CN1634591A - Short peptide modified polylysine-polylactic copolymer nano particle and its preparation method and use - Google Patents
Short peptide modified polylysine-polylactic copolymer nano particle and its preparation method and use Download PDFInfo
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- CN1634591A CN1634591A CNA2004100680618A CN200410068061A CN1634591A CN 1634591 A CN1634591 A CN 1634591A CN A2004100680618 A CNA2004100680618 A CN A2004100680618A CN 200410068061 A CN200410068061 A CN 200410068061A CN 1634591 A CN1634591 A CN 1634591A
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Abstract
The invention belongs to nanometer technology field. A short peptide modified nanometer of polylysine-poly lactic acid copolymer is disclosed. The nanometer particle comprises medicine and nanometer particle carrier of polylysine-poly lactic acid copolymer modified by arginyl-glycyl-aspartyl sequence short peptide. The nanometer carrier material can be used as organic drug, water soluble drug or water insoluble drug. The preparation process is simple and is suitable for mass production especially for preparing the targeted tumor resistant drug.
Description
Technical field
The invention belongs to field of nanometer technology.Be specifically related to short peptide modified polylysine-polylactic copolymer nano particle and preparation method thereof and the purposes in medicine.
Background of invention:
Nineteen ninety Weidner adopts the endothelial cell surface label to show the breast carcinoma new vessels, finds that tumor vessel density (MVD) is relevant with tumor invasion, lymphatic metastasis, patient's prognosis. and after this MVD and tumor invasion relations of metastasis are proved in many tumors.The therapeutic intervention of anti-angiogenic formation also is in clinical experimental stage.First entered the anti-neovascularization medicaments interferon (α IFN α) of clinical trial in 1989, and existing so far 13 kinds of these medicines are carrying out the clinical trial of II-III phase.Agniostatin and Endostatin are the strongest angiogenesis inhibitors, are reported by the Falkman laboratory 1994 and 1997 respectively.U.S. FDA approved Endostatin entered the I clinical trial phase in 1999.But the use of medicine needs to take for a long time even all the life, and this can make troubles and financial burden to the patient, explores the direction that the method for putting things right once and for all also is vascularization research.
Pair cell identification both at home and abroad and adherent Study on Molecular Mechanism have obtained very big progress in recent years, wherein to containing arginyl-glycyl-aspartoyl (Arg-Gly-Asp, RGD) sequence is tens kinds of receptors of integral plasma membrane protein and extracellular matrix such as collagen at the noticeable .RGD of the report aspect cell recognition and the adhesion, identification of parts such as vascular cell adhesion molecule and bonded aminoacid minmal sequence. under certain condition, the solubility micromolecule polypeptide of the RGD sequence of synthetic can combine with the integral protein of cell surface competitively, extracellular information is imported in the cell, causing a series of physiological change of cell. existing in the world a lot of scholars did a large amount of experiments, research RGD sequence peptide suppresses the angiogenesis of malignant tumor and suppresses its growth and shift, and confirms that RGD sequence peptide has the effect of direct killing tumor cell and inducing apoptosis of tumour cell.
There is researcher that RDG class polypeptide is directly used in tumor treatment.Though containing the RGD sequences polypeptide can be various integral protein and discerns, but RGD sequence peptide is unstable in vivo, these polypeptide are decomposed rapidly in vivo and remove, need the heavy dose of ability of multiple injection anticancer to shift, this becomes the unfavorable factor of such polypeptide as practicality antitumor cell diversion medicaments.Though escalated dose can improve blood drug level, in blood, can not urinated row rapidly by the medicine of phosphorylation, not only can not improve curative effect, produce nephrotoxicity on the contrary, and be not killed by the tumor cell that the RGD sequence is sealed, the long duration of still can surviving in vivo, still can cause the transfer of tumor.
Also there is researcher to prepare the conjugate of its Polyethylene Glycol, chitin, wishes to strengthen its anticancer cell transfer effect by prolonging in its body action time.But these conjugates are linearity molecular structure, and very easily degraded in case RGD sequence peptide comes off, still can cause the transfer of tumor in vivo.
Liposome has obtained relatively extensive studies as a kind of pharmaceutical carrier, can there be the sufficiently long time in the spatial stability liposome that includes the PEG quasi-grease derivative and brings into play curative effect in blood circulation. surface combination the liposome of RGD sequence peptide sequence drug targeting can be discharged in the pathological tissues, significantly reducing the toxicity of other tissue and improved curative effect. the easiest preparation of liposome the most difficultly also reaches the Quality Control requirement.Though still use liposome on many documents, the tropism is poor because of the body internal target, uses in vivo, except that the tumor intratumor injection, its prospect still has problems.In addition, certain difficulty is also arranged in Quality Control.
Medical Center of Fudan University's liver cancer research has carried out the experimentation of IFNaIb treatment planting property hepatocarcinoma etc., and the result is satisfactory.But whole body is administered systemically, and tumor inhibition effect is weakened and side reaction arranged.
Studies show that bioactive short peptide RGD can effectively suppress tumor vascular growth, thereby suppress the transfer of tumor cell.At present people have noticed that it treats the using value of neoplasm metastasis clinically.Continue to seek suppress that the adhesion effect is strong, longer duration, to be used for clinical RGD class polypeptide be from now on research direction.
Goal of the invention
Technical problem to be solved by this invention is to select suitable carriers, makes bioactive short peptide can suppress tumor vascular growth effectively.
The invention provides a kind of short peptide modified polylysine-polylactic copolymer nano particle, this nanoparticle comprises that medicine and short peptide modified PL-PL Poly matter makes carrier material.
Another purpose of the present invention has provided a kind of preparation method of short peptide modified polylysine-polylactic copolymer nano particle, this method is with a certain amount of arginyl-glycyl-aspartoyl (Arg-Gly-Asp, RGD) the PL-PL macromolecular material of Xiu Shiing is added in the mixed organic solvents of the dichloromethane (DCM) of certain volume or dichloromethane (DCM)/acetone and constitutes organic facies, getting appropriate amount of drug adds in the organic facies, to form colostrum after its homogenize, colostrum is added to the aqueous phase that deionized water constituted of a certain amount of emulsifying agent and certain volume, emulsifying once more, the gained emulsion was stirred the evaporation organic solvent 1～5 hour, make the organic solvent volatilization fully, promptly get the dispersion of short peptide modified PL-PL Poly (GD-PL-PL) nanoparticle, add or do not add an amount of caffolding agent in colloid solution, conventional lyophilizing is preserved.
Nanoparticulate carriers material of the present invention is with a series of different molecular weights and the Different L-lactic Acid material with-L-lysine ratio and different RGD content, and its molecular weight is 4.0 * 10
3～6.0 * 10
4L-lacticAcid with-the L-lysine ratio is 100: 1-50: 50; RGD content is 0～50%.Its organic solvent is the mixed liquor of ethyl acetate, dichloromethane (DCM) or dichloromethane and acetone (AC), and the volume ratio of DCM and AC is 60～100/0～40.
Water dispersion medium of the present invention is dextran 40 or dextran 70 or pluronic F68, and its concentration is 0.1～5%.Its homogenize mode comprises ultrasonic emulsification, the even mode of high pressure breast.Caffolding agent comprises glucose, lactose or mannose etc., and its content is 0.1～5%.
Another object of the present invention has provided the application of short peptide modified PL-PL Poly in the preparation nano-grade medicine.
PL-PL Poly (the Poly (L-lacticAcid-co-L-lysine) that small peptide provided by the invention (RGD) is modified.This macromolecular material is good pharmaceutical carrier, utilize this material packaging medicine, prepare slow release nano-particle under mechanical agitation or the effect of high pressure dispersing emulsification machine, particle diameter is controlled below 10～1000nm, smooth surface, good evenness, regular particles does not have adhesion, and redispersibility is good, drug loading and envelop rate height, can be used for preparing the slow release nano-particle of vein or intramuscular injection or oral administration, as the cancerous cell target administration.
Medicine of the present invention is an organic drug, water soluble drug or water-insoluble drug anticarcinogen are as anti-folic acid class (as methotrexate), anti-purine class (as mercaptopurine), anti-miazines is (as fluorouracil, ftorafur), nucleotide reducing enzyme inhibitor (as hydroxyurea), deoxyribonucleotide polymerase depressant (as ancitabine), directly the medicine of influence and destruction dna structure and function thereof is (as chlormethine, cyclophosphamide, formylmerphalan, cisplatin, mitomycin, camptothecine), the synthetic medicine of Profilin matter is (as amycin, the L-asparaginase, daunorubicin, mithramycin), influence the medicine (vinblastine that microtubular protein assembling and spindle fiber form, etoposide).
Description of drawings:
Fig. 1 RGD-PL-PL slow release nano-particle particle size distribution figure.
Fig. 2 RGD-PL-PL slow release nano-particle transmission electron microscope (JEM-100SX transmission electron microscope, NEC company) figure.
The specific embodiment:
Below again with embodiment to the present invention's further instruction in addition, but can not limit content of the present invention.
Accurately take by weighing RGD-PL-PL 500mg, be added to and constitute organic facies in the acetone.Fluorouracil or mitoxantrone (DHAQ) 25mg be dissolved in form water in the distilled water.To form colostrum after its homogenize in fluorouracil or the DHAQ solution adding organic facies.Take by weighing pluronic F68 and add in the distilled water it is fully dissolved, regulating and making its concentration is 3%, constitutes outer water.Interior water is 1: 4～1: 8 with the volume ratio of outer water.Colostrum is added to outer aqueous phase, and the emulsifying of high pressure dispersing emulsification machine was evaporated organic solvent 4～5 hours with gained emulsion magnetic agitation, made the acetone volatilization fully, promptly got the dispersion of RGD-PL-PL nanoparticle.The mannose of adding 3% is as caffolding agent, and conventional lyophilizing is preserved.
Accurately take by weighing RGD-PL-PL50mg, be added to that (volume ratio of DCM and AC is 60～100/1～40) constitutes organic facies in the mixed organic solvents of dichloromethane (DCM) and acetone.Fluorouracil or mitoxantrone (DHAQ) 2mg be dissolved in form water in the distilled water.To form colostrum after its homogenize in fluorouracil or the DHAQ solution adding organic facies.Take by weighing dextran 70 and add in the distilled waters it is fully dissolved, regulating and making its concentration is 1%, constitutes outer water.Colostrum is added to outer aqueous phase, and ultrasonic emulsification 30s puts into beaker with the gained emulsion, and magnetic agitation evaporation organic solvent 3 hours makes the volatilization of dichloromethane and acetone fully, promptly gets the dispersion of RGD-PL-PL nanoparticle.The mannose of adding 3% is as caffolding agent, and conventional lyophilizing is preserved.
Embodiment 3
Accurately take by weighing RGD-PL-PL100mg, be added to and constitute organic facies in the acetone.Mitoxantrone (DHAQ) 5mg is dissolved in forms water in the distilled water.To form colostrum after its homogenize in the DHAQ solution adding organic facies.Take by weighing dextran 40 and add in the distilled waters it is fully dissolved, regulating and making its concentration is 1%, constitutes outer water.Colostrum is added to outer aqueous phase, and the emulsifying of high pressure dispersing emulsification machine was evaporated organic solvent 1～5 hour with gained emulsion magnetic agitation, made the acetone volatilization fully, promptly got the dispersion of RGD-PL-PL nanoparticle.The lactose of adding 3% is as caffolding agent, and conventional lyophilizing is preserved.
Claims (9)
1, a kind of short peptide modified polylysine-polylactic copolymer nano particle is characterized in that this nanoparticle comprises as the medicine of active ingredient with by the carrier material of doing of the short peptide modified PL-PL Poly of arginyl-glycyl-aspartoyl sequence.
2, a kind of short peptide modified polylysine-polylactic copolymer nano particle according to claim 1 is characterized in that wherein said medicine is organic drug, water soluble drug and water-insoluble cancer therapy drug.
3, a kind of short peptide modified polylysine-polylactic copolymer nano particle according to claim 1, its spy is wherein said carrier material lysine, lactic acid and the short peptide modified PL-PL Poly of arginyl-glycyl-aspartoyl, and molecular weight is 4.0 * 10
3～6.0 * 10
4Lysine/lactic acid is 100～50: 0～50; Small peptide content is 0.001～50%; Nanometer particle size is at 10～1000nm.
4, a kind of preparation method of short peptide modified polylysine-polylactic copolymer nano particle as claimed in claim 1, it is characterized in that this method is a certain amount ofly to be added to ethyl acetate by arginyl-glycyl-aspartoyl short peptide modified polylysine and polylactic acid macromolecular material, dichloromethane, or constitute organic facies in the mixed organic solvents of dichloromethane and acetone, getting appropriate amount of drug adds in the organic facies, to form colostrum after its homogenize, colostrum is added to the aqueous phase that deionized water constituted of a certain amount of emulsifying agent and certain volume, emulsifying once more, gained emulsion evaporation organic solvent 1～5 hour, make its volatilization fully, promptly get the aqueous dispersion of short peptide modified polylysine-polylactic copolymer nano particle, add or do not add caffolding agent in colloid solution, conventional lyophilizing is preserved;
Wherein polylysine and polylactic acid ratio are 100: 1-100; Described short content is 0.001～50%; Organic solvent is the mixed liquor of ethyl acetate, dichloromethane or dichloromethane and acetone, and volume ratio is 60～100: 1～40;
Described water dispersion medium concentration is 0.1～5% (W/V); Its caffolding agent content is 0.1～5% (W/V).
5, the preparation method of a kind of short peptide modified polylysine-polylactic copolymer nano particle according to claim 4 is characterized in that the homogenize mode comprises that ultrasonic emulsification or high pressure breast are even.
6, the preparation method of a kind of short peptide modified polylysine-polylactic copolymer nano particle according to claim 4 is characterized in that wherein said caffolding agent is to comprise glucose, lactose or mannose.
7, the preparation method of a kind of short peptide modified polylysine-polylactic copolymer nano particle according to claim 4 is characterized in that wherein said disperse medium is dextran 40 or dextran 70 or pluronic F68.
8, the preparation method of a kind of short peptide modified polylysine-polylactic copolymer nano particle according to claim 5, it is characterized in that the even ultransonic intensity of mode colostrum of wherein said high pressure breast is 10～300W, each ultrasonic 5～10 seconds, ultrasonic 1～5 time altogether, the ultransonic intensity of emulsion is 30～600W, each ultrasonic 5～10 seconds, ultrasonic 1～6 time altogether.
9, a kind of purposes of short peptide modified PL-PL Poly nano material as claimed in claim 1 is characterized in that it being the material of preparation medicament sustained-release nano grain.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100404580C (en) * | 2005-11-23 | 2008-07-23 | 上海氯碱化工股份有限公司 | Method for preparing L-lactic acid and amino acid copolymer by melt-solid phase condensation polymerization |
| CN100424112C (en) * | 2007-01-05 | 2008-10-08 | 华南师范大学 | Method for preparing amino acid and lactic acid copolymer |
| CN102008444A (en) * | 2010-11-26 | 2011-04-13 | 北京工业大学 | Preparation method of mitoxantrone-loaded dextran-polylactic acid copolymer nano particles |
| CN102302783A (en) * | 2011-06-28 | 2012-01-04 | 上海市普陀区中心医院 | Bufalin-loaded cyclic peptide-modified polyethylene glycol-polylactic acid hydroxyl glycolic acid-polylysine nanoparticles |
| WO2012159263A1 (en) * | 2011-05-24 | 2012-11-29 | Dai Lijun | Enzyme-degradable polymer and application thereof |
| WO2015032207A1 (en) * | 2013-09-09 | 2015-03-12 | 中国科学院宁波材料技术与工程研究所 | Active targeting antitumor drug and preparation method therefor |
-
2004
- 2004-11-11 CN CNA2004100680618A patent/CN1634591A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100404580C (en) * | 2005-11-23 | 2008-07-23 | 上海氯碱化工股份有限公司 | Method for preparing L-lactic acid and amino acid copolymer by melt-solid phase condensation polymerization |
| CN100424112C (en) * | 2007-01-05 | 2008-10-08 | 华南师范大学 | Method for preparing amino acid and lactic acid copolymer |
| CN102008444A (en) * | 2010-11-26 | 2011-04-13 | 北京工业大学 | Preparation method of mitoxantrone-loaded dextran-polylactic acid copolymer nano particles |
| WO2012159263A1 (en) * | 2011-05-24 | 2012-11-29 | Dai Lijun | Enzyme-degradable polymer and application thereof |
| CN102958938A (en) * | 2011-05-24 | 2013-03-06 | 戴立军 | Enzyme-degradable polymer and application thereof |
| CN102958938B (en) * | 2011-05-24 | 2014-08-27 | 戴立军 | Enzyme-degradable polymer and application thereof |
| US9200033B2 (en) | 2011-05-24 | 2015-12-01 | Karebay Biochem Inc. | Enzyme-degradable polymer and application thereof |
| CN102302783A (en) * | 2011-06-28 | 2012-01-04 | 上海市普陀区中心医院 | Bufalin-loaded cyclic peptide-modified polyethylene glycol-polylactic acid hydroxyl glycolic acid-polylysine nanoparticles |
| WO2015032207A1 (en) * | 2013-09-09 | 2015-03-12 | 中国科学院宁波材料技术与工程研究所 | Active targeting antitumor drug and preparation method therefor |
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