CN109675047B - Method for carrying out liposome modification on compound with free hydroxyl - Google Patents

Method for carrying out liposome modification on compound with free hydroxyl Download PDF

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CN109675047B
CN109675047B CN201910013083.0A CN201910013083A CN109675047B CN 109675047 B CN109675047 B CN 109675047B CN 201910013083 A CN201910013083 A CN 201910013083A CN 109675047 B CN109675047 B CN 109675047B
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lipid
liposome
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CN109675047A (en
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肖海华
陈志刚
康晓旭
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Institute of Chemistry CAS
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Abstract

The invention relates to a method for carrying out liposome modification on a compound with free hydroxyl, in particular to liposome-modified paclitaxel and analogues thereof, and nanoparticles containing liposome-modified drugs. The invention specifically designs and successfully prepares paclitaxel, 10-hydroxycamptothecin, irinotecan and epothilone B modified by liposome N, N' -didodecyl-L-glutamic acid diamide (LG-C12), improves the hydrophobicity of the drugs, and then uses NH bonded by mPEG-DSPE and mitochondrion targeting molecule triphenyl phosphine bromide (TPP)2The mPEG-DSPE encapsulates the liposome modified drug to form nano particles, so that the cytotoxic effect of the drug on cancer cells is improved, and the toxic and side effects of the drug on human or animal bodies are reduced.

Description

Method for carrying out liposome modification on compound with free hydroxyl
Technical Field
The invention relates to the field of drug modification, in particular to a method for carrying out liposome modification on a compound with free hydroxyl, and more particularly relates to liposome-modified paclitaxel and analogues thereof, nanoparticles containing liposome-modified drugs and the like.
Background
In 2015, 4,292,000 new cases of cancer and 2,814,000 deaths were estimated. Over the past few decades, great efforts have been made to treat these serious diseases. Among the various therapies, chemotherapy is currently one of the most clinically effective means for treating cancer. Although various anticancer drugs have been developed and applied to chemotherapy, they often cause adverse side effects to patients, resulting in physical and mental pain, and the treatment efficiency is low. The chemotherapy drugs commonly used in clinic at present comprise adriamycin, paclitaxel, 10-hydroxycamptothecin, irinotecan and the like.
Paclitaxel (Taxol) is a natural antitumor drug originally extracted from the trunk and bark of various plants in taxus genus, and has been found to have significant efficacy on many cancers. Has been widely used for treating breast cancer, ovarian cancer, lung cancer and partial head and neck cancer in clinic. The scarcity of resources makes the taxol-type anticancer drugs always very expensive, have extremely low water solubility and low bioavailability, and the like, and the demand of the taxol-type anticancer drugs is increased. Because the bottleneck of resource shortage is difficult to overcome, researchers focus on developing new formulations and improving the bioavailability of drugs.
Camptothecin (CPT) is an alkaloid antineoplastic drug extracted from skin and fruit of Camptotheca acuminata Decne of China. Camptothecin drugs are topoisomerase I inhibitors used in clinical application, are another anticancer drugs with development prospects after paclitaxel, and become hot spots of research in current anticancer drugs. However, camptothecin lactone ring is very easy to hydrolyze and open under physiological environment to form carboxylate, which leads to drug inactivation; meanwhile, the defects of poor water solubility, large toxic and side effects on normal body tissues and the like of the camptothecin greatly limit the clinical application of the camptothecin medicaments. Since then, scientists developed a series of water-soluble camptothecin derivatives, such as irinotecan (CPT-11).
Epothilone (epothilone) is a macrolide compound, has an action mechanism similar to that of taxol medicaments, and is clinically used for treating breast cancer, prostatic cancer, lung cancer, colon cancer and the like. However, epothilones are also highly cytotoxic to normally proliferating cell tissues, which limits their clinical utility.
Since most chemotherapy drugs achieve anti-tumor effects by interfering with the synthesis process of cancer cell DNA, they often have side effects such as myelosuppression, and there is no effective preventive measure for these accompanying side effects, which limits the application of tumor therapy. Therefore, the search for an anti-tumor related drug which can improve the sensitivity of chemotherapeutic drugs, enhance the inhibition effect on tumor cells, and reduce the toxic and side effects and drug resistance of the drugs becomes an urgent problem to be solved, and is also a hotspot of the research of modern oncologists.
Disclosure of Invention
To solve the above problems, the nano drug-loaded delivery strategy has received much attention. In vivo, the drug-loaded nanoparticles can be phagocytized by macrophages as foreign matters to reach target sites of liver, spleen and the like with concentrated distribution of a reticuloendothelial system and target sites connected with ligands, antibodies and enzyme substrates. The nano particles are highly dispersed, and the surface area is large, so that the contact area of the drug and the biomembrane of the absorption part is increased. The special surface property of the nano-particles greatly prolongs the retention time of the nano-particles in small intestines, and the nano-particles also have a protection effect on the loaded medicine, and the comprehensive effects can obviously improve the absorption and bioavailability of the medicine. Different from the transmembrane transport mechanism of common drugs, the nanoparticles enter cells through endocytosis and other mechanisms, so that the permeability of the drugs to biological membranes can be increased, and the transdermal absorption of the drugs and the exertion of intracellular drug effects are facilitated. The low molecular weight chemotherapeutic drug penetrates the capillary wall of healthy and tumor tissues through nonspecific diffusion, but the drug carried by the nanoparticle carrier can only penetrate into the high-permeability tumor capillary bed. The targeting property of the drug-loaded nanoparticles increases the local drug concentration and reduces the concentration of other parts of the whole body, thereby greatly reducing the systemic toxicity of the drug. In order to improve the curative effect of the nanoparticles and effectively reach tumor sites, Triphenylphosphine (TPP), folic acid, RGD, LHRH polypeptide, transferrin, aptamer and other common targeting elements with targeting effect are modified on the surfaces of the nanoparticles. Acid sensitive groups are further introduced, and the toxic and side effects of the compound are reduced after the compound is condensed into ester through carboxylic acid and amino, so that the compound can be reduced into original drugs after entering cells, and the drug effect is improved.
Specifically, the invention designs and successfully prepares paclitaxel, 10-hydroxycamptothecin, irinotecan and epothilone B modified by liposome N, N' -didodecyl-L-glutamic acid diamide (LG-C12)Improving the hydrophobicity of the drug, and then using mPEG-DSPE and mitochondrion targeting molecule triphenyl phosphine bromide (TPP) modified NH2The mPEG-DSPE encapsulates the liposome modified drug to form nano particles, so that the toxic effect of the drug on cancer cells is improved, and the toxic and side effects of the drug on human or animal bodies are reduced.
In a first aspect, the present invention provides a liposome-modified drug, which has a structure represented by formula (II):
Figure BDA0001938063940000031
wherein n is an integer of 7 or more, preferably 7, 11, 17; r is a compound with active hydroxyl.
The liposome modified drug is characterized in that: the R is selected from the group consisting of: paclitaxel (Paclitaxel), 10-Hydroxycamptothecin (10-Hydroxycamptothecin), Irinotecan (Irinotecan), epothilone B (epothilone B), Vincristine (Vincristine), Docetaxel (Docetaxel), Capecitabine (Capecitabine), Etoposide (Etoposide), triptolide A (Wilforlide A).
The liposome modified drug is characterized in that the liposome has active groups capable of carrying out condensation reaction with carboxyl, including but not limited to amino, hydroxyl, sulfydryl and the like; preferably the liposome is N, N' -di-long chain alkyl-L-glutamic acid diamide (LG).
In a second aspect, the present invention provides a method for preparing the liposome-modified drug, comprising:
(1) modifying the original drug by using acid anhydride or binary organic acid;
(2) carrying out condensation reaction on an anhydride or dibasic organic acid modified technical product (CAR) and the liposome;
(3) washing, recrystallizing and freeze-drying to obtain the liposome modified drug.
The preparation method of the liposome modified drug comprises the following steps:
(1) preparing cis-form aconitic anhydride modified parent drug CAR by taking triethylamine as a catalyst through a ring-opening reaction between active hydroxyl on the parent drug R and cis-form aconitic anhydride CA: dissolving the original drug R and CA in anhydrous DMF, adding triethylamine, and stirring for 24 hours at room temperature under the condition of keeping out of the sun and nitrogen; adding cold ethyl acetate, mixing and washing; drying the organic layer with anhydrous sodium sulfate for 12 hours, filtering and drying to obtain CAR;
(2) dissolving CAR in dichloromethane, activating with EDC and NHS, adding liposome, and performing amide condensation reaction;
(3) after reacting for 48 hours, washing, recrystallizing and freeze-drying to obtain the liposome modified drug.
In a third aspect, the invention provides a nanoparticle comprising the liposome-modified drug, wherein the drug nanoparticle is formed by self-assembly of a pharmaceutically acceptable polymer-entrapped liposome-modified drug.
The nano particle is characterized in that a pharmaceutically acceptable high polymer mPEG-DSPE is modified to form a targeting group, and the targeting group is selected from the group consisting of Triphenylphosphine (TPP), folic acid, RGD, LHRH polypeptide, transferrin and an aptamer.
In a fourth aspect, the present invention provides a method for preparing the nanoparticle, comprising: the pharmaceutically acceptable high molecular mPEG-DSPE and the liposome modified drug are mixed and assembled under the condition of a proper solvent to generate the drug-loaded nano particles.
The preparation method of the nano-particles is characterized by comprising the following steps: mixing mPEG-DSPE, liposome modified drug and optional targeting molecule modified mPEG-DSPE, dissolving in anhydrous DMF, magnetically stirring, slowly dropwise adding secondary water, dialyzing overnight, centrifuging, and collecting supernatant to obtain nanoparticles containing liposome modified drug.
In a fifth aspect, the present invention provides the use of the liposome-modified drug, or the nanoparticle, in:
(1) preparing a medicament for treating cancer;
(2) preparing a medicament with a targeting effect;
(3) prepare the precursor medicine with less toxic side effect and high cytotoxicity to human body or animal body.
Compared with the prior art, the technical scheme of the invention has the following advantages:
(1) the introduction of liposome molecule N, N' -di-long chain alkyl-L-glutamic acid diamide (LG) improves the hydrophobicity and entrapment rate of the drug molecule, and improves the bioavailability of the drug.
(2) Modification of NH with Triphenylphosphine (TPP)2The mPEG-DSPE is mixed with the mPEG-DSPE to prepare the nano-drug with mitochondrion targeting, thereby improving the anti-cancer effect of the drug, increasing the local drug concentration and simultaneously reducing the concentration of other parts of the whole body, and further greatly reducing the systemic toxicity of the drug
(3) Acid sensitive groups are introduced, and the toxic and side effects of the acid sensitive groups are reduced after the acid sensitive groups and the amino groups are condensed into esters, so that the drugs can be reduced into original drugs after entering cells, and the drug effect is improved.
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Various other advantages and benefits will become apparent to those of ordinary skill in the art upon reading the following detailed description of the preferred embodiments. The drawings are only for purposes of illustrating the preferred embodiments and are not to be construed as limiting the invention. Also, like reference numerals are used to refer to like parts throughout the drawings. In the drawings:
FIG. 1: nuclear magnetic characterization of Liposomal N, N' -didodecyl-L-glutamic acid diamide (LGC12)
FIG. 2: MALDI-TOF-MS mass spectrometry characterization of the liposome LGC 12;
a: boc-protected LGC12 mass spectrum; b: LGC12 mass spectrum of Boc deprotection
FIG. 3: nuclear magnetic characterization of LGC 12-modified paclitaxel (PTX-LGC12)
FIG. 4: MALDI-TOF-MS mass spectrometry characterization of PTX-LGC 12;
FIG. 5: preparation condition optimization of nanoparticles containing PTX-LGC12
The X axis is the mass ratio of PTX-LGC12 to mPEG-DSPE; y-axis is diameter (nm)/PDI
FIG. 6A: diameter distribution of PTX-LGC 12-containing nanoparticles
FIG. 6B: the diameter distribution of the PTX-LGC 12-TPP-containing nanoparticles;
FIG. 7: TEM scanning electron micrograph of PTX-LGC12 nanoparticle-containing
FIG. 8: PTX mass concentration and ultraviolet absorption relation curve in PTX-LGC 12-containing nano-particles
FIG. 9: cytotoxicity assay of PTX-LGC 12-containing nanoparticles
Detailed Description
Exemplary embodiments of the present disclosure will be described in more detail below with reference to the accompanying drawings. While exemplary embodiments of the present disclosure are shown in the drawings, it should be understood that the present disclosure may be embodied in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the disclosure to those skilled in the art.
Example 1: preparation and characterization of Liposomal N, N' -Di-Long-chain alkane-L-glutamic acid diamide (LG)
Adding Boc-glutamic acid and two times of equivalent of long-chain amine (octa, dodeca and octadecamine) into a reaction bottle, adding dichloromethane for dissolving, adding 1.1 times of equivalent of EDC and HOBt for amide condensation, then filtering, washing and recrystallizing to obtain N, N '-di-long-chain alkyl-L-Boc-glutamic acid diamide, then removing Boc protection by trifluoroacetic acid, washing and drying to obtain white powder N, N' -di-long-chain alkyl-L-glutamic acid diamide (LG).
The reaction steps are as follows:
Figure BDA0001938063940000051
the prepared LGC12 was subjected to nuclear magnetic hydrogen spectrum characterization, and the results are shown in FIG. 1. Peaks in the nuclear magnetic hydrogen spectrum, all successfully assigned, indicate successful synthesis of LGC 12.
The prepared LGC12 was characterized by MALDI-TOF-MS, and the results are shown in FIG. 2. FIG. 2A is a mass spectrum of Boc-protected LGC12, wherein 604.1 is Boc-LGC12+ Na+620.1 Boc-LGC12+ K+(ii) a FIG. 2B is BMass spectrum of oc deprotection, wherein 481.5 is LGC12,503.6 is LGC12+ Na+All successfully assigned, the MALDI-TOF-MS mass spectrometry results also indicated successful synthesis of LGC 12.
Example 2: preparation method of LGC12 modified Paclitaxel (Paclitaxel), 10-hydroxycamptothecin (10-Hydroxy camptothecin), Irinotecan (Irinotecan) and epothilone B (epothilone B)
Various prodrugs (abbreviated as R, R ═ Paclitaxel (PTX), 10-Hydroxycamptothecin (HCPT), irinotecan (CPT-11), epothilone b (epob)), hereinafter referred to as CAR, were modified with cis-aconitic anhydride (CA) and synthesized by ring-opening reaction between R and CA using triethylamine as a catalyst. Technical R (0.4mmol) and CA (0.44mmol) were added to a completely dry flask and dissolved in 20.0mL of anhydrous DMF followed by 67.0. mu.L of triethylamine. The mixture was left at room temperature in the dark under nitrogen (N)2) Stirring for 24 hours under the protection of atmosphere. Next, the solution was mixed with 200.0mL of cold ethyl acetate, washed first with a saturated sodium chloride solution at pH 2-3 and then with a saturated sodium chloride solution at pH 7.4. The obtained organic layer was dried over anhydrous sodium sulfate for 12 hours. Finally, the solid CAR was isolated by filtration and dried under vacuum at room temperature to give the product.
② adding the drug CAR (R ═ Paclitaxel (PTX), 10-Hydroxycamptothecin (HCPT), irinotecan (CPT-11) and epothilone B (EpoB)) into a reaction bottle, adding dichloromethane to dissolve, adding 2-3 times of equivalent of EDC and NHS to activate for 2-4 hours, adding 1 time of equivalent of N, N' -didodecyl-L-glutamic acid diamide (LGC12) to carry out amide condensation reaction for 48 hours, then washing, recrystallizing and freeze-drying to obtain the LG modified drug (CAR-LGC 12). The reaction steps are as follows:
Figure BDA0001938063940000061
wherein R is
Figure BDA0001938063940000071
Example 3: structural characterization of LGC 12-modified drugs
1. Nuclear magnetic resonance spectrum (NMR)
N, N' -didodecylglutamic diamide (LGC12) modified PTX prepared in example 2 was characterized with Tetramethylsilane (TMS) as internal standard by deuterochloroform (CDCl)3) As solvent, a 400MHZ nuclear magnetic resonance instrument is adopted to carry out the reaction1H NMR was scanned.
The nuclear magnetic hydrogen spectrum of PTX-LGC12 is shown in FIG. 3, and the peaks in the nuclear magnetic hydrogen spectrum of PTX-LGC12 were all successfully assigned.
2. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS)
To further confirm the compound synthesized in example 2, its mass spectrum was tested by MALDI-TOF-MS, matrix selection gentisic acid (DHB).
The MALDI-TOF-MS mass spectrum of PTX-LGC12 is shown in FIG. 4. 1683.1 in FIG. 4 is PTX-LGC12+ Na+。
The experimental results of nuclear magnetic hydrogen spectrum and mass spectrum confirm that the drug PTX-LGC12 modified by LGC12 is successfully synthesized.
Example 4: preparation and characterization of nanoparticles containing PTX-LGC12
Nanoparticles were prepared by loading PTX-LGC12 prepared in example 2 with a polymer. Selecting mPEG-DSPE or mPEG-DSPE modified by mitochondrion targeting molecule triphenylphosphine TPP as an entrapment molecule, dissolving PTX-LGC12 and the entrapment molecule in 1mL of anhydrous DMF according to the mass ratio of 1:1,1:2,1:3,1:4,1:5 and 1:6, magnetically stirring, slowly dripping 5mL of secondary water, dialyzing overnight (molecular weight cut-off 3500) after half an hour, and centrifuging to obtain a supernatant fluid to obtain the nano particles. Changes in particle size and zeta potential were observed by Dynamic Light Scattering (DLS). The optimized results of the conditions for nanoparticle formation from LGC12 modifier PTX-LGC12 are shown in FIG. 5.
According to FIG. 5, PTX-LGC 12: the optimal ratio of mPEG-DSPE is 1:4
And preparing corresponding nanoparticles according to the selected optimal conditions (the optimal ratio of the LGC12 modified drug to the entrapped polymer), detecting the particle size distribution of the nanoparticles, and carrying out TEM morphology observation.
The particle size distribution of PTX-LGC12 nanoparticles formed under optimal conditions is shown in FIG. 6, where FIG. 6A is a PTX-LGC12 nanoparticle prepared by encapsulating PTX-LGC12 with mPEG-DSPE, and FIG. 6B is a PTX-LGC12-TPP nanoparticle prepared by encapsulating PTX-LGC12 with TPP-modified mPEG-DSPE; the electron microscope image is shown in FIG. 7. The results show that the nanoparticles prepared by the method are stable in structure and uniform in size.
Example 5: original medicine content, loading rate and packaging efficiency of nanoparticles containing LGC12 modified medicine
1. Method of producing a composite material
The content of the original drug R in the nanoparticles prepared in example 4 was examined. The determination is carried out by ultraviolet visible spectroscopy (UV-Vis), a sample is firstly dissolved in DMF, the ultraviolet absorbance value of the solution at 227nm (PTX) is determined, and then the linear relation between the content of the drug R and the ultraviolet absorbance value is calculated. 1mL of nano-drug solution is taken and freeze-dried, then a freeze-dried powder sample is dissolved by DMF, and the ultraviolet absorbance value at the characteristic ultraviolet absorption position is measured to calculate the content of the drug;
the loading rate and the wrapping efficiency of the drug R are calculated by the following formulas:
loading rate (%) ([ content of drug R in nanoparticle/mass of total nanoparticle ] × 100
Encapsulation efficiency (%) ([ content of drug R in nanoparticle/mass of drug R administered ] × 100
2. Results
The mass concentration of paclitaxel in the PTX-LGC12 nanoparticles was plotted against the UV absorption, as shown in FIG. 8. The formula is that Y is 6.245 XX +0.2060, R20.9993. Measuring the ultraviolet absorbance value at the ultraviolet absorption position of 227nm to calculate to obtain the drug content of 432 mu M; the loading rate is 7.4%; the wrapping efficiency was 36.85%.
Example 6: cytotoxicity of PTX-LGC 12-containing nanoparticles
The PTX-LGC 12-containing nanoparticles prepared in example 4 were tested for their toxicity against cancer cells.
1. Method of producing a composite material
A549 (human lung cancer cells), A549DDP (human lung cancer platinum-resistant cells), MCF7 (human breast cancer cells) and 4T1 (murine breast cancer cells) are selected for researching the toxicity problem of the medicine. Four cells were cultured in DMEM (GIBCO) medium. DMEM medium contains 10% fetal bovine serum and 1% penicillin streptomycin mixture (100X).
The cytotoxicity is detected by an MTT method, and the specific steps are as follows:
(1) after a549, a549DDP, MCF7 and 4T1 cells were cultured to log phase, digested with pancreatin and counted. The cell solution was diluted to 5X 104cells/mL；
(2) Inoculating the pre-diluted cells into a 96-well plate, wherein each well is 100 mu L, and then placing the plate in an incubator for overnight culture;
(3) PTX, NPS and NPS-TPP are respectively diluted according to a certain multiple, added into a 96-well plate, and 10 mu L of the PTX, the NPS and the NPS-TPP are added into each well, so that the final PTX concentration of the medicine is 100,50,25,12.5,1.25,0.125 and 0.0125 mu M in sequence. Setting four multiple holes for each concentration, and culturing for 72 h;
(4) diluting 10 times of pre-configured 10% MTT solution by using a phenol-free red culture medium, adding the diluted solution into 96-well plates with different culture time, adding 100 mu L of MTT solution into each well, continuously placing the plates in an incubator for culture for 4 hours, then adding 100 mu L of SDS solution into each well, keeping the plates away from light, and placing the plates in a constant-temperature incubator at 37 ℃ for 12 hours;
(5) measuring the absorbance OD value of each hole of the 96-hole plate at 570nm by using a microplate reader, selecting the background wavelength to be 650nm, taking the average value of the OD values of the three multiple holes as the OD value of a target sample, and calculating the cell survival rate:
cell viability ═ sample OD/blank OD
2. Results
2.1 cytotoxicity assay of nanoparticles containing paclitaxel
The cytotoxicity of NPS (PTX-LGC12), NPS-TPP (PTX-LGC12-TPP) and PTX was measured by MTT method, and the time taken for examination was 72 hours, and the results are shown in FIG. 9, IC50The values are listed in table 2.
Table 2: NPS (PTX-LGC12), NPS (PTX-LGC12) -TPP, IC of PTX on four cells50(μM)
Figure BDA0001938063940000091
According to the toxic effects of the three drugs NPS (PTX-LGC12), NPS-TPP (PTX-LGC12-TPP) and PTX on four cell lines, the fact that the cytotoxicity is NPS-TPP (PTX-LGC12-TPP) > NPS (PTX-LGC12) > PTX in sequence from strong to weak indicates that the polymer is used as a carrier, the endocytosis of the drug by cells can be enhanced, and the nanoparticle with the mitochondrion targeting can improve the toxic effect of the drug on cancer cells.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the appended claims.

Claims (10)

1. A lipid-modified drug has a structure represented by formula (II):
Figure FDA0002540727370000011
wherein n is an integer not less than 7; r is a compound with active hydroxyl.
2. The lipid-modified pharmaceutical of claim 1, wherein: and n is 7, 11 or 17.
3. The lipid-modified pharmaceutical of claim 1, wherein: the R is selected from the group consisting of: paclitaxel (Paclitaxel), 10-Hydroxycamptothecin (10-Hydroxycamptothecin), Irinotecan (Irinotecan), epothilone B (epothilone B), Vincristine (Vincristine), Docetaxel (Docetaxel), Capecitabine (Capecitabine), Etoposide (Etoposide), triptolide A (Wilforlide A).
4. A process for the preparation of a lipid-modified pharmaceutical according to any one of claims 1 to 3, comprising:
(1) modifying the original drug by using acid anhydride or binary organic acid;
(2) condensation reaction of the original drug modified by anhydride or binary organic acid and lipid;
(3) washing, recrystallizing and freeze-drying to obtain the lipid modified drug.
5. The method of claim 4, comprising:
(1) preparing cis-form aconitic anhydride modified parent drug CAR by taking triethylamine as a catalyst through a ring-opening reaction between active hydroxyl on the parent drug R and cis-form aconitic anhydride CA: dissolving the original drug R and CA in anhydrous DMF, adding triethylamine, and stirring for 24 hours at room temperature under the condition of keeping out of the sun and nitrogen; adding cold ethyl acetate, mixing and washing; drying the organic layer with anhydrous sodium sulfate for 12 hours, filtering and drying to obtain CAR;
(2) dissolving CAR in dichloromethane, activating with EDC and NHS, adding lipid, and performing amide condensation reaction
(3) After reacting for 48 hours, washing, recrystallizing and freeze-drying to obtain the lipid modified drug.
6. A nanoparticle comprising a lipid-modified drug as claimed in any one of claims 1 to 3, wherein the drug nanoparticle is formed by self-assembly of a pharmaceutically acceptable polymer-loaded lipid-modified drug.
7. Nanoparticles according to claim 6, wherein the nanoparticles are modified with a targeting group selected from the group consisting of Triphenylphosphine (TPP), folic acid, RGD, LHRH polypeptides, transferrin, aptamers using a pharmaceutically acceptable polymeric carrier.
8. A method of preparing nanoparticles as claimed in claim 6 or 7, comprising: mixing a pharmaceutically acceptable high molecular polymer and the lipid-modified drug of any one of claims 1 to 3, and assembling under a suitable solvent condition to form the drug-loaded nanoparticle.
9. A method for preparing nanoparticles according to claim 8, characterized in that: mixing mPEG-DSPE, lipid modified drug and optional targeting modified molecules, dissolving in anhydrous DMF, magnetically stirring, slowly dropwise adding secondary water, dialyzing overnight, centrifuging, and collecting supernatant to obtain nanoparticles containing lipid modified drug.
10. Use of the lipid-modified drug of any one of claims 1 to 3, the nanoparticle of claim 6 or 7 for:
(1) preparing a medicament for treating cancer;
(2) preparing a medicament with a targeting effect;
(3) prepare the precursor medicine with less toxic side effect and high cytotoxicity to human body or animal body.
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100493614C (en) * 2001-08-18 2009-06-03 韩国科学技术研究院 Anticancer medicine-chitosan complex for forming self-aggregates and preparation method thereof
CN102271659A (en) * 2009-12-03 2011-12-07 江苏恒瑞医药股份有限公司 Liposome of irinotecan or its hydrochloride and preparation method thereof
CN102492009A (en) * 2011-12-15 2012-06-13 东北林业大学 Camptothecin 20- position cholic acid derivative and preparation method thereof
CN103012778A (en) * 2013-01-15 2013-04-03 江苏奥赛康药业股份有限公司 Water-soluble taxol polymer with tumor actively-targeted property
CN103120645A (en) * 2009-12-03 2013-05-29 江苏恒瑞医药股份有限公司 Irinotecan or irinotecan hydrochloride lipidosome and preparation method thereof
CN103948936A (en) * 2014-04-29 2014-07-30 宿州学院 Small-molecule modified target paclitaxel precursor medicament, as well as preparation method and application thereof
CN105348506A (en) * 2015-12-01 2016-02-24 沈阳药科大学 Preparation of glutamic acid-TPGS block copolymer and application thereof to targeted drug delivery

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6623729B2 (en) * 2001-07-09 2003-09-23 Korea Advanced Institute Of Science And Technology Process for preparing sustained release micelle employing conjugate of anticancer drug and biodegradable polymer

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100493614C (en) * 2001-08-18 2009-06-03 韩国科学技术研究院 Anticancer medicine-chitosan complex for forming self-aggregates and preparation method thereof
CN102271659A (en) * 2009-12-03 2011-12-07 江苏恒瑞医药股份有限公司 Liposome of irinotecan or its hydrochloride and preparation method thereof
CN103120645A (en) * 2009-12-03 2013-05-29 江苏恒瑞医药股份有限公司 Irinotecan or irinotecan hydrochloride lipidosome and preparation method thereof
CN102492009A (en) * 2011-12-15 2012-06-13 东北林业大学 Camptothecin 20- position cholic acid derivative and preparation method thereof
CN103012778A (en) * 2013-01-15 2013-04-03 江苏奥赛康药业股份有限公司 Water-soluble taxol polymer with tumor actively-targeted property
CN103948936A (en) * 2014-04-29 2014-07-30 宿州学院 Small-molecule modified target paclitaxel precursor medicament, as well as preparation method and application thereof
CN105348506A (en) * 2015-12-01 2016-02-24 沈阳药科大学 Preparation of glutamic acid-TPGS block copolymer and application thereof to targeted drug delivery

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
A novel photosensitizer: An L-glutamide lipid conjugate with improved properties for photodynamic therapy;Erica Nathan et al;《Photochem. Photobiol. Sci.》;20161107;第1-8页 *
Application of Microwave-Assisted Click Chemistry in the Preparation of Functionalized Copolymers for Drug Conjugation;Xiuli Hu et al;《J. APPL. POLYM. SCI.》;20120520;第3365-3373页 *
pH-sensitive polymeric micelles formed by doxorubicin conjugated prodrugs for co-delivery of doxorubicin and paclitaxel;Yakun Ma et al;《Carbohydrate Polymers》;20151019(第137期);第19-29页 *
Preparation and characterization of conjugates of(modified) human serum albumin and liposomes: drug carriers with an intrinsic anti-HIV activity;Jan A.A.M. Kamps et al;《Biochimicaet Biophysica Acta》;19961231(第1278期);第183-190页 *
Synthesis and in Vitro Evaluation of Glutamide-Containing Cationic Lipids for Gene Delivery;Vijaya Gopal et al;《Bioconjugate Chem.》;20061004(第17期);第1530-1536页 *
谷氨酸类脂分子在不同溶剂中的自组装性质及机理研究;王桐，等;《合成化学》;20181231;第26卷(第2期);第94-99页 *

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