CN109675047A - A method of liposome modification is carried out to the compound with free hydroxyl group - Google Patents

A method of liposome modification is carried out to the compound with free hydroxyl group Download PDF

Info

Publication number
CN109675047A
CN109675047A CN201910013083.0A CN201910013083A CN109675047A CN 109675047 A CN109675047 A CN 109675047A CN 201910013083 A CN201910013083 A CN 201910013083A CN 109675047 A CN109675047 A CN 109675047A
Authority
CN
China
Prior art keywords
drug
liposome
modification
nanoparticle
lgc12
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201910013083.0A
Other languages
Chinese (zh)
Other versions
CN109675047B (en
Inventor
肖海华
陈志刚
康晓旭
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Institute of Chemistry CAS
Original Assignee
Institute of Chemistry CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Institute of Chemistry CAS filed Critical Institute of Chemistry CAS
Priority to CN201910013083.0A priority Critical patent/CN109675047B/en
Publication of CN109675047A publication Critical patent/CN109675047A/en
Application granted granted Critical
Publication of CN109675047B publication Critical patent/CN109675047B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • A61K47/54—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 an organic compound
    • A61K47/545—Heterocyclic compounds
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/33—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
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • 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
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • 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
    • A61K47/54—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 an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • 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
    • 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
    • A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6925—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a microcapsule, nanocapsule, microbubble or nanobubble
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C07D519/04—Dimeric indole alkaloids, e.g. vincaleucoblastine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
    • C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
    • C07J73/003—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by oxygen as hetero atom

Abstract

The method that the compound that the present invention relates to a kind of to free hydroxyl group carries out liposome modification, and in particular to a kind of taxol of liposome modification and the like and the nanoparticle comprising the liposome modified medicaments.The present invention is specifically designed and is successfully prepared with liposome N, N '-two-dodecyl-Pidolidone diamides (LG-C12) modification taxol, 10-hydroxycamptothecine, Irinotecan, epothilone B, the hydrophobicity of drug is improved, the NH being then bonded using mPEG-DSPE and Mitochondrially targeted molecule triphenylphosphinebromide (TPP)2- mPEG-DSPE wraps up the drug assemble of the liposome modification into nanoparticle, and improving drug reduces drug to the toxic side effect of human or animal body simultaneously to the cytotoxic effect of cancer cell.

Description

A method of liposome modification is carried out to the compound with free hydroxyl group
Technical field
The present invention relates to drug modification fields, and in particular to a kind of to repair to the compound progress liposome with free hydroxyl group The method of decorations is more particularly to taxol of a kind of liposome modification and the like and modifies medicine comprising the liposome The nanoparticle etc. of object.
Background technique
China is estimated to be 4,292,000 cancer new cases, 2,814,000 cancer mortalities for 2015.Past In decades, very big effort is had been made to treat these serious diseases in people.In various therapies, chemotherapy means are One of clinical treatment cancer most effective way at present.Although a variety of anticancer drugs are developed and are applied to chemotherapy, often The adverse side effect that patient can often be caused, leads to the pain on body & mind, and therapeutic efficiency is very low.It clinically commonly uses at present Chemotherapeutics include adriamycin, taxol, 10-hydroxycamptothecine, Irinotecan etc..
Taxol (Paclitaxel, Taxol) is extracted from the trunk, bark of Taxus various plants A kind of natural antitumor drug, research find that it has apparent curative effect to many cancers.Clinically it is widely used for mammary gland The treatment of cancer, oophoroma, lung cancer and part head and neck cancer.The scarcity of resource makes the very high always of taxol kind anti-cancer drugs object It is expensive, it is water-soluble extremely low, bioavilability is not high the disadvantages of be even more the increase for leading to its demand.Because the bottleneck of shortage of resources is difficult to Overcome, thus researcher just in concern point set to developing novel form, on the directions such as bioavilability for improving drug.
Camptothecine (CPT) is the alkaloids antineoplastic drugs with coating extracted from the skin and fruit of Chinese plant camptotheca acuminata.Camplotheca acuminata Bases drug is for clinical topoisomerase I inhibitor, is the anticarcinogen that another is rising after taxol, Have become the hot spot studied in current anticancer drug.However, camptothecine lactonic ring easily hydrolysis under physiological environment is formed Carboxylate leads to drug inactivation；Poorly water-soluble existing for camptothecine itself, etc. big to normal body tissue toxic side effect lack simultaneously Point significantly limits the clinical application of camptothecine.Hereafter, scientist has developed a series of water-soluble camptothecines Derivative, such as Irinotecan (CPT-11).
Epothilones (epothilone) is a kind of macrolides compound, mechanism of action and taxanes drug class Seemingly, it is used clinically for the treatment of breast cancer, prostate cancer, lung cancer and colon cancer etc..However, Epothilones is to normal proliferative Cell tissue also has compared with strong cytotoxicity, this to be restricted when Epothilones clinical application.
Since most of chemotherapeutics are to reach antineoplastic action by the synthesis process of interference cancer cell DNA, thus Often there are the side effects such as bone marrow suppression in them, and lack effective precautionary measures, limit to these adjoint side effects at present The application to oncotherapy is made.Therefore a kind of sensibility that can promote chemotherapeutics is found, while being enhanced to tumour cell Inhibiting effect, and the antitumor related drugs of its toxic side effect and drug resistance can be reduced, become urgent problem to be solved, also one It is directly the hot spot of modern tumour scholar research.
Summary of the invention
To solve the above problems, nano drug-carrying delivery strategies are receive a lot of attention.In vivo, drug-carrying nanometer particle can be used as Foreign matter and swallowed by macrophage, reach target areas such as liver, spleen that reticuloendothelial system distribution is concentrated and be connected with aglucon, anti- Target area where body, zymolyte.Nano particle high degree of dispersion, surface area is huge, this is conducive to increase drug and absorption site Biofilm contact area.The special surface property of nano particle greatly prolongs its residence time in small intestine, and nanometer Grain also has protective effect to the drug of loading, these comprehensive functions can significantly improve the absorption and bioavilability of drug.With Unlike the transmembrane transport mechanism of general drug, nanoparticle enters cell by mechanism such as endocytosis, therefore can increase drug To the permeability of biomembrane, is conducive to Drug Percutaneous Absorption and intracellular drug effect plays.Low molecular weight chemotherapy drug passes through non-spy Anisotropic diffusion pass through health and tumor tissues capillary walls, but the drug supported by nanoparticulate carriers can only penetrate into it is hypertonic Permeability tumour capillary bed.The targeting of drug-carrying nanometer particle reduces whole body other portions while increasing local drug concentration The concentration of position, thus greatly reduces the systemic toxicity of drug.It swells to improve the curative effect of nanoparticle and more effectively reach Tumor position has the triphenylphosphine (TPP) of targeting in the surface modification of nanoparticle, folic acid, RGD, LHRH polypeptide, turns iron Other common targeting primitives such as albumen, aptamers.It is further introduced into acid sensitive group, and ester is become by carboxylic acid and amino condensation Its toxic side effect often lowers afterwards, and raw medicine can be reduced into the cell by entering drug, to improve drug effect.
Specifically, the present invention is designed and is successfully prepared with liposome N, N '-two-dodecyl-two acyl of Pidolidone Taxol, the 10-hydroxycamptothecine, Irinotecan, epothilone B of amine (LG-C12) modification, improve the hydrophobicity of drug, so The NH modified afterwards using mPEG-DSPE and Mitochondrially targeted molecule triphenylphosphinebromide (TPP)2Described in-mPEG-DSPE package The drug assemble of liposome modification at nanoparticle, improve drug to the toxic effect of cancer cell reduce simultaneously drug to people or The toxic side effect of animal body.
In a first aspect, the present invention provides a kind of drug of liposome modification, shown in structure such as formula (II):
Wherein, the integer that n is >=7, preferably 7,11,17；R is the compound of active hydroxyl.
The drug of liposome modification of the present invention, it is characterised in that: the R is selected from the group being made of following compound: Taxol (Paclitaxel), 10-hydroxycamptothecine (10-Hydroxycamptothecin), Irinotecan (Irinotecan), epothilone B (epothilone B), vincristine (Vincristine), docetaxel (Docetaxel), capecitabine (Capecitabine), Etoposide (Etoposide), wilforlide A (Wilforlide A)。
The drug of liposome modification of the present invention, it is characterised in that the liposome is anti-with that can carry out being condensed with carboxyl The active group answered, including but not limited to amino, hydroxyl, sulfydryl etc.；It is preferred that the liposome is N, N '-two-chain alkyl- Pidolidone diamides (LG).
Second aspect, the present invention provide the preparation method of the liposome modified medicaments, comprising:
(1) raw medicine is modified with acid anhydrides or binary organic acid；
(2) condensation reaction occurs for the raw medicine (CAR) and liposome for modifying acid anhydrides or binary organic acid；
(3) it washs, recrystallize, freeze-drying obtains the drug that liposome is modified.
The preparation method of liposome modified medicaments of the present invention, comprising:
It (1) is catalysis with triethylamine by the ring-opening reaction between the activity hydroxy and cis-aconitic anhydride CA on raw medicine R Agent prepares the raw medicine CAR of cis-aconitic anhydride modification: specifically including and raw medicine R and CA are dissolved in anhydrous DMF, three second are added Amine, room temperature are protected from light, stirred under nitrogen 24 hours；Cold ethyl acetate mixing, washing is added；Organic layer is done with anhydrous sodium sulfate Dry 12 hours, filtering, dry CAR；
(2) CAR is dissolved with methylene chloride, is activated with EDC and NHS, liposome is added and carries out amide condensed reaction；
(3) after reacting 48 hours, by washing, recrystallizing, freeze-drying obtains liposome modified medicaments.
The third aspect, the present invention provide a kind of nanoparticle comprising the liposome modified medicaments, it is characterised in that logical Cross pharmaceutically acceptable macromolecule contain liposome modification drug be self-assembly of medicament nano particle.
Nanoparticle of the present invention, it is characterised in that described to select pharmaceutically acceptable macromolecule mPEG-DSPE warp Cross in modification and target group, the targeting group selected from by triphenylphosphine (TPP), folic acid, RGD, LHRH polypeptide, transferrins, The group of aptamers composition.
Fourth aspect, the present invention provide the preparation method of the nanoparticle, comprising: by pharmaceutically acceptable macromolecule MPEG-DSPE and the drug of liposome of the present invention modification are blended in assembling under suitable solvent condition and generate drug-carrying nanometer particle Son.
The preparation method of nanoparticle of the present invention, it is characterised in that: by mPEG-DSPE, liposome modify drug, And the mPEG-DSPE mixing of optional targeted molecular modification, it is dissolved in anhydrous DMF, magnetic agitation is simultaneously slowly added dropwise secondary Water, dialysed overnight, the nanoparticle of drug of the centrifuging and taking supernatant to obtain the final product comprising liposome modification.
5th aspect, the present invention provide the use of the drug or the nanoparticle of the liposome modification in the following areas On the way:
(1) drug for the treatment of cancer is prepared；
(2) preparation has the drug of targeting；
(3) preparation reduces, to cytotoxicity raised pro-drug human body or animal body toxic side effect.
Compared with prior art, technical solution of the present invention has the advantage that
(1) liposome molecule N, N '-two-chain alkyl-Pidolidone diamides (LG) are introduced, drug molecule is improved Hydrophobicity and rate is contained, improves the bioavilability of drug.
(2) NH is modified using triphenylphosphine (TPP)2- mPEG-DSPE, and be mixed with mPEG-DSPE with line grain The Nano medication of body targeting, improves the anticancer effect of drug, it is other to reduce whole body while increasing local drug concentration The concentration at position thus greatly reduces the systemic toxicity of drug
(3) introduce acid sensitive group, and by carboxylic acid and amino condensation become ester after its toxic side effect often lower, make Drug enters can be reduced into raw medicine into the cell, to improve drug effect.
Detailed description of the invention
By reading the following detailed description of the preferred embodiment, various other advantages and benefits are common for this field Technical staff will become clear.The drawings are only for the purpose of illustrating a preferred embodiment, and is not considered as to the present invention Limitation.And throughout the drawings, the same reference numbers will be used to refer to the same parts.In the accompanying drawings:
Fig. 1: bis--dodecyl of liposome N, N'--Pidolidone diamides (LGC12) nuclear-magnetism characterization
Fig. 2: liposome LGC12 MALDI-TOF-MS mass spectral characteristi；
The LGC12 mass spectrogram of A:Boc protection；The LGC12 mass spectrogram of B:Boc deprotection
The nuclear-magnetism characterization of the taxol (PTX-LGC12) of Fig. 3: LGC12 modification
Fig. 4: PTX-LGC12 MALDI-TOF-MS mass spectral characteristi；
Fig. 5: the nanoparticle preparation condition optimization containing PTX-LGC12
X-axis is the mass ratio of PTX-LGC12 and mPEG-DSPE；Y-axis is diameter (nm)/PDI
Fig. 6 A: the diameter distribution of the nanoparticle containing PTX-LGC12
Fig. 6 B: the diameter distribution of the nanoparticle containing PTX-LGC12-TPP；
Fig. 7: the TEM scanning electron microscope (SEM) photograph of the nanoparticle containing PTX-LGC12
Fig. 8: the mass concentration of PTX and UV absorption relation curve in nanoparticle containing PTX-LGC12
Fig. 9: the cell toxicity test of the nanoparticle containing PTX-LGC12
Specific embodiment
The illustrative embodiments of the disclosure are more fully described below with reference to accompanying drawings.Although showing this public affairs in attached drawing The illustrative embodiments opened, it being understood, however, that may be realized in various forms the disclosure without the reality that should be illustrated here The mode of applying is limited.It is to be able to thoroughly understand the disclosure on the contrary, providing these embodiments, and can be by this public affairs The range opened is fully disclosed to those skilled in the art.
Embodiment 1: the long alkane of liposome N, N '-two-- Pidolidone diamides (LG) preparation and characterization
The long-chain amine (eight, 12, octadecylamine) of Boc- glutamic acid and twice of equivalent is added in reaction flask, dichloro is added Methane dissolution, EDC and the HOBt generation for adding 1.1 times of equivalents are amide condensed, are then filtered, washed, are recrystallized to give N, N '-two-chain alkyl-L-Boc- glutamic acid diamides, then Boc protection is taken off with trifluoroacetic acid, washing is dried to obtain white powder Last N, N '-two-chain alkyl-Pidolidone diamides (LG).
Reaction step is as follows:
To the LGC12 of preparation, nucleus magnetic hydrogen spectrum characterization is carried out, as a result as shown in Figure 1.Peak in nucleus magnetic hydrogen spectrum, all succeeds Ownership, shows the successful synthesis of LGC12.
It to the LGC12 of preparation, is characterized by MALDI-TOF-MS, as a result as shown in Figure 2.Fig. 2A is boc-protected The mass spectrogram of LGC12, wherein 604.1 be Boc-LGC12+Na+, 620.1 be Boc-LGC12+K+；Fig. 2 B is Boc deprotection Mass spectrogram, wherein 481.5 be LGC12,503.6 be LGC12+Na+, all successfully belong to, MALDI-TOF-MS mass spectral analysis knot Fruit, which also indicates that, successfully synthesizes LGC12.
Embodiment 2:LGC12 modifies taxol (Paclitaxel), 10-hydroxycamptothecine (10-Hydroxy Camptothecin), the preparation method of Irinotecan (Irinotecan), epothilone B (Epothilone B)
1. modifying various raw medicine (abbreviation R, R=taxols (PTX), 10- hydroxycamptothecin with cis-aconitic anhydride (CA) (HCPT), Irinotecan (CPT-11), epothilone B (EpoB)), hereinafter referred to as CAR, by the ring-opening reaction between R and CA, Triethylamine is used to synthesize as catalyst.Raw medicine R (0.4mmol) and CA (0.44mmol) are added to the flask being completely dried In, and be dissolved in 20.0mL anhydrous DMF, 67.0 μ L triethylamines are then added.Mixture is placed in room temperature, dark, nitrogen (N2) stir 24 hours under atmosphere protection.Next, solution is mixed with 200.0mL cold ethyl acetate, satisfying for pH 2-3 is first used It washs with sodium chloride solution, is then washed with the saturated sodium chloride solution of pH 7.4.The organic layer anhydrous sodium sulfate that will be obtained It is 12 hours dry.Finally, solid CAR is isolated by filtration, and it is dried in vacuo at room temperature, obtains product.
2. by drug CAR (R=taxol (PTX), 10-hydroxycamptothecine (HCPT), Irinotecan (CPT-11), Ai Bo Mycin B (EpoB)) it is added in reaction flask, methylene chloride dissolution is added, EDC and NHS the activation 2-4 for adding 2-3 times of equivalent are small When, the N of 1 times of equivalent is added, amide condensed reaction, reaction occur for N '-two-dodecyl-Pidolidone diamides (LGC12) 48 hours, then by washing, recrystallization, freeze-drying obtained LG modified medicaments (CAR-LGC12).Reaction step is as follows:
Wherein R is
The structural characterization of embodiment 3:LGC12 modified medicaments
1, NMR spectrum (NMR)
With tetramethylsilane (TMS) for internal standard, to N prepared by embodiment 2, N '-two-dodecane glutamic acid diamides (LGC12) PTX modified is characterized, with deuterated chloroform (CDCl3) it is solvent, using 400MHZ nuclear magnetic resonance apparatus to it1H NMR is scanned.
The nucleus magnetic hydrogen spectrum of PTX-LGC12 all successfully belongs to as shown in figure 3, peak in PTX-LGC12 nucleus magnetic hydrogen spectrum.
2, Matrix-assisted laser desorption ionization (MALDI-TOF-MS)
In order to further confirm that compound synthesized by embodiment 2, by MALDI-TOF-MS, matrix selects gentianic acid (DHB) its mass spectrogram is tested.
The MALDI-TOF-MS mass spectrogram of PTX-LGC12 is as shown in Figure 4.1683.1 be PTX-LGC12+Na in Fig. 4+。
Nucleus magnetic hydrogen spectrum and mass spectrographic experimental result confirm, successfully synthesize the drug PTX-LGC12 of LGC12 modification.
Embodiment 4: the preparation and characterization of the nanoparticle containing PTX-LGC12
The PTX-LGC12 that the preparation of embodiment 2 is contained with macromolecule, prepares nanoparticle.Select mPEG-DSPE or warp grain The mPEG-DSPE of body targeted molecular triphenylphosphine TPP modification PTX-LGC12 and contains molecule in mass ratio as containing molecule It for 1:1,1:2,1:3,1:4,1:5,1:6, is dissolved in 1mL anhydrous DMF, simultaneously 5mL secondary water, half an hour is slowly added dropwise in magnetic agitation Dialysed overnight (molecular cut off 3500) is carried out afterwards, centrifuging and taking supernatant obtains nanoparticle.Pass through dynamic light scattering (DLS) To observe the variation of its partial size and zeta current potential.LGC12 modifier PTX-LGC12 forms the condition optimizing result of nanoparticle such as Shown in Fig. 5.
According to Fig. 5, the most ratio of greater inequality of PTX-LGC12:mPEG-DSPE is 1:4
It is received accordingly according to the optimal conditions of above-mentioned selection (LGC12 modified medicaments and contain high molecular most ratio of greater inequality) preparation Rice corpuscles detects its particle diameter distribution, carries out TEM morphology observations.
As indicated with 6, wherein Fig. 6 A is with mPEG- to the grain size distribution of the PTX-LGC12 nanoparticle formed under optimal conditions DSPE contains the PTX-LGC12 nanoparticle of PTX-LGC12 preparation, and Fig. 6 B is to contain PTX- with the mPEG-DSPE of TPP modification The PTX-LGC12-TPP nanoparticle of LGC12 preparation；Electron microscopic picture is as shown in Figure 7.The above results show receiving for the application preparation Rice grain structure is stable, uniform in size.
Embodiment 5: active compound content in the nanoparticle of the modified medicaments containing LGC12 supports rate, package efficiency
1, method
Detect the content of raw medicine R in nanoparticle prepared by embodiment 4.It is measured by uv-vis spectra (UV-Vis), first Sample is dissolved in DMF, then measurement solution calculates drug R content and purple in the ultraviolet light absorption angle value at 227nm (PTX), place The linear relationship of outer absorbance value.It first takes Nano medication solution 1mL to be lyophilized, then dissolves freeze-dried powder sample with DMF, It measures ultraviolet light absorption angle value at feature UV absorption and the content of drug is calculated；
Supporting rate and wrapping up efficiency for drug R is calculated by following formula:
Support rate (%)=[content of drug R/total nanoparticle quality in nanoparticle] × 100
Wrap up efficiency (%)=[quality of drug R content/investment drug R in nanoparticle] × 100
2, result
The mass concentration of taxol and UV absorption relation curve in PTX-LGC12 nanoparticle, as shown in Figure 8.It calculates public Formula is Y=6.245 × X+0.2060, R2=0.9993.It measures the ultraviolet light absorption angle value at 227nm UV absorption and calculates It is 432 μM to medicament contg；Support rate=7.4%；Wrap up efficiency=36.85%.
Embodiment 6: the cytotoxicity of the nanoparticle containing PTX-LGC12
Detect toxicity of the nanoparticle containing PTX-LGC12 to cancer cell of the preparation of embodiment 4.
1, method
It chooses A549 (human lung carcinoma cell), A549DDP (the human lung cancer medicine of resistance to platinum cell), MCF7 (source of people breast cancer cell), 4T1 (source of mouse breast cancer cell) is used to study the toxicity problem of drug.Four kinds of cells use DMEM (GIBCO) culture medium culture. Contain 10% fetal calf serum and 1% penicillin streptomycin mixed liquor (100 ×) in DMEM culture medium.
Cytotoxicity is detected by mtt assay, the specific steps are as follows:
(1) it to A549, A549DDP, MCF7 and 4T1 cell culture to logarithmic phase, is digested and is counted with pancreatin.It will be thin Cell lysis liquid is diluted to 5 × 104cells/mL；
(2) by prediluted cell inoculation into 96 orifice plates, then every 100 μ L of hole places overnight incubation in incubator；
(3) by PTX, NPS, NPS-TPP respectively according to must multiple dilute, be added in 96 orifice plates, 10 μ are added in every hole L makes the final PTX concentration of drug be followed successively by 100,50,25,12.5,1.25,0.125,0.0125 μM.Each concentration setting four A multiple holes, incubation time 72h；
(4) the 10%MTT solution being pre-configured is diluted 10 times with no phenol red medium and is added to different incubation times In 96 orifice plates, 100 μ L are added in every hole, are continued to be placed in incubator and are cultivated 4h, and later, 100 μ L SDS solution are added in every hole, are kept away Light, 37 DEG C of placement 12h in constant incubator；
(5) the absorbance OD value with microplate reader measurement each hole of 96 orifice plates at 570nm, selects a length of 650nm of background wave, will OD value of the OD value average value of three multiple holes as target sample, and calculate cell survival rate:
Cell viability=sample OD/ blank control group OD
2, result
2.1 cell toxicity tests containing effect of nano-paclitaxel
NPS (PTX-LGC12) is tested using mtt assay, the cytotoxicity of NPS-TPP (PTX-LGC12-TPP) and PTX are examined Examining the time is 72h, as a result as shown in figure 9, IC50Value is listed in Table 2 below.
Table 2:NPS (PTX-LGC12), NPS (PTX-LGC12)-TPP, PTX are to the IC of four kinds of cells50(μM)
According to above-mentioned three kinds of drug NPS (PTX-LGC12), NPS-TPP (PTX-LGC12-TPP) and PTX to four kinds of cells The toxic effect of system, it is known that cytotoxicity is by being followed successively by NPS-TPP (PTX-LGC12-TPP) > NPS (PTX-LGC12) to weak by force > PTX illustrates that as carrier, cell is can be enhanced to the endocytosis of drug in macromolecule, and has Mitochondrially targeted nanoparticle can Drug is improved to the toxic effect of cancer cell.
The foregoing is only a preferred embodiment of the present invention, but scope of protection of the present invention is not limited thereto, In the technical scope disclosed by the present invention, any changes or substitutions that can be easily thought of by anyone skilled in the art, It should be covered by the protection scope of the present invention.Therefore, protection scope of the present invention should be with the protection model of the claim Subject to enclosing.

Claims (10)

1. a kind of drug of liposome modification, shown in structure such as formula (II):
Wherein, the integer that n is >=7, preferably 7,11,17；R is the compound of active hydroxyl.
2. the drug of liposome as described in claim 1 modification, it is characterised in that: the R is selected to be made of following compound Group: taxol (Paclitaxel), 10-hydroxycamptothecine (10-Hydroxycamptothecin), Irinotecan (Irinotecan), epothilone B (epothilone B), vincristine (Vincristine), docetaxel (Docetaxel), capecitabine (Capecitabine), Etoposide (Etoposide), wilforlide A (Wilforlide A)。
3. the drug of liposome modification as claimed in claim 1 or 2, it is characterised in that the liposome has and can carry out with carboxyl The active group of condensation reaction, including but not limited to amino, hydroxyl, sulfydryl etc.；It is preferred that the liposome is N, N '-two-long-chain Didodecyl l glutamic acid diamides (LG).
4. the preparation method for the drug that the liposome as described in claim 1-3 is any is modified, comprising:
(1) raw medicine is modified with acid anhydrides or binary organic acid；
(2) condensation reaction occurs for the raw medicine (CAR) and liposome for modifying acid anhydrides or binary organic acid；
(3) it washs, recrystallize, freeze-drying obtains the drug that liposome is modified.
5. preparation method as claimed in claim 4, comprising:
(1) by the ring-opening reaction between the activity hydroxy and cis-aconitic anhydride CA on raw medicine R, using triethylamine as catalyst system The raw medicine CAR of standby cis-aconitic anhydride modification: it specifically includes and raw medicine R and CA is dissolved in anhydrous DMF, triethylamine, room is added Temperature is protected from light, stirred under nitrogen 24 hours；Cold ethyl acetate mixing, washing is added；Organic layer is small with anhydrous sodium sulfate dry 12 When, filtering, dry CAR；
(2) CAR is dissolved with methylene chloride, is activated with EDC and NHS, liposome is added and carries out amide condensed reaction
(3) after reacting 48 hours, by washing, recrystallizing, freeze-drying obtains liposome modified medicaments.
6. a kind of nanoparticle comprising any liposome modified medicaments of claim 1-3, it is characterised in that pass through pharmacy The drug that upper acceptable macromolecule contains liposome modification is self-assembly of medicament nano particle.
7. nanoparticle as claimed in claim 6, it is characterised in that described to be passed through using pharmaceutically acceptable macromolecule carrier Modification have targeting group, the targeting group selected from by triphenylphosphine (TPP), folic acid, RGD, LHRH polypeptide, transferrins, The group of aptamers composition.
8. the preparation method of nanoparticle as claimed in claims 6 or 7, comprising: by pharmaceutically acceptable high molecular polymer Assembling under suitable solvent condition, which is blended in, with the drug of any liposome modification of claim 1-3 forms drug-carrying nanometer particle Son.
9. the preparation method of nanoparticle as claimed in claim 8, it is characterised in that: the medicine for modifying mPEG-DSPE, liposome Object and optional targeting modification molecular mixing, are dissolved in anhydrous DMF, simultaneously secondary water is slowly added dropwise in magnetic agitation, dialyses Night, the nanoparticle of drug of the centrifuging and taking supernatant to obtain the final product comprising liposome modification.
10. the drug of any liposome modification of claim 1-3, the nanoparticle of claim 6 or 7 are in the following areas Purposes:
(1) drug for the treatment of cancer is prepared；
(2) preparation has the drug of targeting；
(3) preparation reduces, to cytotoxicity raised pro-drug human body or animal body toxic side effect.
CN201910013083.0A 2019-01-07 2019-01-07 Method for carrying out liposome modification on compound with free hydroxyl Active CN109675047B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201910013083.0A CN109675047B (en) 2019-01-07 2019-01-07 Method for carrying out liposome modification on compound with free hydroxyl

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201910013083.0A CN109675047B (en) 2019-01-07 2019-01-07 Method for carrying out liposome modification on compound with free hydroxyl

Publications (2)

Publication Number Publication Date
CN109675047A true CN109675047A (en) 2019-04-26
CN109675047B CN109675047B (en) 2020-12-04

Family

ID=66191875

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201910013083.0A Active CN109675047B (en) 2019-01-07 2019-01-07 Method for carrying out liposome modification on compound with free hydroxyl

Country Status (1)

Country Link
CN (1) CN109675047B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114796156A (en) * 2022-04-18 2022-07-29 河北医科大学 Mitochondrion-targeted photo-thermal/chemotherapy synergistic nano-drug delivery particle and preparation method and application thereof

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030017131A1 (en) * 2001-07-09 2003-01-23 Park Tae Gwan Process for preparing sustained release micelle employing conjugate of anticancer drug and biodegradable polymer
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

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030017131A1 (en) * 2001-07-09 2003-01-23 Park Tae Gwan Process for preparing sustained release micelle employing conjugate of anticancer drug and biodegradable polymer
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
ERICA NATHAN ET AL: "A novel photosensitizer: An L-glutamide lipid conjugate with improved properties for photodynamic therapy", 《PHOTOCHEM. PHOTOBIOL. SCI.》 *
JAN A.A.M. KAMPS ET AL: "Preparation and characterization of conjugates of(modified) human serum albumin and liposomes: drug carriers with an intrinsic anti-HIV activity", 《BIOCHIMICAET BIOPHYSICA ACTA》 *
VIJAYA GOPAL ET AL: "Synthesis and in Vitro Evaluation of Glutamide-Containing Cationic Lipids for Gene Delivery", 《BIOCONJUGATE CHEM.》 *
XIULI HU ET AL: "Application of Microwave-Assisted Click Chemistry in the Preparation of Functionalized Copolymers for Drug Conjugation", 《J. APPL. POLYM. SCI.》 *
YAKUN MA ET AL: "pH-sensitive polymeric micelles formed by doxorubicin conjugated prodrugs for co-delivery of doxorubicin and paclitaxel", 《CARBOHYDRATE POLYMERS》 *
王桐，等: "谷氨酸类脂分子在不同溶剂中的自组装性质及机理研究", 《合成化学》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114796156A (en) * 2022-04-18 2022-07-29 河北医科大学 Mitochondrion-targeted photo-thermal/chemotherapy synergistic nano-drug delivery particle and preparation method and application thereof
CN114796156B (en) * 2022-04-18 2023-11-21 河北医科大学 Mitochondria-targeted photo-thermal/chemotherapy synergistic nano drug delivery particle and preparation method and application thereof

Also Published As

Publication number Publication date
CN109675047B (en) 2020-12-04

Similar Documents

Publication Publication Date Title
Song et al. Anti-HIF-1α antibody-conjugated pluronic triblock copolymers encapsulated with Paclitaxel for tumor targeting therapy
AU2017226517B2 (en) Ovarian cancer specifically targeted biodegradable amphiphilic polymer, polymer vesicle prepared thereby and use thereof
CN101791411A (en) Preparation and application of amphiphilic polysaccharide conjugate and medicinal compositions thereof
CN108478794A (en) The structure of photosensitizer-chemotherapeutic " photochemical one " small molecule prodrugs and its self-assembled nanometer grain
Wang et al. Intracellular GSH-activated galactoside photosensitizers for targeted photodynamic therapy and chemotherapy
CN108559091A (en) Polymer drug carrier, carrier micelle with aggregation-induced emission and doubling sensitivity and preparation method thereof
CN113952463B (en) Nanometer diagnosis and treatment agent and preparation method and application thereof
EP4230224A1 (en) Affibody-cytotoxin conjugate used for active tumor targeting therapy, and nanoparticles, preparation method, and application thereof
Gao et al. Preparation, characterization and in vitro activity of a docetaxel–albumin conjugate
CN105001426B (en) A kind of polyaminoacid graft copolymer with tumor-targeting and preparation method thereof
CN112089845B (en) Taxane drug-adriamycin prodrug self-assembly nanoparticles and application thereof
CN108888774B (en) Tripterine-dendrimer conjugate as well as preparation method and application thereof
CN109675048A (en) A kind of anticancer prodrug liposome and artemisine liposome Nano medication
Xu et al. Dual stimuli-activatable versatile nanoplatform for photodynamic therapy and chemotherapy of triple-negative breast cancer
CN112603908B (en) Nano drug-loading system based on amino acid polymer and preparation method and application thereof
CN109675047A (en) A method of liposome modification is carried out to the compound with free hydroxyl group
CN107007550B (en) Redox-responsive amphiphilic copolymer and preparation method and application thereof
CN105903030B (en) A kind of esterification cholic acid/Fe3O4 magnetic Nano complex and its preparation method and application
CN109568599A (en) A kind of adriamycin that liposome is modified and the nanoparticle containing adriamycin
CN107028882B (en) Physically-wrapped tumor-targeted nano drug delivery system, and preparation method and application thereof
CN107970242A (en) A kind of mesoporous silicon oxide of paclitaxel loaded/Tarceva-hyaluronic acid mixing targeting nano particle
Majumdar et al. Anticancer activity of drug conjugates in head and neck cancer cells
CN104069501B (en) Targeted drug delivery carrier based on PAMAM (polyamide amine) and preparation method of targeted drug delivery carrier
CN112023059B (en) pH response type adriamycin carrier-free nano-drug and preparation method and application thereof
CN108299649A (en) A kind of multiple-arm star block polymer and its preparation method and application

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant