CN112675305B - Amphiphilic molecule self-assembled nano-drug for tumor treatment and preparation method and application thereof - Google Patents
Amphiphilic molecule self-assembled nano-drug for tumor treatment and preparation method and application thereof Download PDFInfo
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- CN112675305B CN112675305B CN202110090262.1A CN202110090262A CN112675305B CN 112675305 B CN112675305 B CN 112675305B CN 202110090262 A CN202110090262 A CN 202110090262A CN 112675305 B CN112675305 B CN 112675305B
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A—HUMAN NECESSITIES
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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Abstract
The invention relates to an amphiphilic molecule self-assembled nano-drug for tumor treatment, a preparation method and application thereof. Specifically discloses an amphiphilic compound which is a conjugate of an organic photothermal agent modified by a hydrazine group and an antitumor drug containing carbonyl through a hydrazone bond. Further, a nanoparticle is disclosed, which is obtained by self-assembly of the above amphiphilic compound in an aqueous solution. The nano particles have an anti-tumor effect, can be enriched and dissociated in tumor areas, and have a combined treatment synergistic function of photothermal treatment and chemotherapy.
Description
Technical Field
The invention belongs to the field of medicines, and in particular relates to an amphiphilic molecule self-assembled nano-drug for tumor treatment, a preparation method and application thereof.
Background
Cancer is seriously threatening the life health safety of human beings, and overcoming cancer is one of the hot spot problems worldwide. Although there is some progress in the treatment and prevention of cancer now, the incidence and mortality of cancer is still in a rapidly rising state, and related reports show that mortality in lung cancer patients is up to 18.4%, followed by colorectal cancer (9.2%), gastric cancer and liver cancer are both 8.2%; for the incidence, lung cancer is the first, accounting for 11.6% of cancer cases, female breast cancer (11.6%), male prostate cancer (7.1%), and colorectal cancer (6.1%), so developing new treatments is particularly important. The current clinical treatments for cancer mainly include surgical excision, radiation therapy and chemotherapy. Surgical excision, as the name implies, is to surgically ablate tumor tissue, but residual tumor tissue after ablation is very susceptible to a series of problems such as secondary recurrence of cancer. At present, the radiotherapy mainly kills tumor cells by X-rays, so that the tumor cells die, but normal body organs and tissues are damaged to different degrees while killing the tumor. Chemotherapy is the main means of cancer treatment at present, but the single chemotherapy means has low utilization rate of medicines, and is extremely easy to cause drug resistance problem, especially for patients with malignant tumors and advanced cancer. Therefore, the combined treatment means are mostly adopted clinically, the anti-tumor effect is improved through the synergistic effect among the medicaments, the anti-tumor mechanisms of different medicaments are inconsistent, and the generation of drug resistance can be restrained as much as possible. However, combination therapy does not address the inherent disadvantages of chemotherapeutic drugs, such as the lack of targeting of most drugs to tumor tissue, and the action on tumor cells, as well as normal cells, can result in side effects.
With the development of nanotechnology, researchers have great potential to apply nanotechnology in tumor therapy, and many nanomaterials with good properties have been produced for the delivery of anticancer drugs. The drug system constructed by the nano material can be combined with various ligands and drugs, so that higher targeting and specificity are obtained, the drug resistance mechanism caused by the traditional drugs is overcome, more importantly, the nano system can be enriched in a tumor area by means of passive or active targeting, and the drug concentration in normal tissues is reduced, so that the systemic toxicity is reduced.
The carrier-free self-assembled nano-drug system does not need nano-materials as carriers, and the nano-drug is formed by self-assembly of the drugs, so that the theoretical drug loading rate is 100%, and the system is simpler and more efficient. Therefore, the self-assembled nano-particles for tumor treatment and the preparation method thereof provided by the invention have the advantages that the utilization rate of medicines is improved, the waste of medicines is reduced, the problems of increased production cost, difficult metabolism of human bodies and the like caused by introducing nano-carriers in the manufacturing process are avoided, and the instability and complexity of a nano-system are reduced.
Photothermal therapy is an emerging way of treating cancer, most cancer cells are weaker than normal cells in their ability to withstand high temperatures, and the use of high heat can cause irreversible damage to cancer cells, thereby killing them. The substance which can be heated by laser irradiation is called a photo-thermal agent, and the photo-thermal agent is enriched in a tumor area to locally generate high temperature so as to kill cancer cells, thereby achieving the purpose of treating cancer.
Disclosure of Invention
The invention provides a self-assembled nano-drug for tumor treatment and a preparation method thereof.
In a first aspect, the present invention provides an amphiphilic compound which is a conjugate of an organic photothermal agent modified with a hydrazine group and an antitumor drug containing a carbonyl group coupled via a hydrazone bond.
In an embodiment of the invention, the organic photothermal agent is selected from the group consisting of organic photothermal agents of the heptamethine cyanine class, the organic photothermal agent being selected from the group consisting of IR-780, IR-783, IR-808, IR-825, IR-1045, IR-1048, IR-1061, IR-26.
In an embodiment of the present invention, the carbonyl group-containing antitumor drug is selected from any one of doxorubicin, daunorubicin, doxorubicin B, epirubicin, idarubicin, pirarubicin, paclitaxel, docetaxel, formestane, epothilone.
In an embodiment of the invention, the hydrazine group in the organic photothermal agent modified with the hydrazine group and the carboxyl group in the carbonyl-containing antitumor drug are coupled by dehydration reaction to form a hydrazone bond.
In embodiments of the invention, hydrazine group modification refers to the modification of
Modification is carried out, wherein n is 0, 1, 2, 3, 4.
In embodiments of the invention, hydrazine group modification refers to by reacting
Obtained by reaction with chlorine radicals of organic photothermal agents, having +.>
Group-modified organic photothermal agents, wherein n is 0, 1, 2, 3, 4.
In an embodiment of the invention, the amphiphilic compound has a structural formula as shown in formula I below:
wherein n=0, 1, 2, 3, 4;
x is
A is an antitumor drug containing carbonyl, wherein carbon in the carbonyl is coupled with nitrogen in a hydrazone bond, preferably the antitumor drug containing carbonyl is any one of doxorubicin, daunorubicin, doxorubicin B, epirubicin, idarubicin, pirarubicin, paclitaxel, docetaxel, formestane and epothilone, and the structure of A is, for example
In a preferred embodiment of the present invention, the amphiphilic compound has the formula II
In a second aspect, the present invention provides a nanoparticle obtained by self-assembly of the above amphiphilic compound in an aqueous solution.
In an embodiment of the invention, the nanoparticle has a particle size of 40-200nm.
In an embodiment of the invention, the nanoparticle does not comprise a high molecular polymer.
The third aspect of the invention provides the application of the nanoparticle in preparing an anti-tumor medicament.
In a fourth aspect, the present invention provides a dual effect anti-tumour agent comprising the nanoparticle described above.
In the embodiment of the invention, the dosage form of the double-effect antitumor drug is injection, oral preparation or parenteral preparation.
In an embodiment of the invention, the tumor is selected from the group consisting of osteosarcoma, skin cancer, bladder cancer, ovarian cancer, breast cancer, gastric cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, rectal cancer, esophageal cancer, tongue cancer, kidney cancer, cervical cancer, uterine body cancer, endometrial cancer, testicular cancer, urinary cancer, melanoma, astrocytoma, meningioma, hodgkin's lymphoma, non-hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute myelogenous leukemia, chronic granulocytic leukemia, adult T-cell leukemia lymphoma, hepatocellular carcinoma, bronchogenic cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, seminoma, chondrosarcoma, myosarcoma, fibrosarcoma.
The fifth aspect of the present invention provides a method for preparing the above amphiphilic compound, comprising the steps of:
1) Will be
Obtained by reaction with chlorine groups of organic photothermal agents, has
A group-modified organic photothermal agent;
2) And (2) coupling the modified organic photothermal agent obtained in the step (1) with carboxyl in the carbonyl-containing antitumor drug to form a hydrazone bond through a dehydration reaction to obtain the amphiphilic compound.
In an embodiment of the invention, the organic photothermal agent in step 1) is selected from the group of organic photothermal agents of the heptamethine cyanine class, said organic photothermal agent being selected from the group consisting of IR-780, IR-783, IR-805, IR-808, IR-825, IR-1045, IR-1048, IR-1061, IR-26.
In an embodiment of the present invention, the carbonyl group-containing antitumor drug in step 2) is selected from any one of doxorubicin, daunorubicin, doxorubicin B, epirubicin, idarubicin, pirarubicin, paclitaxel, docetaxel, formestane, epothilone.
In an embodiment of the present invention, the reaction conditions in step 1) are such that under an inert atmosphere
Is dispersed in an organic solvent together with an organic photothermal agent and reacts to completion.
In the embodiment of the invention, the modified organic photothermal agent obtained in the step 1) and the antitumor drug containing carbonyl are dispersed in an organic solvent together under the inert atmosphere of the reaction condition in the step 2), and the catalyst trifluoroacetic acid is added and reacted at 50-80 ℃ until the reaction is completed.
In an embodiment of the invention, step 2) further comprises a purification step.
In an embodiment of the invention, the compounds in step 1)
The preparation method comprises the steps of adding hydrazine hydrate and +.>
Dispersing in organic solvent, and reacting to obtain +.>
The sixth aspect of the present invention provides a method for preparing the above nanoparticle, the method comprising the steps of:
a) Dispersing the amphiphilic compound in an organic solvent to prepare an organic solution;
b) Dispersing the organic solution in an aqueous solution, and volatilizing the organic solvent to obtain a nanoparticle aqueous solution.
In an embodiment of the invention, the step b) further comprises a step of dispersing the aqueous solution by mechanical force.
In an embodiment of the present invention, the organic solvent in the step b) is a mixed solvent of one or more organic solvents capable of dissolving the amphiphilic compound and miscible with water.
In a specific embodiment of the present invention, the organic solvent in the step b) is a mixed solvent of chloroform and acetone, preferably the volume ratio of chloroform to acetone is 1:9.
In a seventh aspect, the present invention provides the use of an amphiphilic compound as described above for the preparation of a nanoparticle for the treatment or prophylaxis of a tumour.
Advantageous effects
1. The carrier-free self-assembled nano-drug system does not need nano materials as carriers, and the nano-drug is formed by self-assembly of the drugs, so that the theoretical drug loading rate is 100%, the method is simpler and more efficient, the drug utilization rate is improved, and the drug waste is reduced.
2. The nanometer medicine prepared with photothermal agent and carbonyl anticancer medicine is concentrated and dissociated in tumor area and has the combined photothermal treatment and chemotherapy function. Experimental results prove that the synergistic effect is generated on the anti-tumor effect.
Drawings
FIG. 1 is a graph showing the hydrodynamic diameter distribution of nanoparticles prepared in example 2.
Fig. 2 is a transmission electron micrograph of the nanoparticle prepared in example 2.
FIG. 3 shows the dissociation effect of nanoparticles under different pH conditions.
FIG. 4 is a graph showing the temperature rise of nanoparticles of different concentrations under laser (808 nm) irradiation.
FIG. 5 is a graph showing cell viability after treatment under different conditions.
FIG. 6 is a mass spectrum of compound c obtained in example 1.
Detailed Description
The following detailed description of the present invention will be made in detail to make the above objects, features and advantages of the present invention more apparent, but should not be construed to limit the scope of the present invention.
In the present invention, IR-780 has the structural formula
IR-783 is of the formula
IR-808 has the formula +.>
IR-825 has the structural formula
IR-1045 has the structural formula
IR-1048 has the structural formula +.>
The structural formula of IR-1061 is +.>
IR-26 has the formula->
In some embodiments of the invention, the amphiphilic compound is selected from the group consisting of
The invention uses photo-thermal agent and anticancer drug containing carbonyl group after chemical modification to prepare hydrazone bond coupled amphiphilic compound, taking photo-thermal agent IR-780, drug doxorubicin hydrochloride and coupling agent methyl thioglycolate as examples.
1) Compound a
Is synthesized by the following steps: dispersing methyl thioglycolate and hydrazine hydrate in methanol under a nitrogen environment, stirring at room temperature, spin-drying the obtained reaction liquid, and passing through a column by chromatography to obtain colorless transparent oily liquid, namely the compound. />
2) Compound b
Is synthesized by the following steps: dispersing the compound a and IR-780 in chloroform under nitrogen, stirring at room temperature, spin-drying the obtained reaction solution, and adding dichloroDissolving methane, washing an organic phase with water, drying the organic phase, and evaporating to dryness to obtain the compound b.
3) Compound c
Is synthesized by the following steps: dispersing the compound b and doxorubicin hydrochloride in methanol in a nitrogen environment, dropwise adding a catalytic amount of trifluoroacetic acid, stirring at 60 ℃, spin-drying the obtained reaction liquid, adding dichloromethane for dissolving, washing an organic phase, concentrating the organic phase after drying, and performing chromatography on the organic phase to obtain a dark green solid, namely the compound c.
Example 1 preparation of amphiphilic Compounds
The synthesis scheme is as follows:
1) Synthesis of compound a: methyl thioglycolate (0.24 g,2 mmol) and hydrazine hydrate (0.24 g,4.8 mmol) were dispersed in 5mL of methanol under nitrogen atmosphere, stirred at room temperature for 12h, the obtained reaction solution was spin-dried and chromatographed over the column to give 0.15g of a colorless transparent oily liquid, namely compound a, yield: 62.5%.
2) Synthesis of compound b: compound a (0.0288 g,0.24 mmol) and IR-780 (0.08 g,0.12 mmol) were dispersed in 20mL chloroform under nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 12h, dried by spinning, dissolved in dichloromethane, washed with water, dried and evaporated to dryness to give compound b.
3) Synthesis of Compound c: compound b (0.04 mmol) and doxorubicin hydrochloride (0.0348 g,0.06 mmol) were dispersed in 20mL methanol under nitrogen atmosphere, a catalytic amount of trifluoroacetic acid was added dropwise, and stirred at 60 ℃ for 48h, the reaction solution obtained was dried by spinning, dichloromethane was added for dissolution, the organic phase was washed with water, dried and concentrated, and the column was chromatographed to give 0.012g of a dark green solid, compound c, yield: 23.5%. The mass spectrum detection molecular weight is 1148.56, and the mass spectrum is shown in fig. 6.
Example 2 preparation of nanoparticles
5mg of compound c is dissolved in 500 mu L of mixed solvent (50 mu L of chloroform+450 mu L of acetone), slowly dripped into 5mL of deionized water with vigorous stirring, and the nanoparticle aqueous solution of compound c is obtained after the organic solvent volatilizes. The hydrodynamic diameter of the nanoparticles of the compound c prepared in this example is shown in fig. 1, and the transmission electron micrograph of the nanoparticles of the compound c prepared in this example is shown in fig. 2.
Example 3 dissociation experiments simulating tumor microenvironment
The tumor microenvironment is simulated in vitro, the nanoparticle aqueous solution of the compound c is placed in a dialysis bag (cut-off rate 2000), soaked in the aqueous solutions with the pH value of=5.0 and 7.5 respectively, sampled at intervals (12, 24, 48, 60, 72, 84, 96, 108 and 120 h), and the dissociation degree of the nanoparticle obtained by measuring the ultraviolet absorbance of the precipitated doxorubicin is calculated as shown in figure 3, so that the nanoparticle of the compound c has good dissociation effect under the acidic condition.
Example 4 photo-thermal heating capability test
The nanoparticles of compound c were prepared in aqueous solutions of different concentrations (5. Mu.g/mL, 10. Mu.g/mL, 20. Mu.g/mL, 40. Mu.g/mL) and laser light at 808nm (2W/cm) 2 ) The temperature rise curve of the measured solution over time is shown in fig. 4, demonstrating that the nanoparticles of compound c have good temperature rise capability.
EXAMPLE 5 anti-tumor Experimental results
The nanoparticles of Compound c (IR-780-DOX), IR-780, doxorubicin hydrochloride and the cell culture solution were prepared to give solutions having concentrations of 1. Mu.g/mL, 2.5. Mu.g/mL and 5. Mu.g/mL, and then co-cultured with 143B cells (osteosarcoma cells) for 3 hours, respectively, and then a portion of the co-cultured compositions in the IR-780-DOX group and IR-780 group were subjected to a 808nm laser (0.8W/cm) 2 ) After 5min of irradiation, another portion of the IR-780-DOX and IR-780 co-culture compositions and doxorubicin groups were incubated without irradiation for 24h, cell viability assays were performed using the MTT method as shown in FIG. 5. Wherein IR-780 is the co-culture of IR-780 and tumor cells, and the group without laser irradiation, the IR-780/Lasser 5min group is the co-culture of IR-780 and tumor cells, and the group with laser irradiation, free IR-780-DOX group is the co-culture of the nano-particles (IR-780-DOX) of the compound c and tumor cellsThe culture is carried out without laser irradiation, the IR-780-DOX/Lasser 5min group is the IR-780-DOX co-cultured with tumor cells and the Free DOX is the doxorubicin co-cultured with the tumor cells without laser irradiation. Experimental results prove that the four groups except the IR-780 group have different degrees of tumor inhibition effect along with the increase of the concentration. Wherein the doxorubicin group and the IR-780-DOX/Laser 5min group were more effective than the Free IR-780-DOX group and the IR-780/Laser 5min group. However, if the comparison is made under the condition of considering the concentration of the amount of the substance, since the molecular weight of IR-780-DOX is much higher than that of doxorubicin, the viability of doxorubicin cells is about twice that of IR-780/Lasser 5min under the condition of the same concentration of the amount of the substance. The nano particles of the compound c have potential application in the aspect of tumor treatment, and combine two treatment modes, so that a nano particle structure can be formed without a carrier, the nano particles are released under the specific pH condition, the passive targeting purpose is realized, and the synergistic effect is realized by the two effects.
Claims (21)
1. An amphiphilic compound, characterized in that the amphiphilic compound has a structural formula shown in the following formula II
2. A nanoparticle, characterized in that it is obtained by self-assembly of the amphiphilic compound of claim 1 in an aqueous solution;
the preparation method of the nano-particles comprises the following steps:
a) Dispersing the amphiphilic compound of claim 1 in an organic solvent to prepare an organic solution;
b) Dispersing the organic solution in an aqueous solution, and volatilizing the organic solvent to obtain a nanoparticle aqueous solution.
3. The nanoparticle of claim 2, wherein the nanoparticle has a particle size of 40-200nm.
4. Use of the nanoparticle according to claim 2 or 3 for the preparation of an antitumor drug.
5. The use according to claim 4, wherein the tumor is selected from osteosarcoma, skin cancer, bladder cancer, ovarian cancer, breast cancer, gastric cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, rectal cancer, esophageal cancer, tongue cancer, kidney cancer, cervical cancer, uterine cancer, testicular cancer, melanoma, astrocytoma, meningioma, hodgkin lymphoma, non-hodgkin lymphoma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, hepatocellular carcinoma, fibrosarcoma.
6. The use according to claim 4, wherein the tumor is a seminoma.
7. The use according to claim 4, wherein the tumor is selected from the group consisting of chondrosarcoma, basal cell carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, endometrial carcinoma, adult T-cell leukemia lymphoma, multiple myeloma, and bronchogenic carcinoma.
8. The use according to claim 4, wherein the tumor is selected from acute myelogenous leukemia, chronic myelogenous leukemia.
9. A dual effect antitumor drug comprising the nanoparticle of claim 2 or 3.
10. The dual-effect anti-tumor medicine according to claim 9, wherein the dosage form of the dual-effect anti-tumor medicine is injection or oral preparation.
11. The dual effect anti-neoplastic agent of claim 9, wherein the dual effect anti-neoplastic agent is in a dosage form for parenteral administration.
12. The method for producing an amphiphilic compound according to claim 1, characterized in that the method comprises the steps of:
1) Reacting a compound with a hydrazine group with an organic photothermal agent to obtain an organic photothermal agent with hydrazine group modification;
2) Coupling the modified organic photothermal agent obtained in the step 1) with carboxyl in the carbonyl-containing antitumor drug to form a hydrazone bond through dehydration reaction to obtain an amphiphilic compound;
the organic photothermal agent in the step 1) is IR-780;
the antitumor drug containing carbonyl in the step 2) is doxorubicin.
13. The process according to claim 12, wherein step 1) is a step of reacting a compound having a hydrazine group
Obtained by reaction with chlorine radicals of organic photothermal agents, having the formula +.>
The organic photothermal agent modified by the hydrazine group is shown.
14. The process according to claim 12, wherein the reaction conditions of step 1) are that the reaction is carried out under an inert atmosphere
Is dispersed in an organic solvent together with an organic photothermal agent and reacts to completion.
15. The preparation method according to claim 12, wherein in the step 2), the modified organic photothermal agent obtained in the step 1) and the antitumor drug containing carbonyl are dispersed in an organic solvent together under inert atmosphere, and the catalyst trifluoroacetic acid is added and reacted at 50-80 ℃ until the reaction is completed.
16. A method of preparing nanoparticles according to claim 2 or 3, characterized in that the method comprises the steps of:
a) Dispersing the amphiphilic compound of claim 1 in an organic solvent to prepare an organic solution;
b) Dispersing the organic solution in an aqueous solution, and volatilizing the organic solvent to obtain a nanoparticle aqueous solution.
17. The method of claim 16, wherein said step b) further comprises the step of mechanically dispersing the aqueous solution.
18. The method according to claim 16, wherein the organic solvent in the step b) is a mixed solvent of one or more organic solvents capable of dissolving the amphiphilic compound and miscible with water.
19. Use of an amphiphilic compound according to claim 1 for the preparation of nanoparticles for the treatment of tumors.
20. The use according to claim 19, wherein the nanoparticle has a particle size of 40-200nm.
21. The use of claim 19, wherein the nanoparticle does not comprise a high molecular polymer.
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