CN103316354A - Tumor targeting polypeptide-polyethylene glycol-polylactic acid compound, preparation method thereof and applications thereof - Google Patents
Tumor targeting polypeptide-polyethylene glycol-polylactic acid compound, preparation method thereof and applications thereof Download PDFInfo
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- CN103316354A CN103316354A CN2013101996829A CN201310199682A CN103316354A CN 103316354 A CN103316354 A CN 103316354A CN 2013101996829 A CN2013101996829 A CN 2013101996829A CN 201310199682 A CN201310199682 A CN 201310199682A CN 103316354 A CN103316354 A CN 103316354A
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Abstract
The invention belongs to the technical field of medicinal preparations, and relates to a tumor targeting polymer material, and particularly relates to a tumor targeting polypeptide-polyethylene glycol-polylactic acid compound. The tumor targeting polypeptide has an amino acid sequence of APARPAR, and is a tumor penetrating peptide. The tumor targeting polypeptide-polyethylene glycol-polylactic acid compound (APARPAR-PEG-PLA) provided by the invention is prepared by covalently linking the tumor penetrating peptide (APARPAR) with maleimide-polyethylene glycol-polylactic acid (Mal-PEG-PLA), and can be used for preparing targeted micelles or nanoparticles that have a function of penetrating tumors, and can be used for improving tissue permeability in tumors of the targeted micelles or the targeted nanoparticles.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to a kind of cancer target polypeptide-polyethylene glycol-polylactic acid complex, is a kind of target polymer material with tumor penetration performance specifically.
Background technology
Tumor is to threaten human life and healthy major disease, and the treatment means of tumor mainly contains operation, radiotherapy, chemotherapy and Biotherapeutics etc. at present.Along with the development of science and technology, although treatment means and optional antitumor drug constantly increase, tumor is still at present one of disease that refractory heals.Even if to the effective treatment means of a certain specific tumors, in therapeutic process, also tend to produce very serious toxic and side effects, and can reduce patient's quality of life of end-stage patients especially.The reason that tumor is difficult to cure has a lot, and mostly traditional chemotherapy is cytotoxic drug, and without obvious targeting, toxicity is large, and easily produces drug resistance.Because the surfaces such as the tumor cell in the tumor tissues, tumor vascular endothelial cell, tumor lympha endothelial cell can be expressed some and are different from the specific receptor of normal structure, therefore utilizing with receptor has the ligand modified material of affinity to produce initiatively targeting to tumor tissues.But at present common targeting material still exist targeting efficient low, in tumor the not good problem of transmission effect.Therefore, be badly in need of at present researching and developing high-performance cancer target material, improving targeting efficient and therapeutic effect to tumor.
Neuropilin-1 is at the receptor of being permitted eurypalynous tumor cell and tumor vascular endothelial cell surface high expressed, does not express or low the expression in normal structure.APARPAR is the ligands specific of neuropilin-1, and is a class " tumor penetrating peptide ", and namely APARPAR can mediate connected drug molecule or phage penetrates tumor vessel and tumor tissues, enters tumor tissues inside.Therefore, compare with common target polypeptide, the modification meeting of tumor penetrating peptide further increases by the targeting efficient of trim confrontation tumor tissues and the transmission efficiency in tumor tissues.Have not yet to see the report that utilizes the peptide modified targeting material of APARPAR.
Summary of the invention
In order to overcome the deficiencies in the prior art, the invention provides a kind of cancer target polypeptide-polyethylene glycol-polylactic acid complex and preparation method and application.
A kind of cancer target polypeptide-polyethylene glycol-polylactic acid complex, it is characterized in that, this material is by the covalently bound linear block copolymers that forms by the target polypeptide with tumor penetration performance, Polyethylene Glycol (PEG) and polylactic acid (PLA) three parts, wherein the mol ratio of cancer target polypeptide, Polyethylene Glycol and polylactic acid is 1:1:1, the aminoacid sequence of described cancer target polypeptide is APARPAR, makes complex have the tumor penetration performance.
The weight average molecular weight of described Polyethylene Glycol is 2000 ~ 5000.
The weight average molecular weight of described polylactic acid is 1000 ~ 8000.
The complex that described cancer target polypeptide is formed by connecting by covalent bond form and polyethylene glycol-polylactic acid.
Described cancer target polypeptide provides a free sulfhydryl groups, and polyethylene glycol-polylactic acid provides a dimaleoyl imino, and both additive reaction occur and connect into covalent complex.
A kind of method for preparing cancer target polypeptide-polyethylene glycol-polylactic acid complex, it is characterized in that, concrete steps are as follows: adopt the synthetic C of solid-phase polypeptide synthetic method to hold the target polypeptide (aminoacid sequence is CAPARPAR) of external cysteine (Cys), be dissolved in the phosphate buffer (PBS) of pH7.0 it for subsequent use; Get maleimide-polyethylene glycol-polylactic acid complex (Mal-PEG-PLA) and be dissolved in the acetonitrile, the rotary evaporation film forming adds PBS(pH 8.0,0.2M) forms micelle 37 ℃ of aquations.Excessive CAPARPAR and the reaction of adding spent the night in the 8h, and excessive polypeptide is removed in ultrafiltration (molecular weight 3kDa), and lyophilization obtains target polypeptide-polyethylene glycol-polylactic acid complex.
The application of cancer target polypeptide-polyethylene glycol-polylactic acid complex in the pharmaceutical carriers such as preparation micelle, nanoparticle.
Above-mentioned cancer target polypeptide-polyethylene glycol-polylactic acid complex can be used to prepare the pharmaceutical carriers such as micelle with tumor penetration performance, nanoparticle, intravenous injection in the animal model for tumour body after, show good tumor-targeting and tumor penetration performance.
The present invention adopts tumor penetrating peptide APARPAR to modify PEG-PLA, obtains having the targeting materials A PARPAR-PEG-PLA of tumor penetration performance, can be used to prepare cancer target micelle or nanoparticle.
Description of drawings
The 1H-NMR collection of illustrative plates of accompanying drawing 1, APARPAR-PEG-PLA.
A is the nuclear magnetic spectrum of Mal-PEG-PLA among the figure, B is the nuclear magnetic spectrum of APARPAR-PEG-PLA, 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-PLA reacts with CAPARPAR.
Accompanying drawing 2, the fluorescein micelle that utilizes APARPAR-PEG-PLA to prepare are absorbed photo by tumor cell.
Utilize fluorescein micelle that APARPAR-PEG-PLA prepares and common fluorescein micelle in 37 ℃ respectively with the fluorescence micrograph of U87 tumor cell effect after 2 hours, as seen from the figure, tumor cell is modified the intake of micelle much larger than common micelle to APARPAR.
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 materials A PARPAR-PEG-PLA and sign.
With tertbutyloxycarbonyl-arginine (p-toluenesulfonyl)-acetparaminosalol benzyl ester) Boc-Arg (Tos)-PAM resin is with trifluoroacetic acid (TFA) deprotection 1 minute; twice; the HBTU(solvent that the Boc protected amino acid is dissolved in 0.5M is DMF) in; room temperature reaction 15min; the DMF washing; TFA removes the Boc protection, reacts successively according to aminoacid sequence to connect all aminoacid.Washing resin, TFA Deprotection after reaction finishes behind the vacuum drying, are put into polypeptide cutting pipe, add an amount of P-cresol, then pass into HF, ice bath stirring reaction 1 hour; HF in the pipe was taken out in decompression after reaction finished, and residual liquid is with an amount of ice ether sedimentation, filtered to get 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 CAPARPAR sterling.80mg Mal-PEG-PLA is dissolved in the 10ml acetonitrile, rotary evaporation, film forming adds 6ml PBS(pH 8.0,0.2M) forms micelle 37 ℃ of aquations.The HPLC detection reaction is spent the night in adding 49.2mg CAPARPAR and reaction in the 8h.Excessive CAPARPAR removes by super filter tube (MWCO 3kDa, Millipore), and lyophilizing is for subsequent use.
1H-NMR characterizes structure, result's demonstration, and the Mal-PEG-PLA collection of illustrative plates shows the characteristic peak of Mal at the 6.67ppm place, and this peak disappears on the APARPAR-PEG-PLA collection of illustrative plates, illustrates that APARPAR-PEG-PLA synthesizes successfully.
Embodiment 2: synthetic, the purification of targeting materials A PARPAR-PEG-PLA and sign.
With tertbutyloxycarbonyl-arginine (p-toluenesulfonyl)-acetparaminosalol benzyl ester) Boc-Arg (Tos)-PAM resin is with trifluoroacetic acid (TFA) deprotection 1 minute; twice; the HBTU(solvent that the Boc protected amino acid is dissolved in 0.5M is DMF) in; room temperature reaction 15min; the DMF washing; TFA removes the Boc protection, reacts successively according to aminoacid sequence to connect all aminoacid.Washing resin, TFA Deprotection after reaction finishes behind the vacuum drying, are put into polypeptide cutting pipe, add an amount of P-cresol, then pass into HF, ice bath stirring reaction 1 hour; HF in the pipe was taken out in decompression after reaction finished, and residual liquid is with an amount of ice ether sedimentation, filtered to get 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 CAPARPAR sterling.80mg Mal-PEG-PLA is dissolved in the 10ml acetonitrile, rotary evaporation, film forming adds 18ml PBS(pH 8.0,0.2M) forms micelle 37 ℃ of aquations.The HPLC detection reaction is spent the night in adding 49.2mg CAPARPAR and reaction in the 8h.Excessive CAPARPAR removes by super filter tube (MWCO 3kDa, Millipore), and lyophilizing is for subsequent use.
1H-NMR characterizes structure, result's demonstration, and the Mal-PEG-PLA collection of illustrative plates shows the characteristic peak of Mal at the 6.67ppm place, and this peak disappears on the APARPAR-PEG-PLA collection of illustrative plates, illustrates that APARPAR-PEG-PLA synthesizes successfully.
Embodiment 3: synthetic, the purification of targeting materials A PARPAR-PEG-PLA and sign.
With tertbutyloxycarbonyl-arginine (p-toluenesulfonyl)-acetparaminosalol benzyl ester) Boc-Arg (Tos)-PAM resin is with trifluoroacetic acid (TFA) deprotection 1 minute; twice; the HBTU(solvent that the Boc protected amino acid is dissolved in 0.5M is DMF) in; room temperature reaction 15min; the DMF washing; TFA removes the Boc protection, reacts successively according to aminoacid sequence to connect all aminoacid.Washing resin, TFA Deprotection after reaction finishes behind the vacuum drying, are put into polypeptide cutting pipe, add an amount of P-cresol, then pass into HF, ice bath stirring reaction 1 hour; HF in the pipe was taken out in decompression after reaction finished, and residual liquid is with an amount of ice ether sedimentation, filtered to get 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 CAPARPAR sterling.80mg Mal-PEG-PLA is dissolved in the 10ml acetonitrile, rotary evaporation, film forming adds 12ml PBS(pH 8.0,0.2M) forms micelle 37 ℃ of aquations.The HPLC detection reaction is spent the night in adding 49.2mg CAPARPAR and reaction in the 8h.Excessive CAPARPAR removes by super filter tube (MWCO 3kDa, Millipore), and lyophilizing is for subsequent use.
1H-NMR characterizes structure, result's demonstration, and the Mal-PEG-PLA collection of illustrative plates shows the characteristic peak of Mal at the 6.67ppm place, and this peak disappears on the APARPAR-PEG-PLA collection of illustrative plates, illustrates that APARPAR-PEG-PLA synthesizes successfully.
Embodiment 4: the preparation of fluorescein-labelled micelle and tumor cell in vitro picked-up experiment thereof.
Take by weighing APARPAR-PEG-PLA(1mg), mPEG-PLA(19mg) and coumarin 6 (0.5mg), be dissolved in the 3ml acetonitrile, 37 ℃ of water-baths, the vacuum rotary steam film forming, the room temperature vacuum drying spends the night, and adds 3ml normal saline aquation 30min, 0.22 μ m membrane filtration, obtain the APARPAR-PEG-PLA micelle, for subsequent use.The preparation of mPEG-PLA micelle is with mPEG-PLA(20mg) and coumarin 6 (0.5mg) be dissolved in the 3ml acetonitrile, film forming, other are with the preparation of APARPAR-PEG-PLA micelle.Two kinds of micelles and tumor cell are hatched 2h altogether, inhale and abandon supernatant, and PBS cleans, confocal laser scanning microscope cell micelle picked-up situation.The result shows that common micelle taken amount being shot is less, and the micelle that APARPAR modifies illustrates that then by huge uptake the targeting materials A PARPAR-PEG-PLA that APARPAR modifies has given micelle the targeting good to tumor cell.
Embodiment 5: the preparation of fluorescein-labelled micelle and tumor cell in vitro picked-up experiment thereof.
Take by weighing APARPAR-PEG-PLA(1mg), mPEG-PLA(19mg) and coumarin 6 (0.2mg), be dissolved in the 3ml acetonitrile, 37 ℃ of water-baths, the vacuum rotary steam film forming, the room temperature vacuum drying spends the night, and adds 3ml normal saline aquation 30min, 0.22 μ m membrane filtration, obtain the APARPAR-PEG-PLA micelle, for subsequent use.The preparation of mPEG-PLA micelle is with mPEG-PLA(20mg) and coumarin 6 (0.2mg) be dissolved in the 3ml acetonitrile, film forming, other are with the preparation of APARPAR-PEG-PLA micelle.Two kinds of micelles and tumor cell are hatched 4h altogether, inhale and abandon supernatant, and PBS cleans, confocal laser scanning microscope cell micelle picked-up situation.The result shows that common micelle taken amount being shot is less, and the micelle that APARPAR modifies illustrates that then by huge uptake the targeting materials A PARPAR-PEG-PLA that APARPAR modifies has given micelle the targeting good to tumor cell.
Claims (7)
1. cancer target polypeptide-polyethylene glycol-polylactic acid complex, it is characterized in that, this material is by the covalently bound linear block copolymers that forms by the target polypeptide with tumor penetration performance, Polyethylene Glycol (PEG) and polylactic acid (PLA) three parts, wherein the mol ratio of cancer target polypeptide, Polyethylene Glycol and polylactic acid is 1:1:1, the aminoacid sequence of described cancer target polypeptide is APARPAR, makes complex have the tumor penetration performance.
2. cancer target polypeptide according to claim 1-polyethylene glycol-polylactic acid complex is characterized in that, the weight average molecular weight of described Polyethylene Glycol is 2000 ~ 5000.
3. cancer target polypeptide according to claim 1-polyethylene glycol-polylactic acid complex is characterized in that, the weight average molecular weight of described polylactic acid is 1000 ~ 8000.
4. cancer target polypeptide according to claim 1-polyethylene glycol-polylactic acid complex is characterized in that, the complex that described cancer target polypeptide is formed by connecting by covalent bond form and polyethylene glycol-polylactic acid.
5. cancer target polypeptide according to claim 1-polyethylene glycol-polylactic acid complex, it is characterized in that, described cancer target polypeptide provides a free sulfhydryl groups, and polyethylene glycol-polylactic acid provides a dimaleoyl imino, and both additive reaction occur and connect into covalent complex.
One kind prepare according to claim 1, the method for 2,3,4,5 each described cancer target polypeptide-polyethylene glycol-polylactic acid complex, it is characterized in that, concrete steps are as follows: adopt the synthetic C of solid-phase polypeptide synthetic method to hold the target polypeptide (aminoacid sequence is CAPARPAR) of external cysteine (Cys), be dissolved in the phosphate buffer (PBS) of pH7.0 it for subsequent use; Get maleimide-polyethylene glycol-polylactic acid complex (Mal-PEG-PLA) and be dissolved in the acetonitrile, the rotary evaporation film forming adds PBS(pH 8.0,0.2M) forms micelle 37 ℃ of aquations; Excessive CAPARPAR and the reaction of adding spent the night in the 8h, and excessive polypeptide is removed in ultrafiltration (molecular weight 3kDa), and lyophilization obtains target polypeptide-polyethylene glycol-polylactic acid complex.
7. according to claim 1-5 application of each described cancer target polypeptide-polyethylene glycol-polylactic acid complex in the pharmaceutical carriers such as preparation micelle, nanoparticle.
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Cited By (6)
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| CN104997727A (en) * | 2015-07-06 | 2015-10-28 | 山东省眼科研究所 | Curcumin micelle nasal solution and preparation method thereof |
| CN105778127A (en) * | 2016-02-26 | 2016-07-20 | 同济大学 | Polylactic acid-polypeptide polymeric micelle and preparation method thereof |
| CN106924731A (en) * | 2015-12-30 | 2017-07-07 | 复旦大学 | One kind is based on PDT and chemotherapeutic combination tumor targeted therapy system |
| CN109939082A (en) * | 2019-03-14 | 2019-06-28 | 苏州大学 | K can be activatedATPThe preparation method and application of the metastatic encephaloma targeting drug delivery system in channel |
| CN112955127A (en) * | 2018-12-17 | 2021-06-11 | 吉爱希公司 | Block copolymer comprising a hydrophilic first block, a hydrophobic second block and a functional group capable of specifically binding to a thiol |
| CN113999290A (en) * | 2021-12-29 | 2022-02-01 | 浙江湃肽生物有限公司南京分公司 | High-stability leuprorelin acetate and application thereof |
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| CN103012562A (en) * | 2011-09-24 | 2013-04-03 | 复旦大学 | Dual-targeting D-configuration polypeptides and drug delivery system thereof |
| CN103040755A (en) * | 2012-12-27 | 2013-04-17 | 上海交通大学 | APARPAR polypeptide-modified invisible liposome and drug delivery system |
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Patent Citations (3)
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| CN103012562A (en) * | 2011-09-24 | 2013-04-03 | 复旦大学 | Dual-targeting D-configuration polypeptides and drug delivery system thereof |
| 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 |
| CN103040755A (en) * | 2012-12-27 | 2013-04-17 | 上海交通大学 | APARPAR polypeptide-modified invisible liposome and drug delivery system |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104997727A (en) * | 2015-07-06 | 2015-10-28 | 山东省眼科研究所 | Curcumin micelle nasal solution and preparation method thereof |
| CN106924731A (en) * | 2015-12-30 | 2017-07-07 | 复旦大学 | One kind is based on PDT and chemotherapeutic combination tumor targeted therapy system |
| CN105778127A (en) * | 2016-02-26 | 2016-07-20 | 同济大学 | Polylactic acid-polypeptide polymeric micelle and preparation method thereof |
| CN112955127A (en) * | 2018-12-17 | 2021-06-11 | 吉爱希公司 | Block copolymer comprising a hydrophilic first block, a hydrophobic second block and a functional group capable of specifically binding to a thiol |
| CN112955127B (en) * | 2018-12-17 | 2024-02-27 | 吉爱希公司 | Block copolymer comprising a hydrophilic first block, a hydrophobic second block and a functional group capable of specifically binding to a thiol |
| CN109939082A (en) * | 2019-03-14 | 2019-06-28 | 苏州大学 | K can be activatedATPThe preparation method and application of the metastatic encephaloma targeting drug delivery system in channel |
| CN113999290A (en) * | 2021-12-29 | 2022-02-01 | 浙江湃肽生物有限公司南京分公司 | High-stability leuprorelin acetate and application thereof |
| CN113999290B (en) * | 2021-12-29 | 2022-03-29 | 浙江湃肽生物有限公司南京分公司 | Stable leuprorelin acetate and application thereof |
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Application publication date: 20130925 |