CN107158399A - Amphiphilic nano medicine and its preparation method and application - Google Patents
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- CN107158399A CN107158399A CN201710397627.9A CN201710397627A CN107158399A CN 107158399 A CN107158399 A CN 107158399A CN 201710397627 A CN201710397627 A CN 201710397627A CN 107158399 A CN107158399 A CN 107158399A
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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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
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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
- A61K31/33—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
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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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
- A61K31/33—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
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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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
- A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
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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
- A61K31/7042—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
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Abstract
The present invention relates to a kind of amphiphilic nano medicine and its preparation method and application, by being connected into hydrophilic radical in the structure of hydrophobic drug, improve the Nano medication of good hydrophilic property, by taking Sorafenib as an example, Sorafenib hydrophilicity after modified is good, and this method is modified for hydrophobic drug and provides new thinking, is not lessening the curative effect simultaneously, it is significant to the targeted therapy of tumour to improve availability and the reduction side effect of medicine.
Description
Technical field
The invention belongs to medicinal chemistry art, it is related to amphiphilic nano medicine, further relates to the preparation of amphiphilic nano medicine
Methods and applications.
Background technology
As the improvement of people's living standards, health problem also becomes increasingly conspicuous.And cancer exactly influences human body at present
Health, threatens one of principal disease of human life.Therefore, the World Health Organization and hygiene department of various countries will capture cancer conduct
One top priority.The method of current treating cancer mainly has three kinds：One is operative treatment, is also most ancient treatment of cancer side
Method, i.e., cut off cancerous issue with the method for surgery excision, prevent cancer cell from spreading.Two be the side using chemotherapy or radiotherapy
Method, three be drug therapy.The method of surgery excision is larger to human body wound, causes patient's immunity degradation, the resistance to disease
Ability declines.And surgery excision belongs to locality treatment, cancer early stage is more only applicable to.Simultaneously operative treatment there is also
This certain risk, postoperative easy occur recurring or shift.With the method for radiotherapy, it can also be killed while cancer cell is killed
Other normal cells, and patient is produced systemic symptomatic reaction.And drug therapy, drug therapy is especially targeted, can
Cancer cell is efficiently killed, and patient body toxic side effect is lowered significantly, the whole structure of patient is very significantly improved.And
Exactly a kind of target therapeutic agent of drugs sorafenib (sorafenib) in our researchs, different from chemotherapeutics, it can have
Effect suppresses tumor cell proliferation and Tumor Angiongesis, rather than cellulotoxic effect, therefore, and Sorafenib has the anti-of potential wide spectrum
Function of tumor.Treatment can not perform the operation or DISTANT METASTASES IN tumor cell of liver；Treat inoperable kidney tumor cell；Treatment is to putting
The no longer valid local recurrence of penetrating property iodine therapy or metastatic, progressively differentiated thyroid gland patient.Toxic effect that Sorafenib is acellular
Should, can stablize the state of an illness, extension patient without progression of disease life cycle.Sorafenib be also in the world first be also only one
Confirmed can significantly extend effective medicine of liver cancer patient life span by medical science.And exactly this series of advantage
Promote the development and application of Sorafenib.The treatment that it is applied to inoperable advanced liver cancer patient is significant.
Sorafenib suppresses tumor cell proliferation and the mechanism of action of Tumor Angiongesis is as follows：By suppress Raf-1 and
The activity of B-Raf serines and threonine kinase, so as to suppress RAS/RAF/MEK/ERK signal transduction pathway, suppresses tumour thin
The propagation of born of the same parents；Sorafenib suppresses tumor angiogenesis.Tumour growth rely on new vessels formation, VEGFR and
PDGFR is the regulatory factor of most important promotion vascularization.Sorafenib has to the tyrosine kinase activity of both acceptors
Inhibitory action, therefore, blocks the nutrition supply of tumor neovasculature formation and cut-out tumour cell, suppresses tumour cell indirectly
Growth.
Sorafenib based on to tumorigenic the Molecular Biology Mechanism further clearly on the basis of succeed in developing
New drug, with unique Mutiple Targets antitumor action.Acellular poison effect, can stablize the state of an illness, extension patient without progression of disease
Life cycle.It is late.Acquired success brings new inspiration to the research and development of targeted drug in kidney treatment, it is European its
Treatment liver cancer has agreed to approval, the opinion also affirmed in the U.S. as the 2nd indication.How optimal side is formulated
Case is the major issue that faces in our current researchs to improve its curative effect.
The hydrophobicity of Sorafenib is strong, and bioavilability is low, so it is our urgent problems to improve its water solubility.
Sorafenib Tosylate is succeeded in developing, and to advanced liver cancer, patient brings Gospel.Existing formulation is that toluenesulfonic acid rope is drawn
Non- Buddhist nun's piece, the dosage of recommendation be 400 milligrams once, twice daily, although having reduced dosage, appointing has inevitably not
The generation of good event.Multiple clinical researches show that the common adverse reaction of Sorafenib has diarrhoea, weak, hand-foot syndrome, height
Blood pressure, fash, vomiting etc..It is generally light moderate, can be alleviated after decrement and symptomatic treatment, topmost 3/4 grade of adverse reaction
Including weak, hand-foot syndrome and diarrhoea.Decrement, interrupt or exit Sorafenib treatment may influence the curative effect of medicine.Therefore,
Early stage efficiently controls adverse reaction, while maintaining Sorafenib treatment, for improving clinical efficacy, improves the life matter of patient
Measure and particularly important to the compliance of medicine.The toxic side effect of Sorafenib is reduced, bioavilability is improved, increases the water of medicine
Dissolubility etc. is still our urgent problems to be solved.
The content of the invention
In view of this, an object of the present invention is to provide a kind of amphiphilic nano medicine；The second object of the present invention
It is the preparation method that amphiphilic nano medicine is provided, the third object of the present invention is to provide answering for amphiphilic nano medicine
With.
To reach above-mentioned purpose, the present invention provides following technical scheme：
1st, a kind of amphiphilic nano medicine, its structure is A-B-L-D, and wherein A is hydrophilic radical, is selected from Or PEG200~10000；B is N is 1
~10 positive integer；L for can cleavable groups, be selected from D is hydrophobic drug, is selected fromAdriamycin, camptothecine, gemcitabine, Irinotecan, taxol or
Triptolide.
In the present invention, PEG200~10000 are straight chain PEG200~10000, side chain PEG200~10000 or 3-8
Arm PEG200~10000.
In the present invention, it is described can cleavable groups be
In the present invention, the hydrophobic drug is selected from
In the present invention, its structure be T-A-B-L-D forms, wherein T for targeting group, selected from galactolipin, LHRH, lactose or
Folic acid.
It is preferred that, its structure is as shown in formula II：
Described a, b and c be hydrogen,
2nd, the preparation method of the amphiphilic nano medicine, comprises the following steps：
(1) disulfide bond that can be broken is connected on the PEG of amino functional by Michael addition reaction, prepares end
Hold functionalization and with amphipathic PEG molecules；
(2) hydrogen on the amide groups of step (1) amphipathic the PEG molecules and hydrophobic drug is reacted, so that
Obtain amphiphilic nano medicine.
It is preferred that, the hydrophobic drug is selected fromAdriamycin,
Camptothecine, gemcitabine, Irinotecan, taxol or triptolide.
3rd, the application in the amphiphilic nano medicine preparation tumor.
It is preferred that, the amphiphilic nano medicine is Sorafenib amphiphilic nano medicine, and the tumour is liver cancer.
The beneficial effects of the present invention are：In numerous anti-tumor medicines, hydrophobicity is strong, and bioavilability is low, and poison is secondary
Effect is big.The present invention of Sorafenib had both improved the water solubility of hydrophobic drug, again using the special construction of amphipathic molecule
The molecule newly obtained is formed nano-particle in water solubility, so as to improve the passive targeting of medicine, enhance medicine
Effect, reduces possible side effect.Novel drugs molecule designed by the present invention, good water solubility, structure determination, it is easy to repeated
And sign, and preferably therapeutic action.
Brief description of the drawings
In order that the purpose of the present invention, technical scheme and beneficial effect are clearer, the present invention provides drawings described below and carried out
Explanation：
Fig. 1 is SCNS hydrogen spectrograms.
Fig. 2 is the particle diameters of SCNS in aqueous.
Fig. 3 is SCNS and Sorafenib anti-liver cancer and anti-cell (HepG2) result (A：Sorafenib；B：SCNS).
Embodiment
Below in conjunction with accompanying drawing, the preferred embodiments of the present invention are described in detail.
Embodiment 1
The disulfide bond that can be broken is connected on the PEG of amino functional by Michael addition reaction, end is prepared
Functionalization and with amphipathic PEG molecules (chemical compounds I), specific route is as follows：
Then compound I is reacted with Sorafenib a partial amides base hydrogen, so that final compound SCNS is obtained,
Specific route is as follows：
Compound SCNS hydrogen spectrogram results are as shown in Figure 1.As a result show：By Michael addition reaction, Sorafenib quilt
Successfully it has been connected on PEG.
Embodiment 2
The water solubility and the dissolubility of Sorafenib for the SCNS that embodiment 1 is synthesized are compared discovery, as a result such as the institute of table 1
Show.
Table 1, SCNS are compared with the water solubility of Sorafenib
As a result show, Sorafenib is almost completely insoluble in water, and it is improved after compound SCNS there is good water
Dissolubility.
Embodiment 3
The patterns of SCNS in aqueous particle size determination is subjected to, as a result as shown in Figure 2.Test result indicates that, obtain
Compound 200nm or so nano particle is formd in water solubility, be conducive to entering cell and intravenously administrable.
Embodiment 4
SCNS and Sorafenib are carried out to liver cancer cells (HepG2) MTT experiment, specific method is as follows：
1st, 96 orifice plates are taken, 100 μ L nutrient solutions are added per hole, after cell suspension is prepared, are gently mixed, then toward added with training
10ul cell suspensions are added in the hole of nutrient solution.5%CO is put into after mixing2, 37 DEG C of incubators are incubated 24 hours.
2nd, after 24 hours, the medicine of corresponding amount, 5%CO are added according to certain concentration gradient2, cultivate in 37 DEG C of incubators
48 hours.
3rd, after 48 hours, suction out in nutrient solution, each hole and add 20 μ L MTT solution (the final concentration of 5mg/ that MTT is made into
Ml, solvent is made with PBS), 5%CO2, cultivate 4 hours in 37 DEG C of incubators.
4th, 100 μ L DMSO are added in each hole, you can see that purpuric first a ceremonial jade-ladle, used in libation is separated out.Solvent and first a ceremonial jade-ladle, used in libation are fully mixed
It is even, ELIASA detection absorbance, you can draw cells survival state.
As a result as shown in figure 3, result is shown, as SCNS concentration gradually increases, the survival rate reduction of liver cancer cells, and
Trend is basically identical with Sorafenib, shows that SCNS produced by the present invention equally has good antihepatocarcinoma effect.
Finally illustrate, preferred embodiment above is merely illustrative of the technical solution of the present invention and unrestricted, although logical
Cross above preferred embodiment the present invention is described in detail, it is to be understood by those skilled in the art that can be
Various changes are made to it in form and in details, without departing from claims of the present invention limited range.
Claims (10)
1. a kind of amphiphilic nano medicine, it is characterised in that：Its structure is A-B-L-D, and wherein A is hydrophilic radical, is selected fromOr PEG200~10000；B is N is 1~10 positive integer；L for can cleavable groups, be selected from D is hydrophobic drug,
It is selected fromAdriamycin, camptothecine, gemcitabine, Irinotecan, Japanese yew
Alcohol or triptolide.
2. amphiphilic nano medicine according to claim 1, it is characterised in that：PEG200~10000 are straight chain
PEG200~10000, side chain PEG200~10000 or 3-8 arms PEG200~10000.
3. amphiphilic nano medicine according to claim 1, it is characterised in that：It is described can cleavable groups be
4. amphiphilic nano medicine according to claim 1, it is characterised in that：The hydrophobic drug is selected from
5. amphiphilic nano medicine according to claim 1 or claim 2, it is characterised in that：Its structure is T-A-B-L-D forms, its
Middle T is targeting group, selected from galactolipin, LHRH, lactose or folic acid.
6. amphiphilic nano medicine described in claim 1 or 2, it is characterised in that its structure is as shown in formula II：
Described a, b and c be hydrogen,
7. the preparation method of any one of the claim 1~6 amphiphilic nano medicine, it is characterised in that comprise the following steps：
(1) disulfide bond that can be broken is connected on the PEG of amino functional by Michael addition reaction, prepares end work(
It can change and with amphipathic PEG molecules；
(2) hydrogen on the amide groups of step (1) amphipathic the PEG molecules and hydrophobic drug is reacted, so as to obtain
Amphiphilic nano medicine.
8. the preparation method of amphiphilic nano medicine according to claim 7, it is characterised in that：The hydrophobic drug is selected fromAdriamycin, camptothecine, gemcitabine, Irinotecan, taxol or
Triptolide.
9. the preparation of any one of the claim 1~6 amphiphilic nano medicine and its application in treatment tumour.
10. application according to claim 9, it is characterised in that：The amphiphilic nano medicine is that Sorafenib is amphipathic
Nano medication, the tumour is liver cancer.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108578712A (en) * | 2018-05-14 | 2018-09-28 | 杭州市肿瘤医院 | A kind of polymer-drug conjugate and preparation method thereof |
| CN108653748A (en) * | 2018-06-06 | 2018-10-16 | 北京林业大学 | A kind of triptolide-multi-arm polyethylene glycol-Hydroxycamptothecin conjugates nano-particle and preparation method thereof |
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| CN105457038A (en) * | 2015-11-09 | 2016-04-06 | 东南大学 | Quick release type medicine phosphatide compound and medicine composition thereof |
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2017
- 2017-05-31 CN CN201710397627.9A patent/CN107158399B/en not_active Expired - Fee Related
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| US20150231271A1 (en) * | 2014-02-19 | 2015-08-20 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Formulations and carrier systems including farnesylthiosalycylic moities |
| CN105457038A (en) * | 2015-11-09 | 2016-04-06 | 东南大学 | Quick release type medicine phosphatide compound and medicine composition thereof |
| CN106620717A (en) * | 2016-12-13 | 2017-05-10 | 上海交通大学 | Amphipathic conjugate anti-tumor nano-drug with function of reversing multidrug resistance of tumors and preparation method and application thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108578712A (en) * | 2018-05-14 | 2018-09-28 | 杭州市肿瘤医院 | A kind of polymer-drug conjugate and preparation method thereof |
| CN108578712B (en) * | 2018-05-14 | 2021-08-24 | 宁波市杭州湾医院 | Polymer-drug conjugate and preparation method thereof |
| CN108653748A (en) * | 2018-06-06 | 2018-10-16 | 北京林业大学 | A kind of triptolide-multi-arm polyethylene glycol-Hydroxycamptothecin conjugates nano-particle and preparation method thereof |
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