CN103263674A - Tumor targeting material with tumor penetrating property, preparation method and applications thereof - Google Patents
Tumor targeting material with tumor penetrating property, preparation method and applications thereof Download PDFInfo
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- CN103263674A CN103263674A CN201310166384XA CN201310166384A CN103263674A CN 103263674 A CN103263674 A CN 103263674A CN 201310166384X A CN201310166384X A CN 201310166384XA CN 201310166384 A CN201310166384 A CN 201310166384A CN 103263674 A CN103263674 A CN 103263674A
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Abstract
The present invention relates to a targeting material with a tumor penetrating property. The material is characterized in that the material is a linear block copolymer formed by covalent linkage of three parts such as a targeting polypeptide with a tumor penetrating property, polyethylene glycol and phospholipid, wherein a molar ratio of the targeting polypeptide to the polyethylene glycol to the phospholipid is 1:1:1. The invention further provides a preparation method and applications of the targeting material. The targeting material can be used for preparing tumor targeting liposomes or micelle drug delivery systems so as to provide a tumor penetrating property and increase intratumoral delivery efficiency of the drug delivery system.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to a kind of cancer target material, is that a kind of tumor penetrates peptide modified targeting material and preparation method and application specifically.
Background technology
Tumor is the principal disease that threatens human health and life, and its sickness rate is tangible ascendant trend in recent years.Be the tumor resection primary tumor to the conventional treatments of tumor clinically at present and carry out carrying out systemic chemotherapy or radiotherapy after the lymph cleaning.But surgical operation can not thoroughly be removed tumor cell and neoplasm metastasis lymph node, thereby causes tumor recurrence; After the quiet notes administration of chemotherapeutics, to the tumor tissues non-selectivity, has serious general toxic and side effects; Radiotherapy tends to cause the serious local skin reaction of patient, hemogram variation, local mucous membrane reaction etc.Express on tumor cell or the tumor vascular endothelial cell a series of specific receptors are arranged, the cancer target material that utilizes its ligand modified biocompatible materials and prepare is owing to it can be positioned to the extensive concern that tumor tissues is subjected to researcher by the active targeting in vivo.But because the cancer target performance is poor, drug effect improves problems such as not obvious, present most cancer target materials do not enter clinical practice yet.Therefore, research and development high-performance cancer target material, improve extremely urgent to Targeting Performance and the therapeutic effect of tumor.
The RPAKPAR polypeptide is straight chain seven peptides that obtain by the display technique of bacteriophage screening, and it belongs to a kind of " CendR polypeptide ", namely has R/K-X-X-R/K structure (wherein X represents any one aminoacid) at the C end.This class polypeptide belongs to " tumor penetrating peptide ", and many existing cancer target polypeptide all meet this structure, as LyP-1, F3, iRGD etc.Studies show that RPAKPAR is gliomatous ligands specific, show tumor cell and tumor vascular dual affinity.Can make its target tumor blood vessel wall to tumor vascular affinity, and can making it penetrate the tumor vessel wall, the tumor penetrance penetrates into tumor tissues inside, affinity to tumor cell can make it be combined with tumor cell specific, therefore as targeted molecular, this class polypeptide is compared with general tumor cell targeted molecular has more obvious advantage.Prove that at present the RPAKPAR polypeptide has the mediation phage and penetrates the ability that tumor vessel enters tumor tissues inside, but Shang Weijian utilizes the report of the peptide modified targeting material of RPAKPAR.
Summary of the invention
In order to overcome the deficiencies in the prior art, the invention provides a kind of have tumor penetration performance cancer target material and preparation method and application.
A kind of targeting material with tumor penetration performance, it is characterized in that, this material be by the target polypeptide with tumor penetration performance, Polyethylene Glycol and phospholipid three parts by the covalently bound linear block copolymers that forms, wherein the mol ratio of target polypeptide, Polyethylene Glycol and phospholipid is 1:1:1.
Described aminoacid sequence with target polypeptide of tumor penetration performance is RPAKPAR.
The weight average molecular weight of described Polyethylene Glycol is 2000 ~ 5000.
Described phospholipid is a kind of in DSPE (DSPE), two palmityl PHOSPHATIDYL ETHANOLAMINE (DPPE), DOPE (DOPE), hydrogenated soya phosphatide acyl ethanolamine (HSPE), hydrogenation egg phosphatide acyl ethanolamine, soybean phospholipid acyl ethanolamine, the egg phosphatide acyl ethanolamine.
The complex that described target polypeptide is formed by connecting by covalent bond form and Polyethylene Glycol-phospholipid.
Described target polypeptide provides a free sulfhydryl groups, and Polyethylene Glycol-phospholipid provides a dimaleoyl imino, and both specific reaction take place and connect into covalent complex.
A kind of method for preparing above-mentioned targeting material, it is characterized in that, the concrete steps of this method are: adopt the synthetic C of solid-phase polypeptide synthetic method to hold the target polypeptide (aminoacid sequence is CRPAKPAR) of external cysteine (Cys), it is dissolved in the phosphate buffer (PBS) of pH7.0, get maleimide-Polyethylene Glycol-phosphatide complexes (Mal-PEG-PE) and be dissolved in dimethyl formamide (DMF), both mix the back stirring reaction and react completely to Mal-PEG-PE, remove excessive polypeptide and DMF, lyophilization, obtain target polypeptide-Polyethylene Glycol-phosphatide complexes, namely have the targeting material of tumor penetration performance.
The described application of targeting material in pharmaceutical carriers such as preparation liposome, micelle with tumor penetration performance.
Above-mentioned targeting material can be used to prepare pharmaceutical carriers such as liposome with tumor penetration performance, micelle, be expelled in the lotus tumor mouse body after, penetrable tumor vessel penetrates into tumor tissues inside, realizes the efficient targeting drug delivery to tumor.The present invention adopts tumor penetrating peptide RPAKPAR decorated phospholipid to obtain having the targeting material RPAKPAR-PEG-PE of tumor penetration performance, can be used to prepare cancer target liposome or micelle.
The targeting material of the present invention's protection can be used for preparing cancer target liposome or micelle delivery system, gives its tumor penetration performance, improves the interior transmission efficiency of tumor of delivery system.
Description of drawings
The 1H-NMR collection of illustrative plates of accompanying drawing 1, RPAKPAR-PEG-DSPE.
A is the nuclear magnetic spectrum of Mal-PEG-DSPE among the figure, and B is RPAKPAR
-The nuclear magnetic spectrum of PEG-DSPE, as can be seen from Figure, A figure demonstrates the maleimide peak, and this peak disappears among the B figure, and all the other peaks remain unchanged substantially, show that the maleimide base group among the Mal-PEG-DSPE reacts with CRPAKPAR.
Accompanying drawing 2, the fluorescein-labelled liposome that utilizes RPAKPAR-PEG-DSPE to prepare are absorbed photo by tumor cell.
Utilize fluorescein-labelled liposome that RPAKPAR-PEG-DSPE prepares and common fluorescein-labelled liposome in 37 ℃ respectively with the fluorescence micrograph of U87 tumor cell effect after 2 hours, as seen from the figure, tumor cell to the intake of RPAKPAR modified liposome much larger than conventional liposome.
The specific embodiment
To help further to understand the present invention by following embodiment, but not limit content of the present invention.
Embodiment 1: synthetic, the purification of targeting material RPARPAR-PEG-DSPE and sign.
Be tertbutyloxycarbonyl-arginine (p-toluenesulfonyl)-acetparaminosalol benzyl ester of 0.6mmol/g with substitution value) oc-Arg (Tos)-PAM resin N, dinethylformamide DMF swelling is drained, and reuse trifluoroacetic acid TFA sloughs the Boc protecting group, take out TFA, wash with DMF; With BTA-N, N, N', DMF solution and the N of N'-tetramethylurea hexafluorophosphate HBTU, N-diisopropylethylamine DIEA activates tertbutyloxycarbonyl-alanine Boc-Ala, gets the Boc-Ala activating solution; With the Boc-Ala activating solution of the resin adding gained after the DMF washing, 25 ℃ of joltings were reacted 25 minutes, took out dereaction liquid, and used the DMF washing resin; Repeat above steps, connect all the other aminoacid in turn by the CRPAKPAR sequence; Reaction finishes back washing resin, TFA deprotection base, behind the vacuum drying, puts into polypeptide cutting pipe, adds an amount of P-cresol, feeds HF then, ice bath stirring reaction 1 hour; Reaction finishes the back decompression and takes out HF in the pipe, and residual liquid is with an amount of ice ether sedimentation, filter precipitation and with icing the ether washing precipitation; Precipitation with the TFA dissolving, filters to get filtrate again; Filtrate is precipitated in the ice ether again, filters, and filtering residue redissolves with water, and lyophilizing gets the pure product of CRPAKPAR; Get then in the 2ml PBS solution that the pure product 50mg of CRPAKPAR is dissolved in pH7.0, getting maleimide-Polyethylene Glycol-phosphatide complexes Mal-PEG-DSPE(molar equivalent is 0.8 times of CRPAKPAR) be dissolved in DMF, stirring reaction reacts completely to Mal-PEG-DSPE, remove excessive CRPARPAR and DMF, lyophilization, obtain RPARPAR-PEG-DSPE, NMR characterizes its structure, the result shows, the Mal-PEG-DSPE collection of illustrative plates shows the characteristic peak of Mal at the 6.67ppm place, and this peak disappears on the RPARPAR-PEG-DSPE collection of illustrative plates, illustrates that RPARPAR-PEG-DSPE synthesizes successfully.
Embodiment 2: synthetic, the purification of targeting material RPARPAR-PEG-HSPE and sign.
Be tertbutyloxycarbonyl-arginine (p-toluenesulfonyl)-acetparaminosalol benzyl ester of 0.6mmol/g with substitution value) oc-Arg (Tos)-PAM resin N, dinethylformamide DMF swelling is drained, and reuse trifluoroacetic acid TFA sloughs the Boc protecting group, take out TFA, wash with DMF; With BTA-N, N, N', DMF solution and the N of N'-tetramethylurea hexafluorophosphate HBTU, N-diisopropylethylamine DIEA activates tertbutyloxycarbonyl-alanine Boc-Ala, gets the Boc-Ala activating solution; With the Boc-Ala activating solution of the resin adding gained after the DMF washing, 25 ℃ of joltings were reacted 25 minutes, took out dereaction liquid, and used the DMF washing resin; Repeat above steps, connect all the other aminoacid in turn by the CRPAKPAR sequence; Reaction finishes back washing resin, TFA deprotection base, behind the vacuum drying, puts into polypeptide cutting pipe, adds an amount of P-cresol, feeds HF then, ice bath stirring reaction 1 hour; Reaction finishes the back decompression and takes out HF in the pipe, and residual liquid is with an amount of ice ether sedimentation, filter precipitation and with icing the ether washing precipitation; Precipitation with the TFA dissolving, filters to get filtrate again; Filtrate is precipitated in the ice ether again, filters, and filtering residue redissolves with water, and lyophilizing gets the pure product of CRPAKPAR; Get then in the 2ml PBS solution that the pure product 50mg of CRPAKPAR is dissolved in pH7.0, getting maleimide-Polyethylene Glycol-phosphatide complexes Mal-PEG-HSPE(molar equivalent is 0.8 times of CRPAKPAR) be dissolved in DMF, stirring reaction reacts completely to Mal-PEG-HSPE, remove excessive CRPARPAR and DMF, lyophilization, obtain RPARPAR-PEG-HSPE, NMR characterizes its structure, the result shows, the Mal-PEG-HSPE collection of illustrative plates shows the characteristic peak of Mal at the 6.67ppm place, and this peak disappears on the RPARPAR-PEG-HSPE collection of illustrative plates, illustrates that RPARPAR-PEG-HSPE synthesizes successfully.
Embodiment 3: synthetic, the purification of targeting material RPARPAR-PEG-DOPE and sign.
Be tertbutyloxycarbonyl-arginine (p-toluenesulfonyl)-acetparaminosalol benzyl ester of 0.6mmol/g with substitution value) oc-Arg (Tos)-PAM resin N, dinethylformamide DMF swelling is drained, and reuse trifluoroacetic acid TFA sloughs the Boc protecting group, take out TFA, wash with DMF; With BTA-N, N, N', DMF solution and the N of N'-tetramethylurea hexafluorophosphate HBTU, N-diisopropylethylamine DIEA activates tertbutyloxycarbonyl-alanine Boc-Ala, gets the Boc-Ala activating solution; With the Boc-Ala activating solution of the resin adding gained after the DMF washing, 25 ℃ of joltings were reacted 25 minutes, took out dereaction liquid, and used the DMF washing resin; Repeat above steps, connect all the other aminoacid in turn by the CRPAKPAR sequence; Reaction finishes back washing resin, TFA deprotection base, behind the vacuum drying, puts into polypeptide cutting pipe, adds an amount of P-cresol, feeds HF then, ice bath stirring reaction 1 hour; Reaction finishes the back decompression and takes out HF in the pipe, and residual liquid is with an amount of ice ether sedimentation, filter precipitation and with icing the ether washing precipitation; Precipitation with the TFA dissolving, filters to get filtrate again; Filtrate is precipitated in the ice ether again, filters, and filtering residue redissolves with water, and lyophilizing gets the pure product of CRPAKPAR; Get then in the 2ml PBS solution that the pure product 50mg of CRPAKPAR is dissolved in pH7.0, getting maleimide-Polyethylene Glycol-phosphatide complexes Mal-PEG-DOPE(molar equivalent is 0.8 times of CRPAKPAR) be dissolved in DMF, stirring reaction reacts completely to Mal-PEG-DOPE, remove excessive CRPARPAR and DMF, lyophilization, obtain RPARPAR-PEG-DOPE, NMR characterizes its structure, the result shows, the Mal-PEG-DOPE collection of illustrative plates shows the characteristic peak of Mal at the 6.67ppm place, and this peak disappears on the RPARPAR-PEG-DOPE collection of illustrative plates, illustrates that RPARPAR-PEG-DOPE synthesizes successfully.
Embodiment 4: synthetic, the purification of targeting material RPARPAR-PEG-DPPE and sign.
Be tertbutyloxycarbonyl-arginine (p-toluenesulfonyl)-acetparaminosalol benzyl ester of 0.6mmol/g with substitution value) oc-Arg (Tos)-PAM resin N, dinethylformamide DMF swelling is drained, and reuse trifluoroacetic acid TFA sloughs the Boc protecting group, take out TFA, wash with DMF; With BTA-N, N, N', DMF solution and the N of N'-tetramethylurea hexafluorophosphate HBTU, N-diisopropylethylamine DIEA activates tertbutyloxycarbonyl-alanine Boc-Ala, gets the Boc-Ala activating solution; With the Boc-Ala activating solution of the resin adding gained after the DMF washing, 25 ℃ of joltings were reacted 25 minutes, took out dereaction liquid, and used the DMF washing resin; Repeat above steps, connect all the other aminoacid in turn by the CRPAKPAR sequence; Reaction finishes back washing resin, TFA deprotection base, behind the vacuum drying, puts into polypeptide cutting pipe, adds an amount of P-cresol, feeds HF then, ice bath stirring reaction 1 hour; Reaction finishes the back decompression and takes out HF in the pipe, and residual liquid is with an amount of ice ether sedimentation, filter precipitation and with icing the ether washing precipitation; Precipitation with the TFA dissolving, filters to get filtrate again; Filtrate is precipitated in the ice ether again, filters, and filtering residue redissolves with water, and lyophilizing gets the pure product of CRPAKPAR; Get then in the 2ml PBS solution that the pure product 50mg of CRPAKPAR is dissolved in pH7.0, getting maleimide-Polyethylene Glycol-phosphatide complexes Mal-PEG-DPPE(molar equivalent is 0.8 times of CRPAKPAR) be dissolved in DMF, stirring reaction reacts completely to Mal-PEG-DPPE, remove excessive CRPARPAR and DMF, lyophilization, obtain RPARPAR-PEG-DPPE, NMR characterizes its structure, the result shows, the Mal-PEG-DPPE collection of illustrative plates shows the characteristic peak of Mal at the 6.67ppm place, and this peak disappears on the RPARPAR-PEG-DPPE collection of illustrative plates, illustrates that RPARPAR-PEG-DPPE synthesizes successfully.
Embodiment 5: the preparation of liposome and tumor cell in vitro picked-up experiment thereof.
Liposome membrane material prescription consists of the HSPC(hydrogenated soya phosphatide)/the Chol(cholesterol)/mPEG-DSPE(Polyethylene Glycol-DSPE complex) (55:45:2, mol/mol), the PEG liposome membrane material prescription that RPARPAR modifies for HSPC/Chol/mPEG-DSPE/RPARPAR-PEG-DSPE (55:45:2:0.5, mol/mol).Take by weighing above-mentioned membrane material and be dissolved in chloroform, the decompression rotary evaporation is removed organic solvent, gets even lipid film, vacuum drying 24 hours.Add FAM aqueous solution aquation, 60 ℃ of water-baths were shaken 2 hours, got liposome turbid liquor.In 60 ℃ of water-baths, use miniature extruder successively liposome to be pushed 400,200,100 and the 50nm nucleopore membranes, its particle diameter is reduced.Be that eluent is crossed sephadex G-50 chromatographic column and separated and to remove non-encapsulated FAM then with the normal saline, get liposome.Two kinds of liposomees and tumor cell are hatched 4h altogether, inhale and abandon supernatant, and PBS cleans, laser confocal microscope observation of cell liposome picked-up situation.The result shows that conventional liposome is ingested hardly, and the liposome that RPARPAR modifies illustrates that then by huge uptake the targeting material RPARPAR-PEG-DSPE that RPARPAR modifies has given the external targeting of liposome to tumor cell.
Claims (8)
1. targeting material with tumor penetration performance, it is characterized in that, this material be by the target polypeptide with tumor penetration performance, Polyethylene Glycol and phospholipid three parts by the covalently bound linear block copolymers that forms, wherein the mol ratio of target polypeptide, Polyethylene Glycol and phospholipid is 1:1:1.
2. according to the described targeting material with tumor penetration performance of claim 1, it is characterized in that described aminoacid sequence with target polypeptide of tumor penetration performance is RPAKPAR.
3. according to the described targeting material with tumor penetration performance of claim 1, it is characterized in that the weight average molecular weight of described Polyethylene Glycol is 2000 ~ 5000.
4. according to the described targeting material with tumor penetration performance of claim 1, it is characterized in that described phospholipid is a kind of in DSPE (DSPE), two palmityl PHOSPHATIDYL ETHANOLAMINE (DPPE), DOPE (DOPE), hydrogenated soya phosphatide acyl ethanolamine (HSPE), hydrogenation egg phosphatide acyl ethanolamine, soybean phospholipid acyl ethanolamine, the egg phosphatide acyl ethanolamine.
5. according to the described targeting material with tumor penetration performance of claim 1, it is characterized in that the complex that described target polypeptide is formed by connecting by covalent bond form and Polyethylene Glycol-phospholipid.
6. according to the described targeting material with tumor penetration performance of claim 1, it is characterized in that, described target polypeptide provides a free sulfhydryl groups, and Polyethylene Glycol-phospholipid provides a dimaleoyl imino, and both specific reaction take place and connect into covalent complex.
7. one kind prepares according to claim 1,2,3,4,5, the method of 6 each described targeting materials, it is characterized in that, the concrete steps of this method are: adopt the synthetic C of solid-phase polypeptide synthetic method to hold the target polypeptide (aminoacid sequence is CRPAKPAR) of external cysteine (Cys), it is dissolved in the phosphate buffer (PBS) of pH7.0, get maleimide-Polyethylene Glycol-phosphatide complexes (Mal-PEG-PE) and be dissolved in dimethyl formamide (DMF), both mix the back stirring reaction and react completely to Mal-PEG-PE, remove excessive polypeptide and DMF, lyophilization, obtain target polypeptide-Polyethylene Glycol-phosphatide complexes, namely have the targeting material of tumor penetration performance.
8. according to the claim 1-6 described application of targeting material in pharmaceutical carriers such as preparation liposome, micelle with tumor penetration performance arbitrarily.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103626993A (en) * | 2013-11-05 | 2014-03-12 | 南京理工大学 | Polyethylene glycol monomethyl ether soybean phosphatidyl ethanolamine derivative and preparation thereof |
| CN103656652A (en) * | 2013-12-10 | 2014-03-26 | 深圳先进技术研究院 | Dual-sensing response type polymer nano-micelle as well as preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102516391A (en) * | 2011-12-23 | 2012-06-27 | 上海纳米技术及应用国家工程研究中心有限公司 | Neuropilin-1 ligand polypeptide-polyethylene glycol-phospholipid composite, its active targeting liposome vector system and preparation method thereof |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102516391A (en) * | 2011-12-23 | 2012-06-27 | 上海纳米技术及应用国家工程研究中心有限公司 | Neuropilin-1 ligand polypeptide-polyethylene glycol-phospholipid composite, its active targeting liposome vector system and preparation method thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103626993A (en) * | 2013-11-05 | 2014-03-12 | 南京理工大学 | Polyethylene glycol monomethyl ether soybean phosphatidyl ethanolamine derivative and preparation thereof |
| CN103626993B (en) * | 2013-11-05 | 2016-01-20 | 南京理工大学 | Polyethylene glycol monomethyl ether soybean phosphatidyl ethanolamine derivative and preparation thereof |
| CN103656652A (en) * | 2013-12-10 | 2014-03-26 | 深圳先进技术研究院 | Dual-sensing response type polymer nano-micelle as well as preparation method and application thereof |
| CN103656652B (en) * | 2013-12-10 | 2015-09-09 | 深圳先进技术研究院 | A kind of sensitive response type polymer nano-micelle and its preparation method and application |
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Application publication date: 20130828 |