CN115040526B - Targeted nano-drug compound and preparation method thereof - Google Patents
Targeted nano-drug compound and preparation method thereof Download PDFInfo
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- CN115040526B CN115040526B CN202210717599.5A CN202210717599A CN115040526B CN 115040526 B CN115040526 B CN 115040526B CN 202210717599 A CN202210717599 A CN 202210717599A CN 115040526 B CN115040526 B CN 115040526B
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- 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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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
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Abstract
The invention discloses a targeting nano-drug compound and a preparation method thereof, wherein the compound is liposome coated doxorubicin or pharmaceutically acceptable salt thereof, and is characterized in that the liposome contains a targeting peptide-lipid molecule covalent conjugate, and the targeting peptide has an amino acid sequence of SEQ ID NO. 1. The invention improves the enrichment of doxorubicin at the tumor part by containing the targeting peptide-lipid molecule covalent conjugate in the liposome, thereby obtaining good tumor inhibiting effect.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a targeting nano-drug compound and a preparation method thereof.
Background
Doxorubicin is an antitumor antibiotic, can inhibit synthesis of RNA and DNA, has the strongest inhibitory effect on RNA, has a broad antitumor spectrum, has an effect on various tumors, belongs to a periodic nonspecific drug, and has a killing effect on tumor cells in various growth periods.
Clinically, doxorubicin has large toxic and side effects. Mainly comprises the following steps: affecting bone marrow hematopoietic function, manifested by thrombocytopenia and leukopenia; cardiotoxicity, severe heart failure; nausea, vomiting, stomatitis, alopecia, hyperpyrexia, phlebitis, skin pigmentation, etc. can be seen; few patients have fever, hemorrhagic erythema and impaired liver function. These toxic side effects severely limit the clinical application of doxorubicin.
With the development of medical technology, attempts have been made to use liposomes as carriers of doxorubicin. Clinical results show that the toxic and side effects of the doxorubicin liposome are obviously reduced, the half life of the drug is obviously prolonged, and the drug effect is also improved. In order to further improve the therapeutic effect of doxorubicin, a new research hotspot is realized by preparing the doxorubicin into a targeting nano-drug complex.
For example, chinese patent application CN114209853a discloses a preparation method and application of double ligand modified liver cancer targeting liposome, which comprises the following steps: dissolving soybean lecithin, cholesterol, distearoyl phosphatidylethanolamine-polyethylene glycol 2000 and distearoyl phosphatidylethanolamine-polyethylene glycol 1000 connected with TAT peptide with proper amount of chloroform; the dissolved solution is decompressed, rotated and evaporated to form a uniform hyaluronic film, and then dried in vacuum; adding a proper amount of distearoyl phosphatidylethanolamine-polyethylene glycol 3400 connected with SP94 peptide into the dried hyaluronic film; in the invention, doxorubicin is taken as a model drug and is entrapped in SP94 and TAT co-modified liposome, and after the liposome reaches the inside of liver cancer cells through targeting, the doxorubicin is released, so that good tumor inhibiting effect is exerted, and side effects of the drug are reduced.
For another example, chinese patent CN113440610B discloses a liposome co-carrying CD73 antibody and doxorubicin, and a preparation method and application thereof, wherein the liposome co-carrying CD73 antibody and doxorubicin is a lipid core coated with doxorubicin, the CD73 antibody is modified outside the lipid core, and the CD73 antibody is coupled to phospholipid PEG active ester micelle, and then modified on the surface of the lipid core. The liposome carrying the CD73 antibody and the doxorubicin reduces the drug resistance and toxic and side effects of the doxorubicin in the treatment of the triple negative breast cancer, improves the biological distribution of the doxorubicin in the body, improves the bioavailability, twists the immune microenvironment in the triple negative breast cancer tumor, converts the immune microenvironment into a thermal tumor, and realizes the better treatment effect on the triple negative breast cancer.
For another example, chinese patent CN112891381B discloses a preparation method of bacterial wall modified liposome-carried doxorubicin and application thereof, comprising dissolving soybean lecithin, cholesterol, doxorubicin in an organic solvent, rotary evaporating to obtain a dried lipid film; hydrating the lipid membrane, and adding bacterial walls while hydrating to obtain DOX-BW-LP; the bacterial wall is of staphylococcus aureus. The bacterial wall fusion liposome is prepared into immunoliposome, and acts on human tongue squamous carcinoma cells, and the bacterial wall of staphylococcus aureus prepared by the invention has immunoregulation effect on macrophages, induces the macrophages to polarization of M1 type, enhances the recognition and phagocytic functions of the macrophages on tumor cells, realizes the functions of killing tumors and inhibiting tumor growth, and simultaneously realizes multiple effects of chemotherapy and immunotherapy on the tumors by using the bacterial wall fusion liposome to carry doxorubicin, thereby providing a new idea for the immunotherapy of oral cancer.
Although some targeting nano-drug complexes of doxorubicin have been reported in the prior art, there is still a technical problem to be solved by those skilled in the art as to how to provide more targeting effects and better tumor inhibition effects.
Disclosure of Invention
Based on the reasons, the invention provides a targeting nano-drug compound and a preparation method thereof. Specifically, in order to achieve the purpose of the present invention, the present invention adopts the following technical scheme:
the invention relates to a targeting nano-drug complex, which is liposome coated doxorubicin or pharmaceutically acceptable salt thereof, and is characterized in that the liposome contains a targeting peptide-lipid molecule covalent conjugate, and the targeting peptide has an amino acid sequence of SEQ ID NO. 1.
In a preferred embodiment of the invention, the targeting peptide-lipid molecule covalent conjugate is the reaction product of a phospholipid polyethylene glycol maleimide and the targeting peptide.
In another preferred embodiment of the invention, the liposome is made from dipalmitoyl phosphatidylcholine, cholesterol, and a targeting peptide-lipid molecule covalent conjugate.
In a preferred embodiment of the invention, the molar ratio of the targeting peptide-lipid molecule covalent conjugate in the liposome is 0.2-1.0%; preferably 0.4 to 0.6%. The invention can realize good targeting effect by using a small amount of targeting peptide-lipid molecule covalent conjugate, thereby being beneficial to saving cost.
In a preferred embodiment of the present invention, the targeted nano-drug complex has an average particle size of 100-200 nanometers. The average grain diameter of the targeting nano-drug compound is controlled below 200nm, so that the high permeability and retention effect of tumors can be utilized to improve the enrichment of doxorubicin at tumor sites, and thus, good tumor inhibition effect is obtained.
The invention also relates to a preparation method of the targeting nano-drug compound, which comprises the following steps:
(1) Preparing liposome; (2) The liposome is incubated with doxorubicin or a pharmaceutically acceptable salt thereof.
In a preferred embodiment of the present invention, the step of preparing a liposome comprises: placing the ethanol solution of the mixed lipid molecules into a container, placing the container on a rotary evaporator for rotary evaporation, adding PBS solution, placing the container on the rotary evaporator for rotary hydration for 8-16 hours until the lipid molecular films are fully dispersed in the solution, performing water bath ultrasound at 0-4 ℃, using a liposome extruder, and repeatedly extruding by adopting a polycarbonate film to obtain the targeted liposome solution.
The invention also relates to application of the targeting nano-drug compound in preparation of drugs for inhibiting tumors.
In a preferred embodiment of the invention, the neoplasm includes, but is not limited to, cervical cancer, acute leukemia, malignant lymphoma, breast cancer, ovarian cancer, bladder cancer, thyroid cancer, prostate cancer, testicular cancer, gastric cancer, liver cancer.
Advantageous effects
The invention improves the enrichment of doxorubicin at the tumor part by containing the targeting peptide-lipid molecule covalent conjugate in the liposome, thereby obtaining good tumor inhibiting effect.
Drawings
FIG. 1 is a graph showing the distribution of the targeted nano-drug complex of example 1 of the present invention in mice;
FIG. 2 is a graph showing the change in body weight of the experimental mice of the present invention for 14 days;
FIG. 3 is a graph comparing tumor volumes of experimental mice of the present invention after 14 days of administration.
Detailed Description
In order to further understand the present invention, a technical solution in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Unless otherwise specified, all reagents involved in the examples of the present invention are commercially available products and are commercially available.
Example 1:
(1) Preparation of targeting peptide-lipid molecule covalent conjugates
Mixing phospholipid polyethylene glycol maleimide (DSPE-PEG-MAL, PEG molecular weight 2000) and targeting peptide HEDGC (sequence SEQ ID NO.1, synthesized by solid phase synthesis process) in a molar ratio of 1.5:1 in neutral phosphate buffer solution, reacting for 24 hours, transferring to a dialysis bag (Mw=3500), dialyzing for 3 days, and freeze-drying to obtain the targeting peptide-lipid molecule covalent conjugate.
(2) Preparation of targeted liposome solutions
The lipid molecules of the targeted liposome are dissolved in absolute ethanol according to a certain proportion (molar ratio) to prepare 20mL of 5mg/mL mixed lipid molecule solution, and the lipid molecule proportion (molar ratio) is as follows: dipalmitoyl phosphatidylcholine 57%; cholesterol 42.5% and targeting peptide-lipid molecule covalent conjugate 0.5%. Placing the mixed lipid molecular solution into a round bottom flask, placing the round bottom flask on a rotary evaporator for rotary evaporation at 50 ℃, evaporating ethanol, filling nitrogen for overnight drying, then adding 5mL of PBS solution containing 20mg of FITC-labeled albumin (or 2mg of green fluorescent protein plasmid), placing the mixture on the rotary evaporator for rotation, hydrating the mixture for 12 hours under the protection of nitrogen until the lipid molecular film is fully dispersed in the solution, performing ultrasonic treatment for 5min at 0-4 ℃ in a water bath, and repeatedly extruding for 10 times by adopting a 50nm polycarbonate film by using a liposome extruder to obtain the targeted liposome solution.
(3) Preparation of Targeted nanomedicine complexes
Doxorubicin (1 mg/ml) was added to the targeted liposome solution and incubated for 30min at ambient temperature to give the targeted nanopharmaceutical complex. The average particle size of the obtained nano-drug compound is 125+/-25 nanometers, and the encapsulation rate of the doxorubicin is 73 percent. The encapsulation efficiency of the invention refers to the ratio of the drug entrapped in the liposome to the dosage, and the calculation formula of the encapsulation efficiency is as follows:
encapsulation efficiency = drug content entrapped in liposomes/total drug added x 100%
Comparative example 1:
the same as in example 1, except that the peptide sequence was replaced with RGD. The average particle size of the obtained nano-drug compound is 129+/-31 nanometers, and the encapsulation rate of the doxorubicin is 68%. The average particle size of the nano-drug complex of comparative example 1 was not significantly different from that of example 1, and the encapsulation efficiency was slightly lowered.
Experimental example 2: in vivo tumor inhibition experiment of mice
1. Experimental method
Cervical cancer cells (U14) were inoculated with Kunming female mice (body weight 18-22 g). Inoculating U14 cells into abdominal cavity of healthy Kunming female mouse, taking out ascites under aseptic condition after 5-7 days, and diluting cell number to 5×10 with physiological saline 6 And each mL. 200 mu LU14 cells were subcutaneously injected to tumor the right hind limb of Kunming females. After 3 days of tumor bearing, the mice with the seed tumor are randomly divided into 4 groups of 6 mice, namely (a) physiological saline group; (b) a free doxorubicin hydrochloride group; (c) comparative example 1 group; (d) example 1 group. Mice were dosed every 2 days by tail vein injection at 1mL (concentration calculated as doxorubicin, 1 mg/mL). The changes in body weight and tumor size of the mice were recorded daily during the experiment. Mice were anesthetized on day 15 and sacrificed by cervical scission, tumors were dissected out, weighed, and photographed.
2. Experimental results
The experimental results of in vivo tumor inhibition are shown in figure 1, and the experimental results show that the targeting nano-drug complex of the example 1 group is enriched at the tumor site.
Figure 2 is a change in body weight of the prepared nanomicelle injection mice for 14 days. In the experiment, the body weight of the free doxorubicin hydrochloride mice is obviously reduced on the 6 th day of administration, the body weight of the comparative example 1 mice is slowly reduced, but the body weight of the mice in the example 1 mice and the normal saline mice do not obviously reduce. The mouse body weight experiment can show that the prepared targeting nano-drug compound has lower toxicity compared with free doxorubicin.
FIG. 3 is a graphical representation of tumor volume after 14 days in mice. Figure 3 demonstrates that the targeted nano-drug complex has a better tumor inhibition effect.
Statistical results show that the tumor volume of the physiological saline injection group can be observed from 118.56 +/-18.92 mm of initial test time in the experiment 3 2456.74 + -119.45 mm continuously rising to day 14 3 This indicates a rapid tumor growth, and the tumor volume injected with free doxorubicin hydrochloride was 115.72.+ -. 19.37mm from the initial time 3 Rapidly rising and stabilizing substantially to 573.25 + -35.87 mm on day 14 3 Tumor volume of the targeted nano-drug complex of comparative example 1 was injected 117.34 + -17.54 mm from initial time 3 Stabilized to 404.3.+ -. 45.58mm on day 14 3 Injection example 1 targeting nanomedicine complex tumor volumes 118.42 ±19.38mm from initial time 3 203.42 + -28.37 mm stabilized to day 14 3 . Example 1 has a significant difference in tumor volume on day 14 compared to comparative example 1, indicating that the targeted nanomedicine complex of example 1 has a better tumor inhibiting effect.
The foregoing describes preferred embodiments of the present invention, but is not intended to limit the invention thereto. Modifications and variations to the embodiments disclosed herein may be made by those skilled in the art without departing from the scope and spirit of the invention.
Sequence listing
<110> university of Chongqing
<120> a targeting nano-drug complex and method for preparing the same
<141> 2022-06-23
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 5
<212> PRT
<213> Unknown (Unknown)
<400> 1
His Glu Asp Gly Cys
1 5
Claims (6)
1. A targeting nano-drug complex, wherein the complex is liposome coated doxorubicin or pharmaceutically acceptable salt thereof, and is characterized in that the liposome contains a targeting peptide-lipid molecule covalent conjugate, and the amino acid sequence of the targeting peptide is the amino acid sequence shown in SEQ ID NO. 1; the targeting peptide-lipid molecule covalent conjugate is a reaction product of phospholipid polyethylene glycol maleimide and the targeting peptide; the liposome is made from dipalmitoyl phosphatidylcholine, cholesterol, and the targeting peptide-lipid molecule covalent conjugate; the molar ratio of the targeting peptide-lipid molecule covalent conjugate in the liposome is 0.2-1.0%.
2. The complex of claim 1, wherein the targeted nanomedicine complex has an average particle size of 100-200 nanometers.
3. A method of preparing the targeted nano-drug complex of claim 1 or 2, the method comprising:
(1) Preparing liposome; (2) The liposome is incubated with doxorubicin or a pharmaceutically acceptable salt thereof.
4. A method of preparing according to claim 3, the step of preparing liposomes comprising: placing the ethanol solution of the mixed lipid molecules into a container, placing the container on a rotary evaporator for rotary evaporation, adding PBS solution, placing the container on the rotary evaporator for rotary hydration for 8-16 hours until the lipid molecular films are fully dispersed in the solution, performing water bath ultrasound at 0-4 ℃, using a liposome extruder, and repeatedly extruding by adopting a polycarbonate film to obtain the targeted liposome solution.
5. Use of the targeted nano-drug complex according to claim 1 or 2 for the preparation of a medicament for inhibiting a tumor.
6. The use according to claim 5, wherein the tumor is selected from cervical cancer, acute leukemia, malignant lymphoma, breast cancer, ovarian cancer, bladder cancer, thyroid cancer, prostate cancer, testicular cancer, gastric cancer or liver cancer.
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