CN103536930B - Polylactic acid-polyethylene glycol-tumor penetrating peptide compound, preparation and application thereof - Google Patents
Polylactic acid-polyethylene glycol-tumor penetrating peptide compound, preparation and application thereof Download PDFInfo
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- CN103536930B CN103536930B CN201310437613.7A CN201310437613A CN103536930B CN 103536930 B CN103536930 B CN 103536930B CN 201310437613 A CN201310437613 A CN 201310437613A CN 103536930 B CN103536930 B CN 103536930B
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Abstract
The invention relates to a polylactic acid-polyethylene glycol-tumor penetrating peptide compound. The compound is a linear segmented copolymer (PLA-PEG-iNGR for short) composed of polylactic acid (PLA), polyethylene glycol (PEG) and a targeting peptide iNGR with tumor penetration performance which are in covalent linkage; the molar ratio of the polylactic acid to the polyethylene glycol to the targeting peptide is 1:1:1. The invention also provides a preparation method of the polylactic acid-polyethylene glycol-tumor penetrating peptide compound. The polylactic acid-polyethylene glycol-tumor penetrating peptide compound can be applied to preparation of a targeted micelle or nanoparticles with tumor penetration performance; the tumor targeting property and the tumor penetration performance are improved.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to a kind of polylactic acid-polyglycol-tumor penetrating peptide complex PLA-PEG-iNGR, is a kind of target polymer material and Synthesis and applications with tumor penetration performance specifically.
Background technology
Tumor is the principal disease threatening human health and life, and its sickness rate is obvious ascendant trend in recent years.Be at present tumor resection primary tumor and after implementing lymphadenectomy to the conventional treatments of tumor clinically, carry out systemic chemotherapy or radiotherapy.But surgical operation thoroughly can not remove tumor cell and neoplasm metastasis lymph node, easily causes tumor recurrence, or is not suitable for the tumor of some especial patient or privileged sites; Local skin reaction, blood change, local mucous membrane reaction etc. that radiotherapy often causes patient serious; After classic chemotherapy medicine Bolos intravenous administration, to tumor tissues non-selectivity, there is serious general toxic and side effects.Tumor cell or tumor vascular endothelial cell are expressed and has a series of specific receptor, utilize its ligand modified biocompatible materials and the cancer target material for preparing, because it can initiatively be positioned to tumor tissues and be subject to the extensive concern of researcher by targeting in vivo.But because cancer target performance is poor, drug effect improves the problems such as not obvious, current most cancer target material enters clinical practice not yet.Therefore, research and develop high-performance cancer target material, improve to the Targeting Performance of tumor and therapeutic effect extremely urgent.
INGR polypeptide is latter design a kind of tumor penetrating peptide out, and it penetrates sequence by tumor blood vessel targeted polypeptide NGR connection tumor and forms.NGR and iNGR all can targeting to tumor vessel, but the advantage of the latter compared with is forward that it can penetrate into tumor tissues.INGR and NGR is the ligands specific of CD13 on vascular endothelial cell, and in addition, iNGR, by after degraded, also can be combined with neuropilin-1 receptor-specific, thus mediates its tumor and penetrate behavior.Have not yet to see the report of the targeting material utilizing iNGR peptide modified.
The present invention adopts iNGR to modify PLA-PEG, and synthesis has the cancer target material penetrating tumor vessel and tumor tissues ability, and the pharmaceutical carrier for preparation with tumor penetration performance provides material base.
Summary of the invention
In order to overcome the deficiencies in the prior art, the invention provides a kind of polylactic acid-polyglycol-tumor penetrating peptide complex and Synthesis and applications.
A kind of polylactic acid-polyglycol-tumor penetrating peptide complex, it is characterized in that, described complex be by polylactic acid (PLA), Polyethylene Glycol (PEG) and there is tumor penetration performance target polypeptide iNGR tri-part by covalently bound linear block copolymers (being abbreviated as PLA-PEG-iNGR), the molar ratio of three is 1:1:1.
The aminoacid sequence of described tumor penetrating peptide iNGR is CRNGRGPDC, and it makes complex be provided with tumor penetration performance.
The weight average molecular weight of described Polyethylene Glycol is 1800 ~ 3800.
The weight average molecular weight of described polylactic acid is 1000 ~ 5000.
The complex that described tumor penetrating peptide is formed by connecting by covalent bond form and polyethylene glycol-polylactic acid.
Described polylactic acid-polyglycol provides a dimaleoyl imino, and tumor penetrating peptide provides a free sulfhydryl groups, and both additive reaction occur and connect into covalent complex.
Prepare a method for described polylactic acid-polyglycol-tumor penetrating peptide complex, it is characterized in that the concrete steps of the method are:
(1) solid phase polypeptide synthesis synthesis C is adopted to hold the target polypeptide C-iNGR(2Acm of external cysteine (Cys)) (aminoacid sequence is C-C(Acm) RNGRGPDC(Acm)), be dissolved in the phosphate buffer (PBS) of pH7.0 for subsequent use;
(2) getting maleimide-polyethylene glycol-polylactic acid compound (PLA-PEG-Mal) is dissolved in acetonitrile, and rotary evaporation film forming, adds PBS(pH 8.0,0.2M) form micelle 37 DEG C of aquations; Add excessive C-iNGR(2Acm) and reaction spend the night, dialysis (molecular weight 3kDa) remove excessive polypeptide and salt, lyophilization, obtain PLA-PEG-iNGR(2Acm);
(3) by PLA-PEG-iNGR(2Acm) it is dissolved in methanol, add the hydrochloric acid solution of citric acid solution and 1M, after dropwise add iodine methanol solution and make solution remain micro-yellow sustained response 2hr, adding appropriate ascorbic acid solution after reaction terminates makes micro-yellow take off, reactant liquor dialysis removing salt (molecular cut off 3.5kDa, dialysis medium is water), lyophilization obtains PLA-PEG-iNGR.
A kind of polylactic acid-polyglycol-tumor penetrating peptide complex is preparing the application in the pharmaceutical carrier such as micelle, nanoparticle.
Above-mentioned PLA-PEG-iNGR complex can be used for preparing the pharmaceutical carrier with tumor penetration performance, as micelle, nanoparticle etc., after these pharmaceutical carrier intravenous injections enter in animal model for tumour body, compared with common drug carrier, show good tumor-targeting and tumor penetration performance, it obviously increases in tumor locus distribution, and the display of immunofluorescence analysis result can penetrate tumor vessel and penetrate into whole tumor tissues.
Accompanying drawing explanation
The nuclear magnetic spectrum of accompanying drawing 1, PLA-PEG-iNGR.
In figure, 1 is the nuclear magnetic spectrum of PLA-PEG-Mal, and 2 is the nuclear magnetic spectrum of PLA-PEG-iNGR, as can be seen from Figure, 1 figure demonstrates maleimide peak, and this peak disappears in 2 figure, and all the other peaks remain unchanged substantially, and the maleimide base group in display PLA-PEG-Mal reacts with iNGR.
Accompanying drawing 2, the fluorescein micelle utilizing PLA-PEG-iNGR to prepare are absorbed photo by U87 tumor cell.
The fluorescein micelle utilizing PLA-PEG-iNGR to prepare and common fluorescein micelle in 37 DEG C respectively with the fluorescence micrograph of U87 tumor cell effect after 2 hours, as seen from the figure, tumor cell modifies the intake of micelle much larger than common micelle to PLA-PEG-iNGR.
Detailed description of the invention
To contribute to understanding the present invention further by following embodiment, but not limit content of the present invention.
Embodiment 1: the synthesis of complex PLA-PEG-iNGR, purification and sign.
4-methyldiphenyl base methylamine resin (MBHA) is used trifluoroacetic acid (TFA) deprotection 1 minute; twice; HBTU(solvent Boc protected amino acid being dissolved in 0.5M is DMF) in; room temperature reaction 20min; DMF washs; TFA removes Boc protection, according to all aminoacid of aminoacid sequence successively reaction forming.Reaction terminates rear washing resin, TFA Deprotection, after vacuum drying, puts into polypeptide cutting pipe, adds appropriate P-cresol, then pass into HF, ice bath stirring reaction 1 hour; Reaction terminates rear decompression and pumps HF in pipe, the appropriate ice ether sedimentation of residual liquid, filters precipitate and uses ice washed with diethylether to precipitate; Precipitation is dissolved with TFA again, filters to get filtrate; Filtrate is precipitated in ice ether again, and filter, filtering residue redissolves with water, and lyophilizing obtains iNGR(2Acm) (sequence is C-C(Acm) RNGRGPDC(Acm)) sterling.By 80mg PLA-PEG-Mal(PLA molecular weight: 2000; PEG molecular weight: 2000) be dissolved in 10ml acetonitrile, rotary evaporation, film forming, add 6ml PBS(pH 8.0,0.2M) form micelle 37 DEG C of aquations.Add 49.2mg C-C(Acm in 8h) RNGRGPDC(Acm) and reaction spend the night, HPLC detection reaction.Excessive iNGR(2Acm) by dialysis (MWCO 3kDa, Millipore) removing, lyophilizing obtains PLA-PEG-iNGR(2Acm).Get 26mg PLA-PEG-iNGR(2Acm) be dissolved in 5ml methanol, add 20ml citric acid solution (0.2M) and 2.5ml hydrochloric acid solution (1M), after dropwise add 5mM iodine methanol solution and make solution remain micro-yellow sustained response 2hr, adding appropriate ascorbic acid solution after reaction terminates makes micro-yellow take off, reactant liquor dialysis removing salt (molecular cut off 3.5kDa, dialysis medium is water), lyophilization obtains PLA-PEG-iNGR.
1h-NMR characterisation of structures, result shows, and PLA-PEG-Mal collection of illustrative plates is at the characteristic peak of 6.67ppm place display Mal, and on PLA-PEG-iNGR collection of illustrative plates, this peak disappears, and illustrates that PLA-PEG-iNGR synthesizes successfully.
Embodiment 2: the synthesis of complex PLA-PEG-iNGR, purification and sign.
4-methyldiphenyl base methylamine resin (MBHA) is used trifluoroacetic acid (TFA) deprotection 1 minute; twice; HBTU(solvent Boc protected amino acid being dissolved in 0.5M is DMF) in; room temperature reaction 25min; DMF washs; TFA removes Boc protection, according to all aminoacid of aminoacid sequence successively reaction forming.Reaction terminates rear washing resin, TFA Deprotection, after vacuum drying, puts into polypeptide cutting pipe, adds appropriate P-cresol, then pass into HF, ice bath stirring reaction 1 hour; Reaction terminates rear decompression and pumps HF in pipe, the appropriate ice ether sedimentation of residual liquid, filters precipitate and uses ice washed with diethylether to precipitate; Precipitation is dissolved with TFA again, filters to get filtrate; Filtrate is precipitated in ice ether again, and filter, filtering residue redissolves with water, and lyophilizing obtains iNGR(2Acm) (sequence is C-C(Acm) RNGRGPDC(Acm)) sterling.By 80mg PLA-PEG-Mal(PLA molecular weight: 4000; PEG molecular weight: 3500) be dissolved in 10ml acetonitrile, rotary evaporation, film forming, add 6ml PBS(pH 8.0,0.2M) form micelle 37 DEG C of aquations.Add 49.2mg C-C(Acm in 8h) RNGRGPDC(Acm) and reaction spend the night, HPLC detection reaction.Excessive iNGR(2Acm) by dialysis (MWCO 3kDa, Millipore) removing, lyophilizing obtains PLA-PEG-iNGR(2Acm).Get 26mg PLA-PEG-iNGR(2Acm) be dissolved in 5ml methanol, add 20ml citric acid solution (0.2M) and 2.5ml hydrochloric acid solution (1M), after dropwise add 5mM iodine methanol solution and make solution remain micro-yellow sustained response 2hr, adding appropriate ascorbic acid solution after reaction terminates makes micro-yellow take off, reactant liquor dialysis removing salt (molecular cut off 3.5kDa, dialysis medium is water), lyophilization obtains PLA-PEG-iNGR.
1h-NMR characterisation of structures, result shows, and PLA-PEG-Mal collection of illustrative plates is at the characteristic peak of 6.67ppm place display Mal, and on PLA-PEG-iNGR collection of illustrative plates, this peak disappears, and illustrates that PLA-PEG-iNGR synthesizes successfully.
Embodiment 3: the synthesis of complex PLA-PEG-iNGR, purification and sign.
4-methyldiphenyl base methylamine resin (MBHA) is used trifluoroacetic acid (TFA) deprotection 1 minute; twice; HBTU(solvent Boc protected amino acid being dissolved in 0.5M is DMF) in; room temperature reaction 20min; DMF washs; TFA removes Boc protection, according to all aminoacid of aminoacid sequence successively reaction forming.Reaction terminates rear washing resin, TFA Deprotection, after vacuum drying, puts into polypeptide cutting pipe, adds appropriate P-cresol, then pass into HF, ice bath stirring reaction 1 hour; Reaction terminates rear decompression and pumps HF in pipe, the appropriate ice ether sedimentation of residual liquid, filters precipitate and uses ice washed with diethylether to precipitate; Precipitation is dissolved with TFA again, filters to get filtrate; Filtrate is precipitated in ice ether again, and filter, filtering residue redissolves with water, and lyophilizing obtains iNGR(2Acm) (sequence is C-C(Acm) RNGRGPDC(Acm)) sterling.By 80mg PLA-PEG-Mal(PLA molecular weight: 5000; PEG molecular weight: 3500) be dissolved in 10ml acetonitrile, rotary evaporation, film forming, add 6ml PBS(pH 8.0,0.2M) form micelle 37 DEG C of aquations.Add 49.2mg C-C(Acm in 8h) RNGRGPDC(Acm) and reaction spend the night, HPLC detection reaction.Excessive iNGR(2Acm) by dialysis (MWCO 3kDa, Millipore) removing, lyophilizing obtains PLA-PEG-iNGR(2Acm).Get 26mg PLA-PEG-iNGR(2Acm) be dissolved in 5ml methanol, add 20ml citric acid solution (0.2M) and 2.5ml hydrochloric acid solution (1M), after dropwise add 5mM iodine methanol solution and make solution remain micro-yellow sustained response 2hr, adding appropriate ascorbic acid solution after reaction terminates makes micro-yellow take off, reactant liquor dialysis removing salt (molecular cut off 3.5kDa, dialysis medium is water), lyophilization obtains PLA-PEG-iNGR.
1h-NMR characterisation of structures, result shows, and PLA-PEG-Mal collection of illustrative plates is at the characteristic peak of 6.67ppm place display Mal, and on PLA-PEG-iNGR collection of illustrative plates, this peak disappears, and illustrates that PLA-PEG-iNGR synthesizes successfully.
Embodiment 4: the preparation of fluorescein-labelled micelle and tumor cell in vitro picked-up experiment thereof.
Take 1mg PLA-PEG-iNGR(PLA molecular weight: 5000; 3500), 19mg PLA-mPEG(PLA molecular weight PEG molecular weight:: 5000; 2000) and 0.5mg coumarin 6 PEG molecular weight:, be dissolved in 3ml acetonitrile, 37 DEG C of water-baths, vacuum rotary steam film forming, room temperature in vacuo dried overnight, add 3ml normal saline aquation 30min, 0.22 μm of membrane filtration, obtains PLA-PEG-iNGR micelle, for subsequent use; The preparation of PLA-mPEG micelle, by 20mg PLA-mPEG(PLA molecular weight: 5000; PEG molecular weight: 2000) and 0.5mg coumarin 6 be dissolved in 3ml acetonitrile, film forming, other are with the preparation of PLA-PEG-iNGR micelle.Two kinds of micelles and tumor cell hatch 2h altogether, inhale and abandon supernatant, and PBS cleans, confocal laser scanning microscope cell micelle picked-up situation.It is less that result shows common micelle taken amount being shot, and the micelle that iNGR modifies, then by huge uptake, illustrates that the targeting material PLA-PEG-iNGR that iNGR modifies imparts the micelle targeting good to tumor cell.
Embodiment 5: the preparation of fluorescein-labelled micelle and tumor cell in vitro picked-up experiment thereof.
Take 1mg PLA-PEG-iNGR(PLA molecular weight: 4000; 3500), 19mg PLA-mPEG(PLA molecular weight PEG molecular weight:: 4000; 2000) and 0.2mg coumarin 6 PEG molecular weight:, be dissolved in 3ml acetonitrile, 37 DEG C of water-baths, vacuum rotary steam film forming, room temperature in vacuo dried overnight, add 3ml normal saline aquation 30min, 0.22 μm of membrane filtration, obtains PLA-PEG-iNGR micelle, for subsequent use; The preparation of PLA-mPEG micelle, by 20mg PLA-mPEG(PLA molecular weight: 4000; PEG molecular weight: 2000) and 0.2mg coumarin 6 be dissolved in 3ml acetonitrile, film forming, other are with the preparation of PLA-PEG-iNGR micelle.Two kinds of micelles and tumor cell hatch 2h altogether, inhale and abandon supernatant, and PBS cleans, confocal laser scanning microscope cell micelle picked-up situation.It is less that result shows common micelle taken amount being shot, and the micelle that iNGR modifies, then by huge uptake, illustrates that the targeting material PLA-PEG-iNGR that iNGR modifies imparts the micelle targeting good to tumor cell.
Claims (5)
1. polylactic acid-polyglycol-tumor penetrating peptide complex, it is characterized in that, described complex be by polylactic acid (PLA), Polyethylene Glycol (PEG) and there is tumor penetration performance target polypeptide iNGR tri-part by covalently bound linear block copolymers (being abbreviated as PLA-PEG-iNGR), the molar ratio of three is 1:1:1;
The aminoacid sequence of described tumor penetrating peptide iNGR is CRNGRGPDC, and it makes complex be provided with tumor penetration performance;
The weight average molecular weight of described Polyethylene Glycol is 1800 ~ 3800;
The weight average molecular weight of described polylactic acid is 1000 ~ 5000.
2. a kind of polylactic acid-polyglycol according to claim 1-tumor penetrating peptide complex, is characterized in that, the complex that described tumor penetrating peptide is formed by connecting by covalent bond form and polyethylene glycol-polylactic acid.
3. a kind of polylactic acid-polyglycol according to claim 1-tumor penetrating peptide complex, it is characterized in that, described polylactic acid-polyglycol provides a dimaleoyl imino, and tumor penetrating peptide provides a free sulfhydryl groups, and both additive reaction occur and connect into covalent complex.
4. prepare a method for polylactic acid-polyglycol-tumor penetrating peptide complex according to any one of claim 1,2,3, it is characterized in that the concrete steps of the method are:
(1) solid phase polypeptide synthesis synthesis C is adopted to hold the target polypeptide C-iNGR(2Acm of external cysteine (Cys)), aminoacid sequence is C-C(Acm) RNGRGPDC(Acm), be dissolved in the phosphate buffer (PBS) of pH7.0 for subsequent use;
(2) getting maleimide-polyethylene glycol-polylactic acid compound (PLA-PEG-Mal) is dissolved in acetonitrile, and rotary evaporation film forming adds the 0.2M PBS of pH 8.0, form micelle 37 DEG C of aquations; Add excessive C-iNGR(2Acm) and reaction spend the night, excessive polypeptide and salt are removed in dialysis, and lyophilization, obtains PLA-PEG-iNGR(2Acm);
(3) by PLA-PEG-iNGR(2Acm) it is dissolved in methanol, add the hydrochloric acid solution of citric acid solution and 1M, after dropwise add iodine methanol solution and make solution remain micro-yellow sustained response 2hr, adding appropriate ascorbic acid solution after reaction terminates makes micro-yellow take off, reactant liquor dialysis removing salt molecular cut off 3.5kDa, dialysis medium is water, and lyophilization obtains PLA-PEG-iNGR.
5. a kind of polylactic acid-polyglycol according to claim 1-tumor penetrating peptide complex is preparing the application in micelle, nano-granule medicine carrier.
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| CN110339373A (en) * | 2018-04-04 | 2019-10-18 | 中国科学院宁波材料技术与工程研究所 | A kind of nano combined micella and its preparation method and application |
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| 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 |
| CN102579337A (en) * | 2012-03-07 | 2012-07-18 | 山东大学 | Long circulation lipid nano-suspension containing docetaxel and preparation method thereof |
| CN103012562A (en) * | 2011-09-24 | 2013-04-03 | 复旦大学 | Dual-targeting D-configuration polypeptides and drug delivery system 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 |
| 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 |
| CN102579337A (en) * | 2012-03-07 | 2012-07-18 | 山东大学 | Long circulation lipid nano-suspension containing docetaxel and preparation method thereof |
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