum blocks were tested and the results are shown in table 1.
The structure of each monomer is as follows:
Figure BDA0001505698170000151
BCA R＝-CH2-CH2-CH2-CH3 CA-TEG-CA W＝-(CH2CH2O)3-CH2CH2-
MOE-CA R＝-CH2-CH2-O-CH3 CA-PEG600-CA W＝PEG600
MOEOE-CA R＝-CH2-CH2-O-CH2-CH2-O-CH3 CA-PEG2000-CA W＝PEG2000
TABLE 1 formulation of the composition of the glue and the degradation rate and bond strength of the glue pieces
Figure BDA0001505698170000152
a. Apparent degradation rate test method: the polymer cement block is weighed (W)0) Placed in 50ml of PBS solution, shaken in a constant temperature shaker (Ronghua) at 37 ℃ for 14 days, dried and weighed (W)1). Apparent degradation rate ═ W0–W1)/W0
b. The test was performed according to the Standard code "YYT 0729.1-2009 tissue adhesive bonding Performance test method".
c. Indicating that the polymer completely disappeared and dissolved in 24 hours.
As can be seen from table 1, the gum blocks of different structures have differential apparent degradation rates and bond strengths (shear tensile). In practice, the appropriate monomer formulation may be selected according to particular needs (e.g., a certain degradation rate or bond strength of the gum block is desired).
EXAMPLE 2 preparation of drug-loaded gel
The glue in the formula shown in the table 1 is respectively mixed with fluorouracil, curcumin, doxorubicin, paclitaxel and docetaxel, and clear and transparent medicine-carrying glue solutions can be obtained by adopting a plurality of mass ratios (0.1%, 0.25%, 0.5%, 0.75%, 1%, 1.25%, 1.5%, 2% and 2.5%) of all the medicines.
EXAMPLE 3 in vitro drug Release testing of drug-loaded gels of different monomer formulations
Take a drug-loaded gel solution containing 1.25% fluorouracil as an example. And respectively adding 1.25 mass percent of fluorouracil into the formula glue of the groups A, F, G, I, J, K and M, and uniformly mixing to obtain the clear solution-shaped drug-loaded glue. Collecting 0.1g of the drug-loaded gelatin solution, and polymerizing to obtain gelatin block (flour)Product 2.5X 1cm2) The resulting mixture was placed in 50mL of PBS (pH7.4), and the gel-containing solution was placed in a constant temperature shaker (SHZ-82A, JINTAN RONGHUA, China,60rpm) at 37 ℃. Sampling at a certain time point, testing the fluorouracil content in the solution, and further calculating to obtain the drug release amount of each group. And (3) measuring the content of fluorouracil: firstly, preparing standard substances with different concentrations by a high performance liquid chromatography method, drawing a peak area-concentration standard curve (figure 1), and then calculating to obtain corresponding concentrations by measuring peak areas in specific samples. The results are shown in tables 2, 3 and 4.
TABLE 2 in vitro drug Release amount (%)
Figure BDA0001505698170000161
Figure BDA0001505698170000171
As can be seen from Table 2, the same mono- α -cyanoacrylate was combined with different bis- α -cyanoacrylate diesters in the same ratio to obtain drug-loaded gels with different release rates.
TABLE 3 in vitro drug Release amount (%) -of group I, group J, group K
Figure BDA0001505698170000172
TABLE 4 in vitro drug Release amount (%)
Figure BDA0001505698170000173
As can be seen from tables 3 and 4, the same mono- α -cyanoacrylate and bis- α -cyanoacrylate were combined in different ratios to obtain drug-loaded gels with different release rates.
As can be seen from tables 2, 3 and 4, the polycyanoacrylate materials with different structures can release the drug, but the drug-loaded gels prepared by different formulations have different drug release rates, which may be related to the degradation property of the polymer, the degree of compactness on the microstructure and the interaction force between the material and the drug molecules. The release rate of the drug can be adjusted by adjusting the composition and content of the monomer.
EXAMPLE 4 in vitro Release test of drug-loaded gels at different drug concentrations
The in vitro release profile of the drug loaded gel block was tested according to the method in example 3, with 0.3125%, 0.625% or 1.25% fluorouracil added to the formulation gel of group J, and the results are shown in figure 2. As can be seen from the figure, the drug-loaded gelatin blocks (J-Fu-0.3125, J-Fu-0.625 and J-Fu-1.25) loaded with drugs with different concentrations have similar drug release curves, which shows that the drug-loaded gelatin with the same monomer formula has stable drug release behavior and is less influenced by the drug concentration, and the drug concentration can be flexibly adjusted according to the needs.
Example 5 in vitro antitumor assay
Preparing a material leaching liquor: 7.5mg of the J-group formulation gel (referred to as J group for short) without the drug and the J-group formulation gel (referred to as J-Fu-1.25, J-Fu-0.625, J-Fu-0.3125 for short) loaded with fluorouracil at different concentrations (1.25%, 0.625% and 0.3125%, respectively) were solidified completely in a 48-well cell culture plate (diameter 10.2mm), and then placed in physiological saline (7.5mg/mL) at 37 ℃ with a volume fraction of 5% CO2Leaching for 24 hours in an incubator; filtering the leaching solution with 0.22 μm sterile filter membrane, adding RPMI-1640 culture medium, and diluting according to (1/1, v/v) to obtain sample to be tested.
In vitro cell assay: MCF-7 cells were purchased from synergetics cell banks; digesting MCF-7 cells cultured in a monolayer culture for 48h with 0.25% trypsin, preparing a single cell suspension by using RPMI-1640 medium containing 10% fetal bovine serum, and culturing at 5X 103Inoculating each cell in 96-well culture plate with volume of 100 μ L, placing in carbon dioxide incubator at 37 deg.C and 5% CO2Culturing for 24h under the condition of saturated humidity until the cells adhere to the wall; the culture solution is sucked up, 100 mu L of sample to be tested is added into each hole of the culture plate, wherein, the negative control isRPMI-1640 medium with 10% fetal bovine serum (normal group); positive control is PBS solution containing 1.25% fluorouracil (abbreviated as Fu group); the cell viability was examined by the MTT (tetramethylazozolium) method.
Fig. 3 shows the cell viability of each group, and fig. 4 shows the cell morphology observed under a microscope, in which a: group J, B: J-Fu-1.25 group, C: J-Fu-0.625 group, D: J-Fu-0.3125 group, E: normal group, F: and (4) Fu group.
From the test results of fig. 3 and fig. 4, it can be seen that the drug-loaded gel loaded with fluorouracil at different concentrations showed certain inhibitory activity to MCF-7 compared to the negative control group, and from fig. 3, the J-Fu-1.25 group showed stronger inhibitory activity than the positive control group, indicating that the curative effect of the cyanoacrylate monomer and/or polymer to fluorouracil was promoted.
Example 6 in vivo antitumor assay in nude mice
Constructing a model: 40 Balb/c nude mice (8 weeks old, female, about 20 g) were collected and 200. mu.L of 2X 10 mice were added6MCF-7 cell suspension (physiological saline) is injected subcutaneously into the axilla of the right forelimb of Balb/c nude mice by a disposable plastic syringe (1mL) and normally fed for 15 days.
Administration and evaluation of drug efficacy: 40 Balb/c tumor nude mice were randomly divided into four groups of 10 mice each. Wherein, PBS group: injecting 60 mu L PBS solution into tumor; fu group: intratumoral injection of 60 μ L of PBS solution containing 1.25% fluorouracil; group J: injecting 60 mu L blank J group prescription glue into tumor; J-Fu-1.25 group: 60 μ L of J-group formulation gel containing 1.25% fluorouracil was injected intratumorally. Observing the tumor volume, weight change and survival rate of each group of mice with time change, wherein the tumor volume (V) is calculated as V-short diameter2X major axis x 0.5.
FIG. 5 shows tumor volume changes in groups of mice; figure 6 shows survival rates of groups of mice; figure 7 shows the body weight change of the mice in each group; figure 8 shows the tumor status of the groups of mice on day 14 of the experiment, where a: PBS group, B: fu group, C: group J, D: group J-Fu-1.25.
As can be seen from the data in fig. 5-7, the medicated gel J-Fu-1.25 effectively inhibited tumor growth and increased survival rate of mice compared to the other three groups, and the body weight of the mice did not change significantly during the experiment. As can be seen in FIG. 8, at day 14 post-dose, the tumors in the J-Fu-1.25 mice exhibited more inflammation and necrosis than in the other three groups. The results jointly indicate that the drug-loaded gel J-Fu-1.25 has good anti-tumor effect.
In addition, as can be seen from FIGS. 5 to 7, the antitumor effect of the J-Fu-1.25 group was superior to that of the Fu group and that of the J group. The above results demonstrate that cyanoacrylate monomers and/or polymers can exert a beneficial effect on fluorouracil, at least over a range of dosages, and that the combination of both can produce a synergistic antitumor effect.
Example 7 evaluation of safety
Experiment I, Balb/c nude mouse tumor implantation experiment
On day 36 of the in vivo antitumor test in example 6, the surviving J-Fu-1.25 group of mice were all dislocated and sacrificed, and the main organs such as the heart, liver, spleen, and kidney were fixed with formalin, and the tissues were subjected to H & E staining to analyze the systemic toxicity of J-Fu-1.25. FIG. 9 is a photograph of H & E staining of the major organs. As can be seen from the figure, no inflammation was observed in H & E staining of the major organs (heart, liver, spleen, kidney) of Balb/c nude mice in the J-Fu-1.25 group at 36 days after administration, and there was no significant difference compared with the normal animal control group, indicating that J-Fu-1.25 has no systemic toxicity.
Experiment II, subcutaneous implantation experiment in back of SD rat
Curing 20mg of liquid J-Fu-1.25 formula glue into a round polymer glue block (with the diameter of 60mm) at room temperature; 18 SD rats (about 220g, female) were anesthetized with 10% chloral hydrate, the hair on the back was removed, and the polymer gel blocks were subcutaneously implanted into the skin on the back of the SD rats to observe the inflammation of the skin and muscle contacted with the polymer gel blocks over time (2 days, 4 days, 6 days, 10 days, 14 days, 30 days; 3 animals per time point). Rats were sacrificed by dislocation and the skin, muscle and rat organs (heart, liver, spleen, kidney) were removed for H & E staining pathological analysis.
FIG. 10 shows photographs of H & E staining of skin, muscle and rat organs at day 30 of the experiment. Although some inflammation was observed at the site of the gel block implantation in the first few days after the test, all the rats survived on the 30 th day of the test and the inflammation sites recovered to normal, and as can be seen from fig. 10, no inflammation was observed in the skin, muscle and major organs (heart, liver, spleen and kidney) of the rats contacted with the polymer gel block, indicating that the implanted polymer gel block had no systemic toxicity.
The two above test results confirm together: the drug-loaded polymer gel block has good biocompatibility.
While specific embodiments of the invention have been described in detail, those skilled in the art will understand that: various modifications and changes in detail can be made in light of the overall teachings of the disclosure, and such changes are intended to be within the scope of the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof.

Claims (19)

1. A composition comprising an antineoplastic agent and a cyanoacrylate, wherein the cyanoacrylate is a combination of mono- α -cyanoacrylate and a bis- α -cyanoacrylate diester, the mono- α -cyanoacrylate is n-butyl α -cyanoacrylate (BCA), the bis- α -cyanoacrylate diester is bis- α -cyanoacrylate triethylene glycol diacetate (CA-TEG-CA), bis- α -cyanoacrylate PEG600 ester (CA-PEG600-CA), or bis- α -cyanoacrylate PEG2000 ester (CA-PEG2000-CA),
the anti-tumor drug is selected from: busulfan, dibromomannitol, dibromodulcitol, fluorouracil, paclitaxel, docetaxel, oxaliplatin, epirubicin, gemcitabine, vinblastine, doxorubicin, pirarubicin, capecitabine, hydroxycamptothecin, and any combination thereof.
2. A composition comprising an antineoplastic agent and a cyanoacrylate, wherein the cyanoacrylate is a combination of mono- α -cyanoacrylate and a bis- α -cyanoacrylate diester, the mono- α -cyanoacrylate is methoxyethyl α -cyanoacrylate (MOE-CA) or methoxy diethylene glycol α -cyanoacrylate (MOEOE-CA), and the bis- α -cyanoacrylate is bis- α -cyanoacrylate triethylene glycol bis-ester (CA-TEG-CA), PEG600 bis-cyanoacrylate (CA-PEG600-CA) or PEG2000 bis- α -cyanoacrylate (CA-PEG 2000-CA).
3. The composition of claim 2, wherein the anti-neoplastic drug is selected from the group consisting of: busulfan, dibromomannitol, dibromodulcitol, fluorouracil, paclitaxel, docetaxel, oxaliplatin, epirubicin, gemcitabine, vinblastine, doxorubicin, pirarubicin, capecitabine, hydroxycamptothecin, and any combination thereof.
4. The composition of claim 2, wherein the mono- α -cyanoacrylate is methoxyethyl α -cyanoacrylate (MOE-CA).
5. A composition comprising an antineoplastic drug and a cyanoacrylate, wherein the cyanoacrylate is a combination of two mono- α -cyanoacrylates selected from the group consisting of: n-butyl α -cyanoacrylate (BCA), methoxyethyl α -cyanoacrylate (MOE-CA), and methoxy diethylene glycol α -cyanoacrylate (MOEOE-CA).
6. The composition of claim 5, wherein the anti-neoplastic drug is selected from the group consisting of: busulfan, dibromomannitol, dibromodulcitol, fluorouracil, paclitaxel, docetaxel, oxaliplatin, epirubicin, gemcitabine, vinblastine, doxorubicin, pirarubicin, capecitabine, hydroxycamptothecin, and any combination thereof.
7. The composition of any one of claims 1-4, wherein the composition comprises a mono-alpha-cyanoacrylate and a bis-alpha-cyanoacrylate diester in a molar ratio of 2 to 150: 1.
8. The composition of any one of claims 1-4, wherein the composition comprises mono- α -cyanoacrylate and bis- α -cyanoacrylate diester in a mass ratio of 99:1 to 50: 50.
9. The composition of claim 5 or 6, wherein the composition comprises two mono- α -cyanoacrylates in a molar ratio of 2 to 150: 1.
10. The composition of claim 5 or 6, wherein the composition comprises two mono- α -cyanoacrylates in a mass ratio of 99:1 to 50: 50.
11. The composition of any one of claims 1-6, wherein the anti-neoplastic drug is selected from the group consisting of: fluorouracil, curcumin, doxorubicin, paclitaxel, docetaxel, and any combination thereof.
12. The composition as claimed in any one of claims 1 to 6, wherein the content of the antitumor agent in the composition is 0.001% to 20% by mass.
13. The composition as claimed in claim 12, wherein the content of the antitumor drug in the composition is 0.1% to 10% by mass.
14. The composition of any one of claims 1-6, further comprising an adjuvant.
15. The composition of claim 14, wherein the auxiliary is a synthesis auxiliary, a reactive auxiliary, a functional auxiliary, a process auxiliary and/or a stabilization auxiliary.
16. A pharmaceutical formulation comprising the composition of any one of claims 1-15.
17. The pharmaceutical formulation of claim 16, wherein the pharmaceutical formulation is for administration by injection comprising the composition of any one of claims 1-15.
18. The pharmaceutical formulation of claim 17, wherein the pharmaceutical formulation is for intratumoral injection.
19. Use of a composition according to any one of claims 1 to 15 for the preparation of a medicament for the treatment of a tumor-associated disease in a subject, said tumor-associated disease being a disease treatable by an anti-tumor drug comprised in said composition.
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