CN115040526A - Targeted nano-drug compound and preparation method thereof - Google Patents
Targeted nano-drug compound and preparation method thereof Download PDFInfo
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- CN115040526A CN115040526A CN202210717599.5A CN202210717599A CN115040526A CN 115040526 A CN115040526 A CN 115040526A CN 202210717599 A CN202210717599 A CN 202210717599A CN 115040526 A CN115040526 A CN 115040526A
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Abstract
The invention discloses a targeted nano-drug compound and a preparation method thereof, wherein the compound is liposome-coated adriamycin or pharmaceutically acceptable salt thereof, and is characterized in that the liposome contains a targeted peptide-lipid molecule covalent conjugate, and the targeted peptide has an amino acid sequence of SEQ ID NO. 1. The invention improves the enrichment amount of adriamycin at the tumor part by containing the target peptide-lipid molecule covalent conjugate in the liposome, thereby obtaining good tumor inhibition effect.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a targeted nano-drug compound and a preparation method thereof.
Background
Adriamycin is an antitumor antibiotic, can inhibit the synthesis of RNA and DNA, has the strongest inhibition effect on RNA, has wider antitumor spectrum, has the effect on various tumors, belongs to a periodic nonspecific medicament, and has the effect of killing tumor cells in various growth periods.
Clinically, adriamycin has large toxic and side effects. The method mainly comprises the following steps: affecting the hematopoietic function of bone marrow, manifested as thrombocytopenia and leukopenia; cardiotoxicity, in severe cases heart failure can occur; nausea, vomiting, stomatitis, alopecia, hyperpyrexia, phlebitis, skin pigmentation, etc. can be seen; a small number of patients have fever, hemorrhagic erythema and impaired liver function. These toxic side effects severely limit the clinical use of doxorubicin.
With the development of medical technology, liposomes have been tried as carriers of doxorubicin. Clinical results show that the toxic and side effects of the adriamycin liposome are obviously reduced, the half-life period of the drug is obviously prolonged, and the drug effect is also improved. In order to further improve the treatment effect of the adriamycin, the adriamycin is a new research hotspot by preparing the adriamycin into a targeting nano-drug compound.
For example, chinese patent application CN114209853A discloses a preparation method and application of a dual ligand modified liver cancer targeted liposome, which comprises the following steps: dissolving soybean lecithin, cholesterol, distearoyl phosphatidyl ethanolamine-polyethylene glycol 2000, and distearoyl phosphatidyl ethanolamine-polyethylene glycol 1000 connected with TAT peptide in appropriate amount of chloroform; carrying out reduced pressure rotary evaporation on the dissolved solution to form a uniform transparent film, and then carrying out vacuum drying; adding a proper amount of distearoylphosphatidylethanolamine-polyethylene glycol 3400 connected with SP94 peptide into the dried hyaluronic acid membrane; in the invention, adriamycin is taken as a model drug and is entrapped in a liposome co-modified by SP94 and TAT, and after the liposome reaches the interior of liver cancer cells through a targeting effect, the adriamycin is released, so that a good tumor inhibition effect is exerted, and the side effect of the drug is reduced.
For another example, chinese granted patent CN113440610B discloses a liposome co-carrying CD73 antibody and doxorubicin, and a preparation method and an application thereof, wherein the liposome co-carrying CD73 antibody and doxorubicin has a lipid core wrapped with doxorubicin inside, the outside of the lipid core is modified with CD73 antibody, and the CD73 antibody is coupled on phospholipid PEG active ester micelle and then modified on the surface of the lipid core. The liposome carrying the CD73 antibody and the adriamycin together provided by the invention reduces the drug resistance and toxic and side effects of the adriamycin in the treatment of triple negative breast cancer, improves the biological distribution of the adriamycin in vivo, improves the bioavailability, twists the immune microenvironment in triple negative breast cancer tumor, converts the immune microenvironment into heat tumor, and realizes better treatment effect on triple negative breast cancer.
For another example, chinese granted patent CN112891381B discloses a method for preparing a bacterial wall modified liposome-carried doxorubicin and its application, which comprises dissolving soybean lecithin, cholesterol, and doxorubicin in an organic solvent, and performing rotary evaporation to obtain a dried lipid membrane; hydrating the lipid membrane, and adding a bacterial wall while hydrating to obtain DOX-BW-LP; the bacterial wall is of staphylococcus aureus. The bacterial wall fusion liposome is prepared into the immunoliposome which acts on human tongue squamous carcinoma cells, and the bacterial wall of the staphylococcus aureus prepared by the invention is found to have an immunoregulation effect on macrophages, induce the macrophages to be polarized to M1 type, enhance the recognition and phagocytic functions of the macrophages on tumor cells, realize the functions of killing tumors and inhibiting the growth of the tumors, and simultaneously, the bacterial wall fusion liposome carries adriamycin, so that the multiple effects of chemotherapy and immunotherapy on the tumors are realized, and a new idea is provided for the immunotherapy of oral cancer.
Although some targeted nano-drug complexes of doxorubicin have been reported in the prior art, the technical problem to be solved still remains how to provide more targeted nano-drug complexes with better tumor inhibition effect.
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 following technical solutions are proposed:
the invention relates to a targeted nano-drug compound, which is liposome-coated adriamycin or pharmaceutically acceptable salt thereof, and is characterized in that the liposome contains a targeted peptide-lipid molecule covalent conjugate, and the targeted peptide has an amino acid sequence of SEQ ID NO. 1.
In a preferred embodiment of the present invention, the targeting peptide-lipid molecule covalent conjugate is a reaction product of phospholipid polyethylene glycol maleimide and the targeting peptide.
In another preferred embodiment of the invention, the liposome is made of dipalmitoylphosphatidylcholine, cholesterol, and a targeting peptide-lipid molecule covalent conjugate.
In a preferred embodiment of the present invention, the molar ratio of the targeting peptide-lipid molecule covalent conjugate in the liposome is 0.2-1.0%; preferably 0.4-0.6%. The invention can realize good targeting effect only by using a small amount of targeting peptide-lipid molecule covalent conjugates, and is 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 nm. The average particle size of the targeted nano-drug compound is controlled below 200nm, so that the enrichment amount of the adriamycin at a tumor part can be improved by utilizing the high permeability and retention effect of the tumor, and a good tumor inhibition effect is obtained.
The invention also relates to a preparation method of the targeted nano-drug compound, which comprises the following steps:
(1) preparing liposome; (2) and (3) mixing and incubating the liposome and the adriamycin or pharmaceutically acceptable salt thereof.
In a preferred embodiment of the present invention, the step of preparing the liposome comprises: putting the ethanol solution of the mixed lipid molecules into a container, putting the container on a rotary evaporator for rotary evaporation, adding the PBS solution, putting the container on the rotary evaporator for rotary hydration for 8 to 16 hours until the lipid molecular membrane is fully dispersed in the solution, carrying out water bath ultrasound at 0 to 4 ℃, using a liposome extrusion instrument, and repeatedly extruding by adopting a polycarbonate film to obtain the targeted liposome solution.
The invention also relates to application of the targeted nano-drug compound in preparing a drug for inhibiting tumors.
In a preferred embodiment of the present invention, the tumor 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 amount of adriamycin at the tumor part by containing the target peptide-lipid molecule covalent conjugate in the liposome, thereby obtaining good tumor inhibition effect.
Drawings
FIG. 1 is a distribution diagram of targeted nano-drug complexes of example 1 of the present invention in mice;
FIG. 2 is a graph showing the change of body weight of the experimental mouse over 14 days;
FIG. 3 is a graph showing a comparison of tumor volumes 14 days after administration of the experimental mice of the present invention.
Detailed Description
In order to further understand the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Unless otherwise specified, the reagents involved in the examples of the present invention are all commercially available products, and all of them 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 is SEQ ID NO.1, synthesized by a solid phase synthesis process) in a molar ratio of 1.5:1 in a neutral phosphoric acid buffer solution for reaction for 24 hours, then transferring the mixture to a dialysis bag (Mw is 3500), dialyzing for 3 days, and freeze-drying to obtain the targeting peptide-lipid molecule covalent conjugate.
(2) Preparation of Targeted Liposome solutions
The constituent 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, wherein the proportion (molar ratio) of each lipid molecule is as follows: 57% dipalmitoyl phosphatidylcholine; cholesterol 42.5% and targeting peptide-lipid molecule covalent conjugate 0.5%. Putting the mixed lipid molecular solution into a round-bottomed flask, putting the round-bottomed flask on a rotary evaporator for rotary evaporation at 50 ℃, evaporating ethanol to dryness, filling nitrogen for overnight drying, then adding 5mL of PBS (phosphate buffer solution) containing 20mg of FITC (fluorescein isothiocyanate) labeled albumin (or 2mg of green fluorescent protein plasmid), putting the round-bottomed flask on the rotary evaporator for rotation, hydrating for 12 hours under the protection of nitrogen until a lipid molecular membrane is fully dispersed in the solution, carrying out water bath ultrasound at 0-4 ℃ for 5min, and repeatedly extruding by using a liposome extruder for 10 times by using a 50nm polycarbonate film to obtain the targeted liposome solution.
(3) Preparation of targeting nano-drug complexes
Adding adriamycin (1mg/ml) into the targeted liposome solution, and incubating for 30min at normal temperature to obtain the targeted nano-drug compound. The average particle size of the obtained nano-drug compound is 125 +/-25 nanometers, and the doxorubicin entrapment rate is 73%. The encapsulation efficiency refers to the proportion of the drug loaded in the liposome to the dosage, and the calculation formula of the encapsulation efficiency is as follows:
the entrapment rate is the content of the drug entrapped in the liposome/the total amount of the added drug × 100%
Comparative example 1:
the same as in example 1, except that the peptide sequence was replaced with RGD. The average particle diameter of the obtained nano-drug compound is 129 +/-31 nanometers, and the doxorubicin entrapment rate is 68 percent. There was no significant difference in the average particle size of the nano-drug composite of comparative example 1, and the encapsulation efficiency was slightly decreased, compared to example 1.
Experimental example 2: tumor inhibition experiment in mice
First, experiment method
Cervical cancer cells (U14) were inoculated with Kunming female mice (18-22 g in weight). Inoculating U14 cells into abdominal cavity of female Kunming mouse, taking out ascites 5-7 days later under aseptic condition, and diluting the cells to 5 × 10 with physiological saline 6 One per mL. The right hind limb of the female Kunming mouse was tumor-bearing by subcutaneous injection of 200 μ LU14 cells. After 3 days of tumor bearing, the tumor bearing mice were randomly divided into 4 groups of 6 mice each, namely (a) a normal saline group; (b) free doxorubicin hydrochloride group; (c) group of comparative example 1; (d) example 1 group. Mice were administered by tail vein injection at 2 day intervals in an amount of 1mL (concentration calculated as doxorubicin, 1 mg/mL). Changes in body weight and tumor size of the mice were recorded daily during the course of the experiment. Mice were anesthetized and sacrificed on day 15 by cervical dislocation, tumors dissected out, weighed, and photographed.
Second, experimental results
The results of in vivo tumor inhibition experiments are shown in figure 1, and the experimental results show that the targeted nano-drug complexes of the group of example 1 are enriched at tumor sites.
Fig. 2 is a graph showing the change in body weight of the prepared nanomicelle injection mice over 14 days. In the experiment, the body weight of the mice in the free doxorubicin hydrochloride group is obviously reduced on the 6 th day after administration, the body weight of the mice in the comparative example 1 is reduced slowly, but the weight average of the mice in the example 1 group and the saline group does not have a trend of obviously reducing. The mouse weight experiments may indicate that the prepared targeted nano-drug complexes have lower toxicity compared to free doxorubicin.
FIG. 3 is a pictorial representation of tumor volume after 14 days in mice. Fig. 3 can prove that the targeted nano-drug compound has a better tumor inhibition effect.
The statistical result shows that 118.56 +/-18.92 mm of the tumor volume of the saline injection group from the initial test time can be observed in the experiment 3 Continuously rising up2456.74 + -119.45 mm by day 14 3 This indicates that the tumor is growing rapidly and the tumor volume injected with free doxorubicin hydrochloride is 115.72 + -19.37 mm from the initial time 3 Rapidly ascending and substantially stabilizing to 573.25 + -35.87 mm on day 14 3 Comparative example 1 injection of tumor volumes of targeted NanoTaharmaceutical Complex 117.34. + -. 17.54mm from the time of initial testing 3 Stabilize to 404.3 + -45.58 mm on day 14 3 Injection example 1 Targeted Nanotempound tumor volume 118.42 + -19.38 mm from initial time of trial 3 203.42 + -28.37 mm stable to day 14 3 . Compared with comparative example 1, the tumor volume of example 1 was significantly different at day 14, which indicates that the targeted nano-drug 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 of 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> targeting nano-drug compound and preparation method thereof
<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 (9)
1. A targeted nano-drug compound is liposome-coated adriamycin or pharmaceutically acceptable salt thereof, and is characterized in that the liposome contains a targeted peptide-lipid molecule covalent conjugate, and the targeted peptide has an amino acid sequence of SEQ ID NO. 1.
2. The complex of claim 1, the targeting peptide-lipid molecule covalent conjugate being a reaction product of a phospholipid polyethylene glycol maleimide and the targeting peptide.
3. The complex of claim 1, the liposome made from dipalmitoylphosphatidylcholine, cholesterol, and the targeting peptide-lipid molecule covalent conjugate.
4. The complex of claim 3, wherein the targeting peptide-lipid molecule covalent conjugate is present in the liposome at a molar ratio of 0.2-1.0%.
5. The complex of any one of claims 1-4, wherein the targeted nano-drug complex has an average particle size of 100-200 nm.
6. The method for preparing the targeted nano-drug complex of any one of claims 1 to 5, comprising:
(1) preparing liposome; (2) and (3) mixing and incubating the liposome and the adriamycin or pharmaceutically acceptable salt thereof.
7. The method of claim 6, wherein the step of preparing liposomes comprises: putting the ethanol solution of the mixed lipid molecules into a container, putting the container on a rotary evaporator for rotary evaporation, adding the PBS solution, putting the container on the rotary evaporator for rotary hydration for 8 to 16 hours until the lipid molecular membrane is fully dispersed in the solution, carrying out water bath ultrasound at 0 to 4 ℃, using a liposome extrusion instrument, and repeatedly extruding by adopting a polycarbonate film to obtain the targeted liposome solution.
8. The use of the targeted nano-drug complex of any one of claims 1 to 5 in the preparation of a medicament for inhibiting a tumor.
9. The use according to claim 8, 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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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116115582A (en) * | 2022-11-10 | 2023-05-16 | 重庆大学 | Engineering probiotics packaged by prodrug as well as preparation method and application thereof |
Citations (3)
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|---|---|---|---|---|
| US20170027868A1 (en) * | 2015-12-30 | 2017-02-02 | Mahmoud Reza Jaafari | Peptide-conjugated liposome |
| CN110237268A (en) * | 2019-07-18 | 2019-09-17 | 南方医科大学南方医院 | A kind of double-bang firecracker being loaded with adriamycin answers the preparation method of liposome microbubble compound |
| CN114177306A (en) * | 2021-07-16 | 2022-03-15 | 吉林医药学院 | iNGR/R9 double-modified adriamycin targeted liposome and antitumor activity evaluation |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20170027868A1 (en) * | 2015-12-30 | 2017-02-02 | Mahmoud Reza Jaafari | Peptide-conjugated liposome |
| CN110237268A (en) * | 2019-07-18 | 2019-09-17 | 南方医科大学南方医院 | A kind of double-bang firecracker being loaded with adriamycin answers the preparation method of liposome microbubble compound |
| CN114177306A (en) * | 2021-07-16 | 2022-03-15 | 吉林医药学院 | iNGR/R9 double-modified adriamycin targeted liposome and antitumor activity evaluation |
Non-Patent Citations (1)
| Title |
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| 赵鹏飞等: "纳米药物联合多肽介导肿瘤靶向研究进展" * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116115582A (en) * | 2022-11-10 | 2023-05-16 | 重庆大学 | Engineering probiotics packaged by prodrug as well as preparation method and application thereof |
| CN116115582B (en) * | 2022-11-10 | 2024-04-16 | 重庆大学 | Engineering probiotics packaged by prodrug as well as preparation method and application thereof |
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