CN104371006A - Peptide capable of passing across blood-cerebrospinal fluid barrier - Google Patents
Peptide capable of passing across blood-cerebrospinal fluid barrier Download PDFInfo
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- CN104371006A CN104371006A CN201410403086.2A CN201410403086A CN104371006A CN 104371006 A CN104371006 A CN 104371006A CN 201410403086 A CN201410403086 A CN 201410403086A CN 104371006 A CN104371006 A CN 104371006A
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Abstract
The invention discloses a peptide capable of passing across blood-cerebrospinal fluid barrier, and the polypeptide is shown as the amino acid sequence of SEQ ID NO:1. The peptide can pass across blood-cerebrospinal fluid barrier in blood circulation so as to enrich in the cerebrospinal fluid. The invention also discloses a method for obtaining the peptide capable of passing across the blood-cerebrospinal fluid barrier, the peptide as a targeted functional group can be used in construction of a drug carrier, so that the drug carrier can be enriched in the cerebrospinal fluid, and can be used for diagnosis and treatment of brain diseases.
Description
Technical field
The invention belongs to protein and peptide technical field, relate to the polypeptide crossing over blood cerebrospinal fluid barrier, comprise the molecular structure of described peptide and preparing the application in Brain targeting preparation.
Background technology
Along with the aging of human society, the sickness rate of encephalopathy is just in the trend risen year by year, and the life and health of the mankind in positive serious harm.Usual encephalopathy comprises the diseases such as central nervous system disease (Parkinson's disease, senile dementia), cerebral tumor, cerebrovascular disease, brain virus and bacteriological infection.
Blood brain barrier (BBB) is the barrier system be present between blood and cerebral tissue, outside material nonessential or harmful for cerebral tissue can be isolated in by it, plays the effect of protection cerebral tissue.Brain capillary endothelial cell on hemato encephalic barrier and spongiocyte together constitute compact siro spinning technology, are namely the mechanical barriers of one BBB.Research display, brain capillary endothelial cell film also exist some special enzyme systems, some drugs can be made to degrade, as dopamine decarboxylase enzyme can make L-3,4 dihydroxyphenylalanine and the decarboxylation of L-5-hyroxytrypophan generate not easily through L-3,4 dihydroxyphenylalanine amine and the L-5-hydroxy-tryptamine of BBB, thus form the enzyme barrier of BBB; P-glycoprotein etc. on brain capillary endothelial cell film also plays a part efflux pump, and objectionable impurities in brain or surplus substance can optionally pump outside brain by it, the brain delivery of restrictive substance.The above-mentioned functions of hemato encephalic barrier maintains the constant of cerebral tissue environment under normal physiological condition, but limit in treatment of diseases medicine through.According to the relevent statistics, after current routine clinical preparation administration, the chemicals of nearly 98% and almost 100% protein polypeptide or genomic medicine be difficult to due to the effect of hemato encephalic barrier into brain, limit the treatment of encephalopathy to a great extent.
Blood cerebrospinal fluid barrier (BCSFB) is between the capillary vessel and cerebrospinal fluid of ventricles of the brain choroid plexus, and its architecture basics is that zonuls occludens is arranged at the top in choroid epithelium intercellular substance.The capillary endothelial cell of choroid plexus has fenestra, and does not also form the compact siro spinning technology as BBB, therefore this barrier has certain permeability compared with hemato encephalic barrier, and this also plays the possibility that provides of curative effect for medicine enters brain.
Have at present and increase by instantaneous open blood cerebrospinal fluid barrier the strategy that medicine enters brain, but the method does not possess selectivity and often has invasive, and likely cause neurotoxin potential in a large number and other chemical substances to enter in brain, this has a negative impact to the stable state of CNS, and produces the side effect not wishing to occur.By contrast, nano-carrier, such as liposome and nanoparticle, can provide better selection.Had the nanometer position of more and more kind and liposome available for treatment.The surface of these liposomes or nanoparticle is modified usually, makes this construct can by specific machine-processed target central nervous system.Screening through the peptide of blood cerebrospinal fluid barrier, can help medicine to have more selectivity, thus provide better result for the treatment of, reduce general toxicity simultaneously.
Phage display peptide library technology is a kind of biotechnology of screening function polypeptide, and rondom polypeptide library is expressed in the surface of filobactivirus by it, by " affine-wash-out-amplification " step of taking turns, realizes high-throughput affinity selection more.Research is had to filter out by display technique of bacteriophage the polypeptide be combined with endothelial cell specific, wherein most is representational be can with the arginine-glycine-aspartic acid of tumor vascular endothelial cell specific combination (RGD) tripeptide sequence, RGD combine long circulating nano medicament carrying system show good tumor-targeting.Pasqualini etc. obtain peptide that is a kind of and pneumonocyte specific binding, by being connected and the delivery system of target pepx on cytolemma with Anti-adenovirus antibody.Wan Xiaomei etc. also obtains seven peptide sequences that a kind of energy via intranasal application olfactory mucosa enters brain.Research display, high, the high specificity of polypeptide avidity obtained through phage display screening, security are good, biological degradation and biocompatibility is excellent, synthesis convenient, and are easy to modify at end.
Prior art related to the present invention also has: Ito, et al.The effect of RGD peptide-conjugated magnetitecationic liposomes on cell growth and cell sheet harvesting.Biomaterials, 2005,26:6185; TrepelM, et al.Molecular adaptors for vascular-targeted adenoviral gene delivery.Hum Gene Ther, 2000,11:1971; Xiao-Mei Wan et al.Identification of nose-to-brain homing peptide throughphage display.Peptides, 2009,30:343.
But so far, there is not yet correlative study and the report of the target function base being crossed over blood-CSF barrier by display technique of bacteriophage screening through blood circulation.
Summary of the invention
An aspect of of the present present invention relates to a kind of peptide crossing over blood cerebrospinal fluid barrier, and the aminoacid sequence of wherein said peptide is TPSYDTYAAELR.Described peptide utilizes phage display dodecapeptide storehouse (Ph.D.-12
tMphage display peptidelibrary), the peptide sequence crossing over blood cerebrospinal fluid barrier filtered out.
The present invention relates to a kind of method obtaining the peptide crossing over blood cerebrospinal fluid barrier on the other hand, and described method comprises i) vein and gives phage random displayed polypeptide storehouse, reclaims phage subsequently from cerebrospinal fluid; Ii) phage be recovered to carried out amplification and again repeat step i), until obtain the total polypeptide sequence crossing over blood cerebrospinal fluid barrier.
Another aspect of the present invention relates to described peptide and is preparing the application in targeting preparation.Described targeting preparation as, drug-carrying nanometer particle, liposome, vesicle or micella etc.Described polypeptide can be modified in above-mentioned nanoparticle, liposome, vesicle or micellar surface, thus obtains the targeting preparation modified by peptide of the present invention.By peptide modified in these dosage surface by electrostatic adhesion, affine connection or covalently bound etc., be well known to the skilled person.
Object of the present invention is achieved by following technical proposals:
First, phage display peptide library is adopted to filter out by wheel the peptide crossing over blood cerebrospinal fluid barrier, it comprises step: adopt screening method in body, vein gives phage random displayed polypeptide storehouse, after certain hour, from cerebrospinal fluid, reclaim phage, after amplification, again repeat screening process in a wheel body, and carry out screening in many wheel bodys, final acquisition can cross over the phage mono-clonal of blood cerebrospinal fluid barrier; The aminoacid sequence of peptide can be obtained after order-checking.Screening method in phage body, and the monoclonal sequence measurement of phage is well known to those skilled in the art.
Described phage random displayed polypeptide storehouse can be commercially available phage random displayed polypeptide storehouse, such as phage display ring seven peptide storehouse, phage display seven peptide storehouse, phage display dodecapeptide storehouse, or other suitable Phage display random peptide libraries.
Described phage random displayed polypeptide storehouse can give suitable animal by vein, such as, and rat, mouse, rabbit, dog, sheep, monkey, chicken etc.From cerebrospinal fluid, reclaim phage by extracting the cerebrospinal fluid of proper volume, to hatch altogether with the phage Host Strains intestinal bacteria being in logarithmic phase subsequently, thus reach the object reclaiming phage.The abstracting method of cerebrospinal fluid is well known to those skilled in the art.The recovery of phage is well known to those skilled in the art, and will describe in further detail hereinafter.
Through experiment in vivo and vitro evaluation, result confirms, polypeptide of the present invention has crosses over blood cerebrospinal fluid barrier and the characteristic be enriched in cerebrospinal fluid.Polypeptide of the present invention can be used for modifying drug-carrying nanometer particle, liposome, vesicle or micella, and be built into brain targeting drug delivery system, this delivery system can improve the brain delivery of medicine, strengthens the result for the treatment of for encephalopathy, reduces the toxic side effect of general.
The present invention screens the polypeptide of the SEQ ID NO:1 of acquisition, through bioinformatic analysis comparison display, with the known in US National Biotechnology Information center (NCBI) GenBank DNA sequence data storehouse and Swiss-Prot albumen database and albumen without homology.
Compared with prior art, the present invention has following beneficial effect:
1, the present invention screens the polypeptide obtained, and molecular weight is little, good biocompatibility, and synthesis is convenient, with low cost.
2, the present invention screens the structure that the polypeptide obtained may be used for encephalopathy targeted therapeutic carrier.
Accompanying drawing explanation
Fig. 1 shows the screening first round in phage body and screens the rate of recovery to third round.
Fig. 2 shows after tail vein injection, phage mono-clonal 12-1 and the concentration effect of random peptide library phage in rat CSF.
Fig. 3 shows the live body distribution of TPS peptide in nude mouse.The TPS peptide that nude mice tail vein injection FITC marks, gives nude mice of control group in contrast with the PBS tail vein injection containing FITC.
Embodiment
Hereinafter described embodiment is to help content of the present invention to be understood more readily by, only in order to further illustrate the present invention, and being not intended to limit scope of the present invention.
Damping fluid hereinafter described used in embodiment, substratum etc. are described as follows:
LB liquid nutrient medium: 10g/L microbial culture with Tryptones (Oxford), 5g/L Bacto-yeast extract (Oxford), 5g/L NaCl (Sigma).
Top-agar sugar culture-medium: LB substratum+7g/L agarose (Sigma).
LB/IPTG/Xgal agar plate: 0.05g/L IPTG, 0.04g/L Xgal, 15g/L agar powder (sigma).
TBS damping fluid: 50mmol/L Tris-HCl and 150mmol/L NaCl adds deionized water constant volume, 0.103 × 10
6pa autoclaving 30min.
IPTG/X-gal:1.25g IPTG and 1g X-gal is dissolved in 25mL DMF.Solution-20 DEG C keeps in Dark Place.
PEG/NaCl:20% (w/v) PEG-8000,5mol/L NaCl, pressure sterilizing, room temperature storage.
PBS: the Na preparing 0.2mol/L respectively
2hP0
4solution and 0.2mol/L NaH
2pO
4solution, ordinary method sterilizing, then gets 81mL Na at every turn
2hPO
4solution and 19mL NaH
2pO
4solution mixes, and obtains the PBS solution 100mL of pH7.4; 0.2mol/L PBS (storing at 4 DEG C), adds 0.85g NaCl, is 0.2mol/L PBS.Then getting 50mL0.2mol/L PBS as prepared 0.01mol/LPBS, adding 8.5g NaCl, be settled to 1L with distilled water and be 0.01mol/L PBS.
TE damping fluid: 10mmol/L Tris-HCl, pH8.0mmol/L EDTA.
Screening in the body in embodiment 1 phage display random dodecapeptides storehouse
Select the Ph.D-12 of NEW ENGLAND Biolabs
tMpeptide storehouse.First round screening method is as follows: by the Ph.D-12 of NEWENGLAND Biolabs
tMpeptide storehouse is diluted to 1 × 10
12pfu titre, diluent is TBS damping fluid (tri methylol amino methane, Tris; 50mM Tris, 150mM sodium-chlor), rat tail vein is injected.By rat anesthesia after 12 hours, under aseptic condition, extract cerebrospinal fluid 50 μ L.The ER2738 intestinal bacteria being in logarithmic phase of getting the cultivation of appropriate cerebrospinal fluid LB liquid nutrient medium determine the titre of phage by volumetry, screen after remaining amplification for next round.Carry out three-wheel screening with this, measure each and take turns the phage titre that screening obtains, and taking turns random picking result from last, to go out phage mono-clonal for subsequent use.
The mensuration of embodiment 2 phage titre
The phage of often wheel screening acquisition in embodiment 1 is carried out the dilution of 10 multiple proportions with LB liquid nutrient medium, the intestinal bacteria ER2738 bacterium liquid getting the phage after 10 μ L dilutions and 200 μ L logarithmic phases mixes, join the LB top-agar (top-agar: often liter containing 10g Tryptones of 50 DEG C of preheatings, 5g yeast extract, 5g sodium-chlor, 1g magnesium chloride and 7g agar powder, for subsequent use after autoclaving) pour rapidly LB plate containing isopropyl-β-D-thiogalactoside(IPTG) and the bromo-4-of 5-chloro-3-indoles galactoside (IPTG/Xgal) afterwards into, spend the night, counted by phage locus coeruleus number.
Titre calculation formula: phage titre (pfu)=100 × plaque number × extension rate, namely every 1mL pnagus medius forms unit.
Show the enrichment of brain targeting polypeptide phage: as shown in Figure 1, after three-wheel screening, the rate of recovery of being screened the phage obtained by dodecapeptide storehouse has all had than the first round and has significantly improved (p<0.01), shows that reclaiming the phage obtained obtains obvious enrichment.
Embodiment 3 phage DNA extracts and order-checking
From the third round the selection result of embodiment 1, random choose goes out multiple phage mono-clonal respectively, is known the sequence of displayed polypeptide by order-checking after DNA extraction.
Increased separately by phage mono-clonal: ER2738 overnight culture is inoculated in LB substratum by after 1:100 dilution, separates 1mL in culture tube, will the phage mono-clonal of qualification be needed by often pipe one clone inoculation, 5h be cultivated by 37 DEG C of shaking tables.After medium centrifugal, 500 μ L supernatants are proceeded in clean centrifuge tube, phage of must increasing storage liquid.Add 200 μ L polyoxyethylene glycol/sodium-chlor (PEG/NaCl) in each pipe, after putting upside down mixing, room temperature places 15min; Centrifugal 10min, abandoning supernatant.Throw out is resuspended in (iodide damping fluid: 10mM Tris-HCl pH8.0,1mM ethylenediamine tetraacetic acid (EDTA)-EDTA, 4M NaI) in 100 μ L iodide damping fluids.Add 250 μ L ethanol; Incubation at room temperature 10min.The incubation at room temperature of short period of time makes single stranded phage DNA precipitate, and most of phage protein can keep in the solution.Centrifugal 10min, abandons supernatant, washes precipitation with 70% ethanol, of short duration vacuum-drying.Precipitation is resuspended in 30 μ L TE (10Mm Tris-HCl pH8.0,1mM EDTA).
Get the above-mentioned template solution of 5 μ L to carry out automated cycle dideoxy sequencing, using-96 as the primer of automatic sequencing.(-96gIII sequencing primer: 5 '-
oHcCC TCA T AG TTA GCG TAA CG-3 ', 100pmol/ μ L, 1pmol/mL).This primer is apart from object fragment at a distance of 96bp, and sequencing result is as shown in SEQ ID NO:1 ~ 10 in table 1.
The amino acid sequence analysis result of table 1.SEQ ID NO:1 ~ 10 Phage Display Peptide.
* thickened portion display is the consensus sequence of phage display
As can be seen from Table 1, obtain total polypeptide sequence a: TPSYDTYAAELR by screening in three wheel bodys, by this peptide called after TPS peptide, will the phage mono-clonal called after mono-clonal 12-1 of this peptide be shown.
The rate of recovery in the amplification of embodiment 4 monoclonal phage and cerebrospinal fluid
The phage mono-clonal 12-1 of gained in embodiment 1 is increased.The infectious bacteria liquid 1mL getting mono-clonal 12-1 adds in 200mL LB nutrient solution, incubated overnight in 37 DEG C of shaking tables.The centrifugal 20min of 8000rpm, obtains the supernatant containing phage, adds the PEG/NaCl of 1/6 volume, 4 DEG C of precipitates overnight after precipitation thalline.The centrifugal 20min of 12000rpm, gets precipitation, with the dilution of TBS damping fluid, gets supernatant after the centrifugal 15min of 5000rpm.Again add the PEG/NaCl of 1/6 volume, the centrifugal 20min of ice bath 1h, 12000rpm, after precipitation TBS is resuspended, namely obtain the monoclonal amplification liquid of phage, measure the titre of phage by the method for embodiment 2.
With TBS mixing 10
12the phage mono-clonal 12-1 of pfu, is injected by SD rat tail vein, in addition by the phage in phage dodecapeptide storehouse in contrast, equally with 10
12the titre of pfu gives control rats.By rat anesthesia after 1h, extract appropriate cerebrospinal fluid and carry out titer determination with the method according to embodiment 2 after 10 times of doubling dilutions.The rate of recovery (pfu/g) of Units of Account weight cerebrospinal fluid pnagus medius.From Fig. 2 result, the peptide that phage mono-clonal 12-1 shows obtains very significant enrichment in cerebrospinal fluid of rats, illustrates that TPS peptide can assist phage to cross over blood cerebrospinal fluid barrier.
The live body distribution of embodiment 5 Phage Display Peptide is observed
FITC is utilized to mark TPS peptide to investigate the DYNAMIC DISTRIBUTION situation of described peptide in nude mouse.Choose arbitrarily a nude mice, tail vein injects the TPS peptide that above-mentioned FITC marks, and described peptide is scattered in PBS.Choose 1 nude mice in contrast, tail vein injects the PBS containing equivalent FITC.After injection 1h, small animal living body imager is utilized to carry out observing and taking pictures.Select 695nm as wavelength of transmitted light, fixing each exposure time is 60ms.Result shows, and is significantly better than contrast through TPS peptide in the fluorescence intensity of brain, shows that the Phage Display Peptide that the present invention screens acquisition has good brain drug delivery performance (as shown in Figure 3).
Claims (3)
1. can cross over a peptide for blood cerebrospinal fluid barrier, it is characterized in that, the aminoacid sequence of described polypeptide is as shown in SEQ IDNO:1.
2. obtain a method for the peptide crossing over blood cerebrospinal fluid barrier, described method comprises i) vein and gives phage random displayed polypeptide storehouse, reclaims phage subsequently from cerebrospinal fluid; Ii) phage be recovered to carried out amplification and again repeat step i), until obtain the total polypeptide sequence crossing over blood cerebrospinal fluid barrier.
3. method as claimed in claim 2, wherein said phage random displayed polypeptide storehouse is phage display seven peptide storehouse, phage display ring seven peptide storehouse, phage display dodecapeptide storehouse.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2017143967A1 (en) * | 2016-02-24 | 2017-08-31 | 首都医科大学宣武医院 | Poly(butyl cyanoacrylate) nanoparticle with dual modifications, preparation method thereof and application of same |
| CN109666973A (en) * | 2018-11-21 | 2019-04-23 | 北京大学 | It is a kind of across the peptide library of blood-brain barrier and its screening technique |
| CN112707950A (en) * | 2021-02-23 | 2021-04-27 | 李婧炜 | Screening of polypeptide with brain-targeted drug delivery characteristic by phage display technology |
| CN112851759A (en) * | 2021-02-23 | 2021-05-28 | 李婧炜 | Screening of polypeptides capable of crossing blood-cerebrospinal fluid barrier by phage display technology |
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| CN102174080A (en) * | 2010-09-19 | 2011-09-07 | 复旦大学 | Polypeptide with brain targeted medicine delivery characteristic and preparation method thereof |
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| CN102174080A (en) * | 2010-09-19 | 2011-09-07 | 复旦大学 | Polypeptide with brain targeted medicine delivery characteristic and preparation method thereof |
Non-Patent Citations (4)
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| CONRAD E. JOHANSON ETC.: "Enhanced prospects for drug delivery and brain targeting by the choroid plexus-CSF route", 《PARMACEUTICAL RESEARCH》 * |
| SAMUEL BECK ETC.: "Identification of a peptide that interacts with Nestin protein expressed in brain cancer stem cells", 《BIOMATERIALS》 * |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017143967A1 (en) * | 2016-02-24 | 2017-08-31 | 首都医科大学宣武医院 | Poly(butyl cyanoacrylate) nanoparticle with dual modifications, preparation method thereof and application of same |
| US11351125B2 (en) | 2016-02-24 | 2022-06-07 | Xuanwu Hospital Of Capital Medical University | Poly(n-butyl cyanoacrylate) nanoparticle with dual modifications, preparation method and use thereof |
| CN109666973A (en) * | 2018-11-21 | 2019-04-23 | 北京大学 | It is a kind of across the peptide library of blood-brain barrier and its screening technique |
| CN109666973B (en) * | 2018-11-21 | 2022-11-04 | 北京大学 | Peptide library crossing blood brain barrier and screening method thereof |
| CN112707950A (en) * | 2021-02-23 | 2021-04-27 | 李婧炜 | Screening of polypeptide with brain-targeted drug delivery characteristic by phage display technology |
| CN112851759A (en) * | 2021-02-23 | 2021-05-28 | 李婧炜 | Screening of polypeptides capable of crossing blood-cerebrospinal fluid barrier by phage display technology |
| CN112707950B (en) * | 2021-02-23 | 2023-02-10 | 李婧炜 | Screening of polypeptide with brain-targeted drug delivery characteristic by phage display technology |
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