CN108273066A - A kind of preparation method for the high targeted nano pharmaceutical carrier and antitumor drug being oriented to structure based on hydroxyl - Google Patents
A kind of preparation method for the high targeted nano pharmaceutical carrier and antitumor drug being oriented to structure based on hydroxyl Download PDFInfo
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- CN108273066A CN108273066A CN201810120740.7A CN201810120740A CN108273066A CN 108273066 A CN108273066 A CN 108273066A CN 201810120740 A CN201810120740 A CN 201810120740A CN 108273066 A CN108273066 A CN 108273066A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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Abstract
The invention belongs to Nano medications and biomedical sector, and in particular to a kind of preparation method for the high targeted nano pharmaceutical carrier and antitumor drug being oriented to structure based on hydroxyl.The present invention provides a new cancer targets to position approach, i.e., acid by the parent of the functional group entrained by pharmaceutical carrier itself, to realize the positioning for acidic cancer environment.In the case where not introducing target biology identification molecule, while reducing Nano medication production cost, preferably maintain the size and structure of nano-carrier, to effectively maintain targeting stationkeeping ability of nanometer enrichment effect for tumour cell, the targeting of constructed nanometer medicine-carried system is further improved.Constructed nanometer antitumor drug is not only demonstrated by efficient cancer target ability, and presents excellent pH controlled-release effects and long-term sustained release ability, can realize that the damage to normal cell is very little while efficiently killing tumour cell.
Description
Technical field
The invention belongs to Nano medications and biomedical sector, and in particular to a kind of high targeting being oriented to structure based on hydroxyl
The preparation method of nano-medicament carrier and antitumor drug.
Background technology
Chemotherapy（Chemotherapy）It is one of Present clinical treating cancer most efficient method, and operation, radiotherapy and claims
Three big means for the treatment of of cancer.Effectively different just for the tumour of therapentic part with operation and radiotherapy, chemotherapy is that a kind of whole body is controlled
Treatment means, chemicals can spread all over whole body with blood circulation.Therefore, there is the tumour and of whole body metastasis tendency for some
The Advanced cancers of transfer, chemotherapy are a kind of main treatment means.But the antitumous effect of current chemotherapeutic needs further
It improves, this is mainly due to classic chemotherapy drugs itself not to have targeting, into after human body, is in systemic distribution, is killing
Human normal cell is inevitably injured while tumour cell, body shows great side effect.Therefore, some are to swollen
Tumor and the antitumor drug that the damage difference of normal tissue cell is little but lethality is strong, clinical application and its limited.
The high speed development of nanotechnology and nano material provides completely newly to develop high anti-tumor drugs targeting delivery system
Approach.Research has shown that new vessels contained in the tumour cell of fast-growth are since fault of construction can cause to leak and damage
Wound property lymph outflows, and what this structure was is merely able to stay position to produce Thief zone retention effect, so as to cause Nano medication energy
It is enough to be enriched in tumor locus.Nanometer enrichment effect so that nanometer medicine-carried system has certain passive target ability, but
In clinical practice application, this targeting ability is still quite faint.Therefore, main in current nanometer medicine-carried system research
If drug such as to be inputted to specific identification target spot to the identification of antibody, receptor, immune molecule by way of bio-identification,
To realize the targeting conveying of drug.However, this approach is due to introducing expensive antibody, receptor or immune molecule,
And reaction process complexity is difficult to control, causes final drug price expensive, the ability to shoulder economically of remote super common patient.While by
In the introducing of added ingredient so that Nano medication size and shape is greatly affected, and is unfavorable for Nano medication penetration cell
Film enters tumour cell, and also results in nanometer enrichment effect by prodigious inhibition.Further, since different tumor targets
Specificity, the novel tumor that these labeling methods are formed after being shifted for tumour cell whole body lack effective targeting means.
Invention content
The present invention a kind of being oriented to the high targeted nano pharmaceutical carrier of structure and anti-swollen in view of the above-mentioned problems, providing based on hydroxyl
The preparation method of tumor medicine.
The technical solution used in the present invention is as follows：
A kind of high targeted nano pharmaceutical carrier being oriented to structure based on hydroxyl, main body are the pharmaceutical carrier with hydroxyl group.
The pharmaceutical carrier forms hydroxyl group in drug carrier material by chemical reaction, by hydroxyl to acid tumor environment
Height targeting ability realizes the efficient positioning for tumour cell in conjunction with nanometer enrichment effect.By hydroxylated pharmaceutical carrier packet
Include but be not limited to graphene, carbon nanotube, molybdenum disulfide, quantum dot, rare earth nanometer particle.
Preferably, the pharmaceutical carrier is hydroxyl graphene.The extra specific surface area and special size of graphene, significantly carry
The high slow release effect of medicine-carried system.
Preferably, the hydroxyl graphene is prepared by following steps：
（1）Graphite powder and potassium hydroxide are mixed and are added in ball grinder, at normal temperatures and pressures, with 200-400 revs/min of speed ball
After grinding 6-10 hour, product is shifted with deionized water；
（2）To take supernatant after 1000 revs/min of speed centrifugation, hydroxyl graphene solution is obtained after dialysis treatment.
The graphene of complicated difficult control is prepared reaction to the present invention and hydroxy functionalized reaction is reduced to a step solid-phase ball milling method,
Any toxic chemical is not used in reaction process, carries out at room temperature, at a normal, has efficient, environmentally friendly, economical, convenient etc.
Advantage.
Preferably, graphite powder and potassium hydroxide powder are with mass ratio 1:5~1:20 ratio mixing.
Preferably, the hydroxylic moiety on the hydroxyl graphene is oxidized to carboxyl and is covalently attached ammonia by amidation process
Base polyethylene glycol.Amino polyethylene glycol is introduced into prepared hydroxyl graphene, the life of graphene-based carrier can be improved
The introducing of object compatibility, polyethylene glycol can further improve the half-life period of bio-pharmaceutical in vivo.
Preferably, the hydroxylic moiety on the hydroxyl graphene is oxidized to carboxyl and is covalently attached ammonia by amidation process
Base polyethylene glycol, is realized especially by following steps：
（1）Sodium hydroxide and bromoacetic acid is taken to be added in hydroxyl graphene solution, stirring, centrifugation, dialysis to solution are in neutrality, and are added
1-（3- dimethylamino-propyls）- 3- ethyl carbodiimides and n-hydroxysuccinimide；
（2）Amino-polyethyleneglycols are added, stir, centrifugation abandons supernatant, obtains polyethylene glycol/graphene nano-grade drug carrier.
The hydroxylic moiety on hydroxyl graphene can also be oxidized to carboxyl by others chemical reaction and pass through amide
Change reaction and is covalently attached amino-polyethyleneglycols.
Preferably, the mass ratio of hydroxyl graphene and amino-polyethyleneglycols is 1:5~1:15.
A kind of high anti-tumor drugs targeting being oriented to structure based on hydroxyl, including above-mentioned high targeted nano pharmaceutical carrier,
Carry broad-spectrum anti-cancer drug.
A kind of preparation method of high anti-tumor drugs targeting, including high targeted nano pharmaceutical carrier, by broad-spectrum anti-tumor medicine
Object is added in high targeted nano pharmaceutical carrier solution, stirs, and centrifugation abandons supernatant, obtains pharmaceutical carrier/broad-spectrum anti-cancer drug and receive
Rice antitumor drug.When high targeted nano pharmaceutical carrier be hydroxyl graphene, can by the stacking power of pi-pi bond connect it is antitumor
Drug molecule builds antitumor drug.Since size is small, structure is special, can be entered by the encytosis of tumour cell thin
Born of the same parents, and the vascular system of tumour is optionally passed through, it improves in the dead time of tumor locus, effectively enhances drug to tumour
The lethality of cell.
Preferably, the broad-spectrum anti-cancer drug is doxorubicin hydrochloride solution, and high targeted nano pharmaceutical carrier solution is added
It is being protected from light lower stirring afterwards.In acidic cancer environment, by the deprotonation of adriamycin to realize that controlled drug discharges, reach
PH controlled-release functions.
Beneficial effects of the present invention are as follows：The present invention provides a new cancer targets to position approach, that is, passes through drug
The parent of functional group entrained by carrier itself is acid, to realize the positioning for acidic cancer environment.Do not introducing targeting life
Object identify molecule in the case of, while reducing Nano medication production cost, preferably maintain nano-carrier size and
Structure further improves institute's structure to effectively maintain targeting stationkeeping ability of nanometer enrichment effect for tumour cell
The targeting for the nanometer medicine-carried system built.Constructed nanometer antitumor drug is not only demonstrated by efficient cancer target ability,
And excellent pH controlled-release effects and long-term sustained release ability are presented, it can realize while efficiently killing tumour cell, to just
The damage of normal cell is very little.The preparation process of nano material uses a step solid-phase ball milling of more economical environmental protection simultaneously
Method effectively reduces the influence of the production cost and its production process of Nano medication for environment, has high social value
And economic value.
Description of the drawings
Fig. 1 is hydroxyl graphene, polyethylene glycol/graphene/adriamycin nano antitumor drug made from present example
And the photo of Doxorubicin solution.
Fig. 2 is the atomic force microscopy diagram of hydroxyl graphene made from present example.
Fig. 3 is hydroxyl graphene and polyethylene glycol/graphene nano carrier infrared spectrogram made from present example.
Fig. 4 is polyethylene glycol/graphene nano carrier, polyethylene glycol/graphene/adriamycin made from present example
Nano medication, the ultraviolet spectrogram with adriamycin.
Fig. 5 is the Transwell cell co-culture systems used in the present invention.
Fig. 6 is Nano medication antitumous effect figure produced by the present invention.
Specific implementation mode
Below in conjunction with the accompanying drawings and specific embodiment, the present invention can be better described.
By graphite powder and potassium hydroxide with mass ratio 1:5~1:20 ratio mixing is added in ball grinder, in normal temperature and pressure
Under, after 200-400 revs/min of 6-10 hour of speed ball milling, product is transferred in sample bottle with deionized water.Then with
Supernatant is taken after 1000 revs/min of speed centrifugation, hydroxyl graphene is obtained after dialysis treatment（GOH）Solution.Take sodium hydroxide and bromine
Acetic acid is added in hydroxyl graphene solution, and stirring, centrifugation, dialysis to solution are in neutrality, and 1- is added（3- dimethylamino-propyls）-3-
Ethyl carbodiimide and n-hydroxysuccinimide；Amino-polyethyleneglycols, the matter of hydroxyl graphene and amino-polyethyleneglycols is added
Amount is than being 1:5~1:15, it stirs at room temperature 24 hours, 5000 revs/min of centrifugations three times, obtain polyethylene glycol/graphene nano medicine
Object carrier.By doxorubicin hydrochloride solution（DOX）, it is added to polyethylene glycol/graphene（PEG-GOH）In solution, it is protected from light stirring 24
Hour, 5000 revs/min, supernatant is abandoned, obtains polyethylene glycol/graphene/adriamycin nano antitumor drug（PEG-GOH-DOX）.
Obtained polyethylene glycol/graphene nano-grade drug carrier, polyethylene glycol/graphene/adriamycin nano are antitumor
Drug, Doxorubicin solution photo as shown in Figure 1, by Fig. 1 it can be seen that prepared hydroxyl graphene and Nano medication is equal
With extraordinary aqueous phase dispersibility.The color of graphene solution is gradually turned from black to kermesinus with the addition of adriamycin
Become.
The atomic force microscopy diagram of prepared hydroxyl graphene is as shown in Fig. 2, from figure 2 it can be seen that prepared
Hydroxyl graphene is in typical graphene sheet layer structure, and thickness is about 1.3 nanometers, shows it for single layer to a small number of several layers of stones
Black alkene structure.
Hydroxyl graphene and polyethylene glycol/graphene nano-grade drug carrier are subjected to infrared spectrum detection, testing result is such as
Shown in Fig. 3.It can be in 3400 cm in hydroxyl graphene spectrogram-1With 1100 cm-1Apparent O-H stretching vibrations are seen at two
Peak and ehter bond functional group.After amino-polyethyleneglycols are covalently accessed, the two peaks in addition to that can see reservation, moreover it is possible to see
The characteristic peak of three polyethylene glycol, i.e. 2900 cm-1(the C-H stretching vibrations in CH2), 1250 cm-1（C-O in C-O-C
Stretching vibration）And 950 cm-1（N-H out-of-plane bending vibrations）.In addition, can also see three of amido bond in this spectrogram
Characteristic feature peak：3400 cm-1(the stretching vibration overlap of peaks of N-H stretching vibrations, the peak and O-H), 1680 cm-1（C=O stretches
Contracting vibration）And 1640 cm-1(N-H bending vibrations), it was confirmed that the successful synthesis of polyethylene glycol/graphene.
By obtained polyethylene glycol/graphene nano carrier, polyethylene glycol/graphene/doxorubicin nanometer medicament and Ah
Mycin carries out ultraviolet spectra detection, and testing result is as shown in Figure 4.In figure it can be seen that, on nano-carrier access adriamycin it
Afterwards, the characteristic peak of adriamycin can be significantly seen at 480 nm, it was confirmed that adriamycin is successfully loaded.
Polyethylene glycol/graphene/adriamycin nano antitumor drug is trained altogether by Transwell cells shown in fig. 5
The system of supporting verifies targeting, and control group is polyethylene glycol/graphene nano-grade drug carrier, adriamycin, in upper and lower two spaces
Cultivate different cells（Choroidal melanomas in eye showed cell (OCM-1) and eye normal retina pigment epithelial cell
（ARPE-19））.Transwell cell co-culture systems make two kinds of cells share cell liquid, but by one layer of perforated membrane every
It opens.The targeting anti-tumor effect of Nano medication can be preferably investigated using the system.It is supported in Transwell when by normal cell
Tumour cell is supported the Nano medication that 10 μ g/mL are added in lower space after 48 hours by upper space, and tumour cell is deposited
Motility rate is less than 10%, but the survival rate of normal cell is 80% or more.Tumour cell under the effect of conventional medicament adriamycin is deposited
50% or more motility rate, and the survival rate of normal cell also only has 40%.Show the constructed efficient target of nanometer antitumor drug
To antitumor effectiveness, the lethality to tumour can be increased to 4 times or more of conventional medicament, but almost for normal cell
There is no lethality.
Example the above is only the implementation of the present invention is not used for limiting the scope of the invention；The protection of the present invention
Range is limited by the claim in claims, and every according to equivalence changes made by invention and modification, all in this hair
Within the protection domain of bright patent.
Claims (10)
1. a kind of high targeted nano pharmaceutical carrier being oriented to structure based on hydroxyl, it is characterised in that：Its main body is with hydroxyl base
The pharmaceutical carrier of group.
2. the high targeted nano pharmaceutical carrier according to claim 1 for being oriented to structure based on hydroxyl, it is characterised in that：It is described
Pharmaceutical carrier is hydroxyl graphene.
3. the high targeted nano pharmaceutical carrier according to claim 2 for being oriented to structure based on hydroxyl, which is characterized in that described
Hydroxyl graphene is prepared by following steps：
（1）Graphite powder and potassium hydroxide are mixed and are added in ball grinder, at normal temperatures and pressures, with 200-400 revs/min of speed ball
After grinding 6-10 hour, product is shifted with deionized water；
（2）To take supernatant after 1000 revs/min of speed centrifugation, hydroxyl graphene solution is obtained after dialysis treatment.
4. the high targeted nano pharmaceutical carrier according to claim 3 for being oriented to structure based on hydroxyl, it is characterised in that：Graphite
Powder and potassium hydroxide powder are with mass ratio 1:5~1:20 ratio mixing.
5. the high targeted nano pharmaceutical carrier according to claim 2 for being oriented to structure based on hydroxyl, it is characterised in that：It is described
Hydroxylic moiety on hydroxyl graphene is oxidized to carboxyl and is covalently attached amino-polyethyleneglycols by amidation process.
6. the high targeted nano pharmaceutical carrier according to claim 5 for being oriented to structure based on hydroxyl, which is characterized in that described
Hydroxylic moiety on hydroxyl graphene is oxidized to carboxyl and is covalently attached amino-polyethyleneglycols by amidation process, especially by
Following steps are realized：
（1）Sodium hydroxide and bromoacetic acid is taken to be added in hydroxyl graphene solution, stirring, centrifugation, dialysis to solution are in neutrality；
（2）1- is added（3- dimethylamino-propyls）The poly- second of amino two is added in -3- ethyl carbodiimides and n-hydroxysuccinimide
Alcohol stirs, and centrifugation abandons supernatant, obtains polyethylene glycol/graphene nano-grade drug carrier.
7. the high targeted nano pharmaceutical carrier according to claim 6 for being oriented to structure based on hydroxyl, it is characterised in that：Hydroxyl
The mass ratio of graphene and amino-polyethyleneglycols is 1:5~1:15.
8. a kind of high anti-tumor drugs targeting being oriented to structure based on hydroxyl, it is characterised in that：Including any one of claim 1-7
The high targeted nano pharmaceutical carrier, carries broad-spectrum anti-cancer drug.
9. a kind of preparation method of high anti-tumor drugs targeting, which is characterized in that received including the high targeting described in claim 2-6
Rice pharmaceutical carrier, broad-spectrum anti-cancer drug is added in high targeted nano pharmaceutical carrier solution, is stirred, and centrifugation is abandoned supernatant, obtained
Pharmaceutical carrier/broad-spectrum anti-cancer drug nanometer antitumor drug.
10. the preparation method of high anti-tumor drugs targeting according to claim 9, it is characterised in that：The wide spectrum is anti-swollen
Tumor medicine is doxorubicin hydrochloride solution, and lower stirring is being protected from light after high targeted nano pharmaceutical carrier solution is added.
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| CN201810120740.7A CN108273066A (en) | 2018-02-07 | 2018-02-07 | A kind of preparation method for the high targeted nano pharmaceutical carrier and antitumor drug being oriented to structure based on hydroxyl |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111892046A (en) * | 2020-06-30 | 2020-11-06 | 重庆交通大学 | Hydroxylated graphene and preparation method and application thereof |
| CN113456672A (en) * | 2021-06-17 | 2021-10-01 | 温州医科大学 | Targeted drug of chemodynamics-enhanced photothermal therapy system for treating malignant tumor and preparation method and application thereof |
-
2018
- 2018-02-07 CN CN201810120740.7A patent/CN108273066A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| MIMI LIN ET AL.: ""Hydroxyl-functional groups on grapheme trigger the targeted delivery of antitumor drugs"", 《JOURNAL OF BIOMEDICAL NANOTECHNOLOGY》 * |
| 麻丽薇: ""羟基石墨烯聚乙二醇载药体系抗脉络膜黑色素瘤的生物评价"", 《万方数据知识服务平台》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111892046A (en) * | 2020-06-30 | 2020-11-06 | 重庆交通大学 | Hydroxylated graphene and preparation method and application thereof |
| CN113456672A (en) * | 2021-06-17 | 2021-10-01 | 温州医科大学 | Targeted drug of chemodynamics-enhanced photothermal therapy system for treating malignant tumor and preparation method and application thereof |
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