CN103536930A - 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
- Publication number
- CN103536930A CN103536930A CN201310437613.7A CN201310437613A CN103536930A CN 103536930 A CN103536930 A CN 103536930A CN 201310437613 A CN201310437613 A CN 201310437613A CN 103536930 A CN103536930 A CN 103536930A
- Authority
- CN
- China
- Prior art keywords
- polylactic acid
- ingr
- tumor
- pla
- peg
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Landscapes
- Medicinal Preparation (AREA)
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 preparation and application with tumor penetration performance specifically.
Background technology
Tumor is the principal disease that threatens human health and life, and its sickness rate is obvious ascendant trend in recent years.At present clinically to the conventional treatments of tumor be tumor resection primary tumor and implement lymphadenectomy after, carry out systemic chemotherapy or radiotherapy.But surgical operation can not thoroughly be removed tumor cell and neoplasm metastasis lymph node, easily causes tumor recurrence, or be not suitable for the tumor of some especial patient or privileged sites; Radiotherapy tends to cause local skin reaction that patient is serious, blood change, local mucous membrane reaction etc.; After tradition chemotherapeutics Bolos intravenous administration, to tumor tissues non-selectivity, there is serious general toxic and side effects.On tumor cell or tumor vascular endothelial cell, express and have a series of specific receptors, the cancer target material that utilizes its ligand modified biocompatible materials and prepare, because it can be positioned to the extensive concern that tumor tissues is subject to researcher by active targeting in vivo.But because cancer target performance is poor, drug effect improves the problems such as not obvious, current most cancer target materials do not enter clinical practice yet.Therefore, research and development high-performance cancer target material, improve extremely urgent to the Targeting Performance of tumor and therapeutic effect.
INGR polypeptide is a kind of tumor penetrating peptide designing in the recent period, 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 latter is that with the advantage of comparing forward it can penetrate into tumor tissues.INGR and NGR are the ligands specific of CD13 on vascular endothelial cell, and in addition, iNGR, by after degrading, also can be combined with neuropilin-1 receptor-specific, thereby mediate its tumor, penetrates behavior.Have not yet to see the report that utilizes the peptide modified targeting material of iNGR.
The present invention adopts iNGR to modify PLA-PEG, synthesizes and has the cancer target material that penetrates 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 preparation and application.
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 target polypeptide iNGR tri-parts with tumor penetration performance by the covalently bound linear block copolymers forming (being abbreviated as PLA-PEG-iNGR), three's molar ratio is 1:1:1.
The aminoacid sequence of described tumor penetrating peptide iNGR is CRNGRGPDC, and it makes complex have 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.
A method of preparing described polylactic acid-polyglycol-tumor penetrating peptide complex, is characterized in that the concrete steps of the method are:
(1) adopt the synthetic C of solid-phase polypeptide synthetic method 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 standby;
(2) get maleimide-polyethylene glycol-polylactic acid complex (PLA-PEG-Mal) and be dissolved in acetonitrile, rotary evaporation film forming, adds PBS(pH 8.0,0.2M) 37 ℃ of aquations, forms micelle; Add excessive C-iNGR(2Acm) and react and spend the night, excessive polypeptide and salt are removed in dialysis (molecular weight 3kDa), and lyophilization, obtains PLA-PEG-iNGR(2Acm);
(3) by PLA-PEG-iNGR(2Acm) it is dissolved in methanol, the hydrochloric acid solution that adds citric acid solution and 1M, after dropwise add iodine methanol solution to make solution remain micro-yellow sustained response 2hr, after finishing, reaction add appropriate ascorbic acid solution that micro-yellow is taken off, salt (molecular cut off 3.5kDa is removed in reactant liquor dialysis, dialysis medium is water), lyophilization obtains PLA-PEG-iNGR.
The application of a kind of polylactic acid-polyglycol-tumor penetrating peptide complex in preparing the pharmaceutical carriers such as micelle, nanoparticle.
Above-mentioned PLA-PEG-iNGR complex can be used for the pharmaceutical carrier that preparation has tumor penetration performance, as micelle, nanoparticle etc., after these pharmaceutical carrier intravenous injections enter in animal model for tumour body, compare with common drug carrier, show good tumor-targeting and tumor penetration performance, it distributes and obviously increases at tumor locus, and immunofluorescence analysis result shows that can penetrate tumor vessel penetrates into whole tumor tissues.
Accompanying drawing explanation
The nuclear magnetic spectrum of accompanying drawing 1, PLA-PEG-iNGR.
1 nuclear magnetic spectrum that is PLA-PEG-Mal in figure, 2 nuclear magnetic spectrums that are 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, show that the maleimide base group in PLA-PEG-Mal reacts with iNGR.
Accompanying drawing 2, utilize fluorescein micelle that PLA-PEG-iNGR prepares by U87 tumor cell picked-up photo.
Utilize fluorescein micelle that PLA-PEG-iNGR 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, the intake that tumor cell is modified micelle to PLA-PEG-iNGR is much larger than common micelle.
The specific embodiment
By following embodiment, will contribute to further to understand the present invention, but not limit content of the present invention.
Embodiment 1: synthetic, the purification of complex PLA-PEG-iNGR and sign.
4-methyldiphenyl base methylamine resin (MBHA) is used to trifluoroacetic acid (TFA) deprotection 1 minute; twice; the HBTU(solvent that Boc protected amino acid is dissolved in to 0.5M is DMF) in; room temperature reaction 20min; DMF washing; TFA removes Boc protection, according to aminoacid sequence, reacts successively and connects all aminoacid.Reaction finishes rear washing resin, TFA Deprotection, after vacuum drying, puts into polypeptide cutting pipe, adds appropriate P-cresol, then passes into HF, ice bath stirring reaction 1 hour; Reaction finishes rear decompression and pumps HF in pipe, and appropriate ice ether sedimentation for residual liquid, filters to such an extent that precipitate and use the washing precipitation of ice ether; Precipitation is dissolved with TFA again, filters to get filtrate; Filtrate is precipitated in ice ether again, filters, and 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, adds 6ml PBS(pH 8.0,0.2M) 37 ℃ of aquations, forms micelle.In 8h, add 49.2mg C-C(Acm) RNGRGPDC(Acm) and react and spend the night, HPLC detection reaction.Excessive iNGR(2Acm) by dialysis (MWCO 3kDa, Millipore), remove, 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 to make solution remain micro-yellow sustained response 2hr, after finishing, reaction add appropriate ascorbic acid solution that micro-yellow is taken off, salt (molecular cut off 3.5kDa is removed in reactant liquor dialysis, dialysis medium is water), lyophilization obtains PLA-PEG-iNGR.
1h-NMR characterizes structure, result demonstration, and PLA-PEG-Mal collection of illustrative plates shows the characteristic peak of Mal at 6.67ppm place, and on PLA-PEG-iNGR collection of illustrative plates, this peak disappears, and illustrates that PLA-PEG-iNGR synthesizes successfully.
Embodiment 2: synthetic, the purification of complex PLA-PEG-iNGR and sign.
4-methyldiphenyl base methylamine resin (MBHA) is used to trifluoroacetic acid (TFA) deprotection 1 minute; twice; the HBTU(solvent that Boc protected amino acid is dissolved in to 0.5M is DMF) in; room temperature reaction 25min; DMF washing; TFA removes Boc protection, according to aminoacid sequence, reacts successively and connects all aminoacid.Reaction finishes rear washing resin, TFA Deprotection, after vacuum drying, puts into polypeptide cutting pipe, adds appropriate P-cresol, then passes into HF, ice bath stirring reaction 1 hour; Reaction finishes rear decompression and pumps HF in pipe, and appropriate ice ether sedimentation for residual liquid, filters to such an extent that precipitate and use the washing precipitation of ice ether; Precipitation is dissolved with TFA again, filters to get filtrate; Filtrate is precipitated in ice ether again, filters, and 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, adds 6ml PBS(pH 8.0,0.2M) 37 ℃ of aquations, forms micelle.In 8h, add 49.2mg C-C(Acm) RNGRGPDC(Acm) and react and spend the night, HPLC detection reaction.Excessive iNGR(2Acm) by dialysis (MWCO 3kDa, Millipore), remove, 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 to make solution remain micro-yellow sustained response 2hr, after finishing, reaction add appropriate ascorbic acid solution that micro-yellow is taken off, salt (molecular cut off 3.5kDa is removed in reactant liquor dialysis, dialysis medium is water), lyophilization obtains PLA-PEG-iNGR.
1h-NMR characterizes structure, result demonstration, and PLA-PEG-Mal collection of illustrative plates shows the characteristic peak of Mal at 6.67ppm place, and on PLA-PEG-iNGR collection of illustrative plates, this peak disappears, and illustrates that PLA-PEG-iNGR synthesizes successfully.
Embodiment 3: synthetic, the purification of complex PLA-PEG-iNGR and sign.
4-methyldiphenyl base methylamine resin (MBHA) is used to trifluoroacetic acid (TFA) deprotection 1 minute; twice; the HBTU(solvent that Boc protected amino acid is dissolved in to 0.5M is DMF) in; room temperature reaction 20min; DMF washing; TFA removes Boc protection, according to aminoacid sequence, reacts successively and connects all aminoacid.Reaction finishes rear washing resin, TFA Deprotection, after vacuum drying, puts into polypeptide cutting pipe, adds appropriate P-cresol, then passes into HF, ice bath stirring reaction 1 hour; Reaction finishes rear decompression and pumps HF in pipe, and appropriate ice ether sedimentation for residual liquid, filters to such an extent that precipitate and use the washing precipitation of ice ether; Precipitation is dissolved with TFA again, filters to get filtrate; Filtrate is precipitated in ice ether again, filters, and 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, adds 6ml PBS(pH 8.0,0.2M) 37 ℃ of aquations, forms micelle.In 8h, add 49.2mg C-C(Acm) RNGRGPDC(Acm) and react and spend the night, HPLC detection reaction.Excessive iNGR(2Acm) by dialysis (MWCO 3kDa, Millipore), remove, 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 to make solution remain micro-yellow sustained response 2hr, after finishing, reaction add appropriate ascorbic acid solution that micro-yellow is taken off, salt (molecular cut off 3.5kDa is removed in reactant liquor dialysis, dialysis medium is water), lyophilization obtains PLA-PEG-iNGR.
1h-NMR characterizes structure, result demonstration, and PLA-PEG-Mal collection of illustrative plates shows the characteristic peak of Mal at 6.67ppm place, 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; PEG molecular weight: 2000) and 0.5mg coumarin 6, be dissolved in 3ml acetonitrile, 37 ℃ of water-baths, vacuum rotary steam film forming, room temperature vacuum drying spends the night, and adds 3ml normal saline aquation 30min, and 0.22 μ m membrane filtration, obtains PLA-PEG-iNGR micelle, standby; 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 are hatched 2h altogether, inhale and abandon supernatant, and PBS cleans, confocal laser scanning microscope cell micelle picked-up situation.Result shows that common micelle taken amount being shot is less, and the micelle that iNGR modifies, by huge uptake, illustrates that the targeting material PLA-PEG-iNGR that iNGR 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 1mg PLA-PEG-iNGR(PLA molecular weight: 4000; 3500), 19mg PLA-mPEG(PLA molecular weight PEG molecular weight:: 4000; PEG molecular weight: 2000) and 0.2mg coumarin 6, be dissolved in 3ml acetonitrile, 37 ℃ of water-baths, vacuum rotary steam film forming, room temperature vacuum drying spends the night, and adds 3ml normal saline aquation 30min, and 0.22 μ m membrane filtration, obtains PLA-PEG-iNGR micelle, standby; 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 are hatched 2h altogether, inhale and abandon supernatant, and PBS cleans, confocal laser scanning microscope cell micelle picked-up situation.Result shows that common micelle taken amount being shot is less, and the micelle that iNGR modifies, by huge uptake, illustrates that the targeting material PLA-PEG-iNGR that iNGR modifies has given micelle the targeting good to tumor cell.
Claims (8)
1. polylactic acid-polyglycol-tumor penetrating peptide complex, it is characterized in that, described complex be by polylactic acid (PLA), Polyethylene Glycol (PEG) and target polypeptide iNGR tri-parts with tumor penetration performance by the covalently bound linear block copolymers forming (being abbreviated as PLA-PEG-iNGR), three's molar ratio is 1:1:1.
2. a kind of polylactic acid-polyglycol-tumor penetrating peptide complex according to claim 1, is characterized in that, the aminoacid sequence of described tumor penetrating peptide iNGR is CRNGRGPDC, and it makes complex have tumor penetration performance.
3. a kind of polylactic acid-polyglycol-tumor penetrating peptide complex according to claim 1, is characterized in that, the weight average molecular weight of described Polyethylene Glycol is 1800～3800.
4. a kind of polylactic acid-polyglycol-tumor penetrating peptide complex according to claim 1, is characterized in that, the weight average molecular weight of described polylactic acid is 1000～5000.
5. a kind of polylactic acid-polyglycol-tumor penetrating peptide complex according to claim 1, is characterized in that the complex that described tumor penetrating peptide is formed by connecting by covalent bond form and polyethylene glycol-polylactic acid.
6. a kind of polylactic acid-polyglycol-tumor penetrating peptide complex according to claim 1, 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.
7. prepare according to a method for polylactic acid-polyglycol-tumor penetrating peptide complex described in claim 1,2,3,4,5,6 any one, it is characterized in that the concrete steps of the method are:
(1) adopt the synthetic C of solid-phase polypeptide synthetic method 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 standby;
(2) get maleimide-polyethylene glycol-polylactic acid complex (PLA-PEG-Mal) and be dissolved in acetonitrile, rotary evaporation film forming, adds PBS(pH 8.0,0.2M) 37 ℃ of aquations, forms micelle;
Add excessive C-iNGR(2Acm) and react and spend the night, excessive polypeptide and salt are removed in dialysis (molecular weight 3kDa), and lyophilization, obtains PLA-PEG-iNGR(2Acm);
(3) by PLA-PEG-iNGR(2Acm) it is dissolved in methanol, the hydrochloric acid solution that adds citric acid solution and 1M, after dropwise add iodine methanol solution to make solution remain micro-yellow sustained response 2hr, after finishing, reaction add appropriate ascorbic acid solution that micro-yellow is taken off, salt (molecular cut off 3.5kDa is removed in reactant liquor dialysis, dialysis medium is water), lyophilization obtains PLA-PEG-iNGR.
8. the application of a kind of polylactic acid-polyglycol-tumor penetrating peptide complex claimed in claim 1 in preparing the pharmaceutical carriers such as micelle, nanoparticle.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310437613.7A CN103536930B (en) | 2013-09-24 | 2013-09-24 | Polylactic acid-polyethylene glycol-tumor penetrating peptide compound, preparation and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310437613.7A CN103536930B (en) | 2013-09-24 | 2013-09-24 | Polylactic acid-polyethylene glycol-tumor penetrating peptide compound, preparation and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103536930A true CN103536930A (en) | 2014-01-29 |
| CN103536930B CN103536930B (en) | 2015-06-24 |
Family
ID=49961037
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310437613.7A Expired - Fee Related CN103536930B (en) | 2013-09-24 | 2013-09-24 | Polylactic acid-polyethylene glycol-tumor penetrating peptide compound, preparation and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103536930B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105267983A (en) * | 2014-06-30 | 2016-01-27 | 复旦大学 | iNGR-modified targeted self-assembly RNAi nano drug delivery system for brain glioma and preparation method of system |
| 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 nanocomposite micelle and its preparation method and application |
| CN110384681A (en) * | 2019-07-29 | 2019-10-29 | 中国药科大学 | A kind of nanometer formulation and preparation method thereof for pulmonary fibrosis |
| CN115869312A (en) * | 2022-12-27 | 2023-03-31 | 哈尔滨吉象隆生物技术有限公司 | PDC (polycrystalline diamond compact) antitumor drug as well as preparation method and application thereof |
Citations (3)
| 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 |
| 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 |
-
2013
- 2013-09-24 CN CN201310437613.7A patent/CN103536930B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105267983A (en) * | 2014-06-30 | 2016-01-27 | 复旦大学 | iNGR-modified targeted self-assembly RNAi nano drug delivery system for brain glioma and preparation method of system |
| CN105267983B (en) * | 2014-06-30 | 2021-01-26 | 复旦大学 | iNGR modified brain glioma targeted self-assembly RNAi nano drug delivery system and preparation method thereof |
| 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 nanocomposite micelle and its preparation method and application |
| CN110384681A (en) * | 2019-07-29 | 2019-10-29 | 中国药科大学 | A kind of nanometer formulation and preparation method thereof for pulmonary fibrosis |
| CN110384681B (en) * | 2019-07-29 | 2020-04-28 | 中国药科大学 | Nanometer preparation for pulmonary fibrosis and preparation method thereof |
| CN115869312A (en) * | 2022-12-27 | 2023-03-31 | 哈尔滨吉象隆生物技术有限公司 | PDC (polycrystalline diamond compact) antitumor drug as well as preparation method and application thereof |
| CN115869312B (en) * | 2022-12-27 | 2024-02-27 | 哈尔滨吉象隆生物技术有限公司 | PDC anti-tumor medicine and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103536930B (en) | 2015-06-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102516361B (en) | NRP-1 ligand polypeptide-polyethylene glycol-phosphatide compound, active targeting liposome drug delivery system mediated thereby and preparation method thereof | |
| CN103536930B (en) | Polylactic acid-polyethylene glycol-tumor penetrating peptide compound, preparation and application thereof | |
| CN103316354A (en) | Tumor targeting polypeptide-polyethylene glycol-polylactic acid compound, preparation method thereof and applications thereof | |
| WO2019061561A1 (en) | Medicament delivery system, and preparation method and application thereof | |
| CN108524947B (en) | A drug-loaded nanoparticle of Ganoderma lucidum polysaccharide-phenylboronic acid-methotrexate conjugate with pH response and its preparation method | |
| CN106267229B (en) | A kind of Liver targeting carries the structure and preparation method thereof of platinum nano-prodrug | |
| CN104650194A (en) | Peptide dentritic macromolecular drug and preparation method and application thereof | |
| CN104341488A (en) | c(LyP-1) polypeptide and nano-delivery system constructed thereby and application of nano-delivery system | |
| US12171886B2 (en) | Mussel adhesive protein-based photothermal agent and photothermal-responsive adhesive nanoparticles | |
| CN114533698B (en) | A preparation method of ferritin drug-loaded nanoparticles modified with D-type tumor penetrating peptide | |
| CN110746490B (en) | A kind of polypeptide composition based on click reaction blocking immune checkpoint and its preparation method and application | |
| CN107625968A (en) | A tumor-specific tissue-cell double-permeable nanoparticle, preparation method and application thereof | |
| CN113679849B (en) | A highly targeted and low-toxic tumor microenvironment intelligent responsive nanocarrier and its preparation method | |
| WO2011083845A1 (en) | Targeting agent for tumor site | |
| CN113797335B (en) | Polypeptide-based self-assembled photosensitive nanofiber material, preparation method thereof and application thereof in preparation of antitumor drugs | |
| CN111481507A (en) | A kind of enzymatic cationized liposome and its application | |
| RU2451509C1 (en) | Anti-tumour preparation | |
| CN102240265A (en) | Liposome vector system for tumor-targeted drug delivery | |
| WO2011013792A1 (en) | Kidney imaging agent comprising genetically modified gelatin | |
| CN114377141A (en) | Drug delivery carrier and anti-tumor application thereof | |
| CN113121642A (en) | Self-assembly polypeptide, redox response polypeptide hydrogel and preparation method and application thereof | |
| JP2011162569A (en) | Camptothecin polymer derivative and use thereof | |
| CN104069515A (en) | Paramagnetic metal complex modified by aspartic acid-leucine copolymer as well as preparation and application of paramagnetic metal complex | |
| CN114668742B (en) | Bacteria-imitating nano medicine delivery system and preparation method and application thereof | |
| CN103263674A (en) | Tumor targeting material with tumor penetrating property, preparation method and applications thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150624 Termination date: 20170924 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |