CN107158399B - Amphiphilic nano-drug and preparation method and application thereof - Google Patents

Amphiphilic nano-drug and preparation method and application thereof Download PDF

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CN107158399B
CN107158399B CN201710397627.9A CN201710397627A CN107158399B CN 107158399 B CN107158399 B CN 107158399B CN 201710397627 A CN201710397627 A CN 201710397627A CN 107158399 B CN107158399 B CN 107158399B
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drug
sorafenib
amphiphilic
amphiphilic nano
nano
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CN107158399A (en
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冯旭利
汤嘉堃
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Chongqing University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

The invention relates to an amphiphilic nano-drug, a preparation method and application thereof, wherein a hydrophilic group is connected to the structure of a hydrophobic drug, so that the nano-drug with good hydrophilicity is improved.

Description

Amphiphilic nano-drug and preparation method and application thereof
Technical Field
The invention belongs to the field of medicinal chemistry, relates to an amphiphilic nano-medicament, and further relates to a preparation method and application of the amphiphilic nano-medicament.
Background
With the improvement of living standard of people, the health problem is increasingly prominent. Cancer is one of the main diseases affecting human health and threatening human life. Therefore, the world health organization and the health departments of various countries take overcoming cancer as a primary task. There are three main methods for treating cancer: one of the two methods is surgical treatment, which is the oldest method for treating cancer, that is, removing cancerous tissues by surgical removal to prevent cancer cells from spreading. Secondly, a method of chemotherapy or radiotherapy is adopted, and thirdly, drug therapy is adopted. The surgical excision method has great trauma to human body, which results in the decrease of immunity and resistance to diseases of patients. Moreover, surgical excision is a local treatment, and is more suitable for early cancer. Meanwhile, the surgical treatment also has a certain risk, and relapse or metastasis easily occurs after the operation. When the radiotherapy method is used, cancer cells are killed, other normal cells are killed, and the patient has systemic symptom response. The drug therapy, especially the targeted drug therapy, can efficiently kill cancer cells, greatly reduce the toxic and side effects on the body of a patient and greatly improve the overall effect of the patient. The drug sorafenib (sorafenib) in the research is a targeted therapeutic drug, and different from chemotherapeutic drugs, the drug sorafenib (sorafenib) can effectively inhibit the proliferation of tumor cells and the angiogenesis of tumors, but has no cytotoxic effect, so that the sorafenib has a potential broad-spectrum antitumor effect. Treating liver tumor cells that are inoperable or metastasized at a distance; treating inoperable renal tumor cells; treatment of locally recurrent or metastatic, progressively differentiated thyroid patients who are no longer effective for radioiodine therapy. Sorafenib has no cytotoxic effect, can stabilize the disease condition and prolong the disease-progression-free survival period of patients. Sorafenib is also the first and only one effective therapeutic drug in the world which is medically proven to significantly prolong the survival time of patients with liver cancer. It is this series of advantages that have promoted the development and application of sorafenib. It has important significance in treating patients with advanced liver cancer who can not be operated.
The action mechanism of sorafenib in inhibiting tumor cell proliferation and tumor angiogenesis is as follows: inhibiting RAS/RAF/MEK/ERK signal transduction pathway and inhibiting proliferation of tumor cells by inhibiting the activity of Raf-1 and B-Raf serine and threonine kinase; sorafenib inhibits tumor angiogenesis. Tumor growth is dependent on the formation of new blood vessels, and VEGFR and PDGFR are the most important regulators that promote angiogenesis. Sorafenib has an inhibitory effect on the tyrosine kinase activity of the two receptors, thereby blocking the formation of tumor neovessels, cutting off the nutrient supply of tumor cells and indirectly inhibiting the growth of the tumor cells.
Sorafenib is a new drug developed based on further definition of a molecular biological mechanism of tumorigenesis, and has a unique multi-target antitumor effect. Has no cytotoxic effect, can stabilize the disease condition, and prolong the disease-free progression survival period of patients. It is in the late stage. The success in the treatment of renal cancer has brought a new inspiration for the development of targeted drugs, which have agreed to be approved in europe as the 2 nd indication for the treatment of liver cancer and have been positively suggested in the united states. How to make the best plan to improve the curative effect is an important problem faced in our present study.
Sorafenib is high in hydrophobicity and low in bioavailability, so that improvement of water solubility of sorafenib is an urgent problem to be solved. The successful development of sorafenib tosylate brings good news to patients with late-stage liver cancer. The existing dosage form is sorafenib tosylate and the recommended dose is 400 mg once, twice daily, although the dose has been reduced, there are any inevitable adverse events. A plurality of clinical researches show that the common adverse reactions of sorafenib include diarrhea, hypodynamia, hand-foot syndrome, hypertension, rash, vomiting and the like. It is mild or moderate, and can be relieved after weight reduction and symptomatic treatment, and the most important 3/4-grade adverse reactions comprise hypodynamia, hand-foot syndrome and diarrhea. Decreasing, discontinuing, or exiting sorafenib treatment may affect the efficacy of the drug. Therefore, the early effective control of adverse reactions while maintaining sorafenib treatment is particularly important for improving clinical efficacy, improving the quality of life of patients and compliance with drugs. The toxic and side effects of sorafenib are reduced, the bioavailability is improved, the water solubility of the medicament is increased, and the like, which still remain problems to be solved urgently.
Disclosure of Invention
In view of the above, an object of the present invention is to provide an amphiphilic nano-drug; the second purpose of the invention is to provide a preparation method of the amphiphilic nano-drug, and the third purpose of the invention is to provide the application of the amphiphilic nano-drug.
In order to achieve the purpose, the invention provides the following technical scheme:
1. an amphiphilic nanometer medicine has structure of A-B-L-D, wherein A is hydrophilic group selected from hydrophilic groups
Figure GDA0002366130750000021
Figure GDA0002366130750000022
Or PEG 200-10000; b is
Figure GDA0002366130750000023
Figure GDA0002366130750000024
n is a positive integer of 1-10; l is a cleavable group selected from
Figure GDA0002366130750000025
Figure GDA0002366130750000026
D is a hydrophobic drug selected from
Figure GDA0002366130750000027
Doxorubicin, paclitaxel or triptolide.
In the invention, the PEG 200-10000 is linear chain PEG 200-10000, branched chain PEG 200-10000 or 3-8 arm PEG 200-10000.
In the present invention, the cleavable group is
Figure GDA0002366130750000031
Figure GDA0002366130750000032
In the present invention, the hydrophobic drug is selected from
Figure GDA0002366130750000033
In the invention, the structure is in a form of T-A-B-L-D, wherein T is a targeting group and is selected from galactose, lactose or folic acid.
Preferably, the structure is shown as formula II:
Figure GDA0002366130750000034
2. the preparation method of the amphiphilic nano-drug comprises the following steps:
(1) the cleavable disulfide bond is connected to amino-functionalized PEG through Michael addition reaction to prepare an amphiphilic PEG molecule with functionalized tail end;
(2) and (2) reacting the amphiphilic PEG molecule in the step (1) with hydrogen on an amido group of a hydrophobic drug to obtain the amphiphilic nano-drug.
Preferably, the hydrophobic drug is selected from
Figure GDA0002366130750000035
Doxorubicin, paclitaxel or triptolide.
3. The application of the amphiphilic nano-drug in preparing a drug for treating tumor.
Preferably, the amphiphilic nano-drug is a sorafenib amphiphilic nano-drug, and the tumor is liver cancer.
The invention has the beneficial effects that: among various tumor treatment medicines, the medicine has strong hydrophobicity, low bioavailability and large toxic and side effects. The invention of sorafenib utilizes the special structure of amphiphilic molecules, not only improves the water solubility of hydrophobic drugs, but also enables newly obtained molecules to form nano particles in the water solubility, thereby improving the passive targeting property of the drugs, enhancing the drug effect and reducing possible side effects. The new drug molecule designed by the invention has good water solubility, definite structure, easy repetition and characterization and better treatment effect.
Drawings
In order to make the object, technical scheme and beneficial effect of the invention more clear, the invention provides the following drawings for explanation:
figure 1 is the SCNS hydrogen spectrum.
FIG. 2 shows the particle size of SCNS in aqueous solution.
FIG. 3 shows the results of SCNS and sorafenib anti-hepatoma cells (HepG2) (A: sorafenib; B: SCNS).
Detailed Description
Preferred embodiments of the present invention will be described in detail below with reference to the accompanying drawings.
Example 1
The cleavable disulfide bond is connected to PEG with amino functionalization through Michael addition reaction to prepare PEG molecule (compound I) with end functionalization and amphipathy, and the specific route is as follows:
Figure GDA0002366130750000051
then, the compound I reacts with part of amido hydrogen of Sorafenib a to obtain a final compound SCNS, and the specific route is as follows:
Figure GDA0002366130750000061
the SCNS hydrogen spectrum results of the compound are shown in fig. 1. The results show that: sorafenib was successfully grafted onto PEG via the Michael addition reaction.
Example 2
The water solubility of the SCNS synthesized in example 1 was compared with the solubility of sorafenib, and the results are shown in table 1.
TABLE 1 comparison of water solubility of SCNS and Sorafenib
Figure GDA0002366130750000062
Figure GDA0002366130750000071
The results show that sorafenib is almost completely insoluble in water, while the improved compound SCNS has good water solubility.
Example 3
The morphology of SCNS in aqueous solution was subjected to particle size measurement and the results are shown in fig. 2. Experimental results show that the obtained compound forms nanoparticles of about 200nm in water solubility, and is favorable for entering cells and intravenous administration.
Example 4
MTT experiments of liver cancer cells (HepG2) were carried out on SCNS and Sorafenib, and the specific method was as follows:
1. and (3) adding 100 mu L of culture solution into each hole of a 96-hole plate, preparing the cell suspension, slightly and uniformly mixing, and adding 10ul of cell suspension into the hole added with the culture solution. After mixing uniformly, adding 5% CO2Incubate at 37 ℃ for 24 hours.
2. After 24 hours, the corresponding amount of drug, 5% CO, was added according to a concentration gradient2And cultured in an incubator at 37 ℃ for 48 hours.
3. After 48 hours, the culture medium was aspirated, and 20. mu.L of MTT solution (prepared at a final concentration of 5mg/ml MTT in PBS) and 5% CO were added to each well2And cultured in an incubator at 37 ℃ for 4 hours.
4. After adding 100. mu.L of DMSO to each well, formazan was precipitated as a purple color. And (3) fully and uniformly mixing the solvent and formazan, and detecting absorbance by an enzyme-labeling instrument to obtain the survival state of the cells.
The results are shown in fig. 3, and show that the survival rate of the liver cancer cells is reduced along with the gradual increase of the concentration of the SCNS, and the trend is basically consistent with that of sorafenib, which indicates that the SCNS prepared by the invention also has a good anti-liver cancer effect.
Finally, it is noted that the above-mentioned preferred embodiments illustrate rather than limit the invention, and that, although the invention has been described in detail with reference to the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the invention as defined by the appended claims.

Claims (4)

1. An amphiphilic nano-drug is characterized in that the structure is shown as formula II:
Figure 927822DEST_PATH_IMAGE001
2. the method for preparing the amphiphilic nano-drug according to claim 1, characterized by comprising the following steps:
(1) the cleavable disulfide bond is connected to amino-functionalized PEG through Michael addition reaction to prepare an amphiphilic PEG molecule with functionalized tail end;
(2) and (2) reacting the amphiphilic PEG molecule in the step (1) with hydrogen on an amido group of a hydrophobic drug to obtain the amphiphilic nano-drug.
3. The use of the amphiphilic nano-drug of claim 1 in the preparation of a medicament for the treatment of tumors.
4. Use according to claim 3, characterized in that: the amphiphilic nano-drug is a sorafenib amphiphilic nano-drug, and the tumor is liver cancer.
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CN108578712B (en) * 2018-05-14 2021-08-24 宁波市杭州湾医院 Polymer-drug conjugate and preparation method thereof
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105457038A (en) * 2015-11-09 2016-04-06 东南大学 Quick release type medicine phosphatide compound and medicine composition thereof
CN106620717A (en) * 2016-12-13 2017-05-10 上海交通大学 Amphipathic conjugate anti-tumor nano-drug with function of reversing multidrug resistance of tumors and preparation method and application thereof

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US9855341B2 (en) * 2014-02-19 2018-01-02 University of Pittsburgh—of the Commonwealth System of Higher Education Formulations and carrier systems including farnesylthiosalycylic moities

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105457038A (en) * 2015-11-09 2016-04-06 东南大学 Quick release type medicine phosphatide compound and medicine composition thereof
CN106620717A (en) * 2016-12-13 2017-05-10 上海交通大学 Amphipathic conjugate anti-tumor nano-drug with function of reversing multidrug resistance of tumors and preparation method and application thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Enzyme and Redox Dual-Triggered Intracellular Release from Actively Targeted Polymeric Micelles;Lei Zhang et al.;《ACS Appl. Mater. Interfaces》;20170110;第9卷;第3388-3399页 *

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