CN108324945A - For inhibiting Nano medication particle to penetrate the inhibitor of placental barrier - Google Patents
For inhibiting Nano medication particle to penetrate the inhibitor of placental barrier Download PDFInfo
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- CN108324945A CN108324945A CN201710043443.2A CN201710043443A CN108324945A CN 108324945 A CN108324945 A CN 108324945A CN 201710043443 A CN201710043443 A CN 201710043443A CN 108324945 A CN108324945 A CN 108324945A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
Abstract
The present invention relates to a kind of methods inhibiting Nano medication particle across placental barrier model.Specific method is while using inflammatory factor inhibitor and phagocytosis approach restrainer, investigating variation of the Nano medication particle across the quantity of placental barrier model.Using 96 porocyte culture plates, inflammatory factor inhibitor and phagocytosis approach restrainer are incubated a period of time with cell altogether, the nano-particle of fluorescent marker is added, the case where nano-particle is by cellular uptake is investigated using ELISA method.Every reagent of strong innovation of the present invention, addition is easy to get, and has great importance for reducing the potential embryo's toxic side effect of Nano medication particle.
Description
Technical field
The present invention relates to Nano medication particles, it particularly relates to which a kind of inhibition Nano medication particle penetrates placental barrier
Inhibitor.
Background technology
The phagocytosis approach of nano-particle, the mathematical model for being ingested process and relevant parameter are just gradually being realized and are building
It is vertical[1].The intake of nano-particle is mainly carried out by endocytosis (endocytosis) approach, the size of nano-particle, shape, electricity
Modification group of lotus, the material formed and surface etc. influences nano-particle and enters phagocyte, and it is current to enter born of the same parents' mechanism
It there is no consistent conclusion.Possible endocytic pathway includes giant cell drink (macropinocytosis), pinocytosis (pinocytosis), net
Lattice protein dependent endocytosis (clathrin-dependent endocytosis), small recessed protein dependent endocytosis (caveolin-
Dependent endocytosis) and rely on actin phagocytosis approach (phagocytosis) etc..Research is found almost
All endocytosis signal paths have been involved in the process that superparamagnetism Fe nanometer particles enter RAW264.7 macrophages[2].And surpass
Small paramagnetic iron oxide and Superparamagnetic Iron Oxide nano-particle are by clathrin mediation and scavenger receptor mediation
It gulps down into human cytomegalovirus[3].Another aspect studies have shown that nano-particle as " foreign matter " enter body, inflammation can be activated anti-
Approach is answered, inflammatory cytokine is caused to be secreted[4].Inflammatory reaction is activated with NF-kB (Nuclear factor kB) signal path
Relationship be proven, NF-kB signal paths anticusp inflammation factor TNF-α and IL-1 can be by microbial product lipoprotein
(Lipopolysaccharide, LPS) is activated, the generation of transmitting inflammation.
Drugs during pregnancy is related to the safety of parent and fetus, and nano-medicament carrier/transport system is because of slow/controlled release and targeting
The features such as make its Drugs during pregnancy direction present great potential, at the same time may also penetrate placental barrier to fetus generate poison
Property, further investigation and development and application of the Nano medication in perinatal medicine field are limited to a certain extent；Nano-medicament carrier energy
It is no through placental barrier enter fetus body-internal-circulation generate toxicity, be how through placental barrier etc. relevant issues research tool
It is significant.
Placental barrier is the barrier between placental villus tissues and uterus blood sinus, this special barrier has regulated and controled parent and fetus
Between mass exchange.Research nano-particle penetrates model someone's Choriocarcinoma cell line BeWo cell membranes of placental barrier both at home and abroad
Type, Human plactnta in vitro perfusion model further include using rodent progress in body research etc..Human chorionic cancer cell BeWo
Cell can form trophoderm cell monolayer, be the placental barrier body of effective evaluation nutriment and ingestion of medicines, outer row and transhipment
External model[5-7].Cartwright etc.[8]BeWo models are carried out preferably, model to be established using Transwell diffusion cells, using saturating
Radio mirror, laser co-focusing instrument and photon correlation spectroscopy etc. have effectively observed polystyrene nanoparticle and have penetrated placental barrier
The case where.Human placenta's perfusion model is successfully used to nano-particle and penetrates placental barrier research[9], nano-particle passes through tire
Disk transhipment experiment condition can reach, can get repeat as a result, placental perfusion model can be standardised for assessment receive
Rice corpuscles is through placental transport, but this placental barrier is highly dependent on pregnancy cycle.Using this model, researcher has investigated
Polystyrene nanoparticle, Cd, Te, Si, TiO2With the placental transport situation of the nano-particles such as gold[10].At home, about body
The research of ectoplacenta perfusion model is in the starting stage.There are more and more nano-particles to penetrate the cellular elements machine of placental barrier
System is also being revealed, studies have shown that nano-particle may have diffusion, vesicular traffic by the approach of placental barrier and nourish thin
Born of the same parents' channel system, it is related with the attribute of nano-particle such as particle size, charge and functionalization[10-11].Simple diffusion quickly, film bubble
Transport includes passing through clathrin dependence endocytosis and small recessed protein dependent endocytosis etc..
Pulullan polysaccharide (pullulan) is a kind of water-soluble, neutral straight-chain polysaccharide, and unique connection type imparts general
Some unique physicochemical properties of Shandong orchid, are paid close attention in terms of medicine by more and more researchers[12].Inventor once participated in
It is multinomial using pulullan polysaccharide as the nanometer transport system research of material[13-15], and obtain certain achievement.Pulullan polysaccharide is carried out
Hydrophobically modified has synthesized acetyl pullulan (PA) and has been prepared for acetyl pullulan nano-particle (PANs), investigated the steady of PANs
Qualitative, safety and slow-release function[14], result of study shows：PANs preparation process is simple, and form rule, grain size is in 200-
300nm, Zeta potential absolute value are less than 5；At least two months grain sizes and surface potential can be kept to have no apparent in aqueous solution
Change, there is preferable stability；200mg/kg single intravenous injections give mouse, have no apparent acute toxicity；Vein is noted
It penetrates and gives rat, the display slow releasing function certain to package-contained drug.But, if PANs can be influenced by above-mentioned inhibitor
Through the research of placental barrier, there is not been reported.
Inventor is on the basis of early-stage study, while application inflammatory factor and phagocytosis approach restrainer inhibit PANs across placenta
Barrier cell is received to reduce the influence to embryo to realize with it is expected to reduce the amount that nano-particle penetrates placental barrier model
Rice medicinal application provides scientific basis in perinatal medicine field, and the above research has no any document or patent report.
Invention content
The object of the present invention is to provide a kind of composite restrainer that new inhibition Nano medication particle is transported across placental barrier,
The inhibitor includes a effective amount of inflammatory factor inhibitor and phagocytosis approach restrainer, it is preferable that while including effective quantity
Inflammatory factor inhibitor and phagocytosis approach restrainer；Can also include conventional auxiliary element, such as excipient substance or figuration
Agent.The drug particle that the Nano medication particle is contained by following nano-particle：Acetyl pullulan nano-particle and other with
Polysaccharide is nano-particle prepared by Material synthesis.
The phagocytosis approach restrainer is one or more in following inhibitor：Giant cell drinks inhibitor such as amiloride
(Amiloride, AMR), pinocytosis approach restrainer such as colchicin (Colchicines, COL), clathrin dependence endocytosis
Inhibitor such as chlorpromazine (Chlorpromazine, CPZ), small recessed protein dependent endocytosis and the phagocytosis way for relying on actin
Diameter inhibitor such as Nysfungin (Nystatin, NY) etc..
The inflammatory factor inhibitor is one or more in following inhibitor：NF-kB signal paths specifically inhibit
Agent such as Pyrrolididine dithio-carhamate (Pyrrolidinedithiocarbamate, PDTC) and dexamethasone
(Dexamethasonem, DEX) etc..
Thinking of the present invention is unique, and every reagent of addition is easy to get, and across the placental barrier transhipment of nano-particle is reduced for realizing,
Distribution of the nano-particle in placenta and embryo is effectively reduced, possible embryo's toxic side effect is reduced and has great importance.
Using the technology of the present invention, while giving Nano medication, using inflammatory factor inhibitor and nano-particle across
The inhibitor of BeWo cell traffics, it is expected to realize that reducing Nano medication penetrates placental barrier, to reduce in placenta and embryo
Distribution, reduces potential embryo's toxic side effect, has potential applicability in clinical practice.
Description of the drawings
Fig. 1 show the inhibiting effect of phagocytosis inhibitor and combined depressant to BeWo cellular uptake nano-particles.
Specific implementation mode
NF-kB signal paths specific inhibitor and phagocytosis approach restrainer are applied to BeWo cellular uptake nanoparticles simultaneously
Son verifies the effect of present invention combination mortifier.Using in vitro test method, using 96 porocyte culture plates, by inflammatory factor
Inhibitor and phagocytosis approach restrainer are incubated a period of time altogether with cell, and nano-particle is added, is examined using fluorescence spectrophotometry
Examine the case where across the BeWo cell membranes of Propiram nano-particle PANs are ingested.
[embodiment 1] inhibits BeWo cellular uptakes PANs from NF-kB signal paths and phagocytosis approach
BeWo cells：It is given by University of Texas Erik professors Rytting, in also can coordinating cellular resources from Beijing
The heart is bought.
Inhibitor is prepared, final concentration is respectively 70 μ g/mL of chlorpromazine (CPZ), 500 μM of amiloride (AMR), Nysfungin
(NY) 500 μ g/mL, colchicin (COL) 100 100 μM of μ g/mL, PDTC, 10 μ g/ml of dexamethasone (DEX).
According to bibliography, kind plate culture BeWo cells 24 hours, 10,000/hole kind plate；Culture medium is abandoned in suction, and PBS rinses 3
Time, it is added 200 μ L of inhibitor, every group of 6 multiple holes, setting cell-free medium control group has cell culture medium control group and not
Inhibiting control group is incubated 1 hour, and PBS is washed 3 times, and the second of the marked by fluorescein isothiocyanate containing equivalent inhibitor is added
100 μ L (0.25mg/mL) of acyl Propiram nano-particle (PA-FITC), then be incubated 2 hours, supernatant is abandoned in suction, and PBS is washed 3 times, then
0.25% Qula entire crack solution liquid lysis at room temperature is added 1 hour, piping and druming in every 10 minutes is primary and complete to cell under the microscope in light
Cracking, process are protected from light；Lysate is placed in microplate reader fluorescence intensity, excitation wavelength 494nm is calculated according to the OD values of measurement
The inhibition percentage of inhibitor, the results are shown in Table 1 and Fig. 1.
Inhibit percentage (%)=(1-ODt/ODc) × 100%
By table 1 and Fig. 1 as it can be seen that NF-kB signal path inhibitor PDTC can substantially reduce the intake of nano-particle.Thus it says
Bright, NF-kB signal paths inhibitor can effectively inhibit PANs across the intake of BeWo cells.When simultaneously be added PDTC and CPZ,
When two kinds of inhibitor of AMR, COL or NY, PANs intake inhibiting rates further increase, and thus illustrate, while applying NF-kB signals
Channel inhibitor PDTC and phagocytosis approach restrainer chlorpromazine, amiloride or Nysfungin produce collaboration depression effect.
Inhibiting effect (%) of 1 inhibitor of table to BeWo cellular uptakes PA-FITC
Following documents partially or wholly introduces patent specification, the component part as patent specification.
[1]Lunov O,Zablotskii V,Syrovets T, C,Tron K,Nienhaus GU,Simmet
T.Modeling receptor-mediated endocytosis of polymer-functionalized iron oxide
nanoparticles by human macrophages.Biomaterials[J].2011；32(2):547-55.
The superparamagnetism ferric oxide nanoparticles such as [2] Gu Jingli, Xu Haifei, Han Yehua enter phagocyte
Approach, metabolism, home to return to and biological effect [J] Chinese sciences of RAW264.7:Life science, 2011；41(8):626-39.
[3]Di Gioacchino M,Petrarca C,Lazzarin F,et al.Immunotoxicity of
nanoparticles.Int J Immunopathol Pharmacol.2011；24(1Suppl):65S-71S.
[4]Nicolete R,dos Santos DF,Faccioli LH.The uptake of PLGA micro or
nanoparticles by macrophages provokes distinct in vitro inflammatory
response.Int Immunopharmacol.2011；11(10):1557-63.
[5] Guo Jie, Song hall honor .BeWo cell models and its application [J] Chinese medicines in placental transport Mechanism Study
Magazine, 2012；37(21):3193-3197.
[6] Sun Guyun, Wu Hui, high progress [J] Chinese Pharmacologicals for waiting human placenta's drug permeability experiments
With toxicology magazine, 2011；25(3):327-329.
[7]Castro AS,Alves CM,Angeloni MB,Gomes AO,Barbosa BF,Franco PS,Silva
DA,Martins-Filho OA,Mineo JR,Mineo TW,Ferro EA.Trophoblast cells are able to
regulate monocyte activity to control Toxoplasma gondii infection[J]
.Placenta.2013；34(3):240-7.
[8]Cartwright L,Poulsen MS,Nielsen HM,Pojana G,Knudsen LE,Saunders M,
Rytting E.In vitro placental model optimization for nanoparticle transport
studies[J].Int J Nanomedicine.2012；7:497-510.
[9]Buerki-Thurnherr T,von Mandach U,Wick P.Knocking at the door of
the unborn child:engineered nanoparticles at the human placental barrier[J]
.Swiss Med Wkly.2012；142:w13559.
[10]Kulvietis V,Zalgeviciene V,Didziapetriene J,Rotomskis R.Transport
of nanoparticles through the placental barrier[J].Tohoku J Exp Med.2011；225
(4):225-34.
[11]Wick P,Malek A,Manser P,Meili D,Maeder-Althaus X,Diener L,Diener
PA,Zisch A,Krug HF,von Mandach U.Barrier capacity of human placenta for
nanosizedmaterials[J].Environ Health Perspect.2010；118(3):432-6.
[12]Cheng KC,Demirci A,Catchmark JM.Pullulan:biosynthesis,production,
and applications[J].Appl Microbiol Biotechnol.2011；92(1):29-44.
[13]Tang H,Feng X,Zhang T,Dai Y,Zhou Z,Chen H,Liu L,Li X,Zhuang T,Liu
X,Zhang Q.Stability,Pharmacokinetics,Biodistribution and Safety Assessment of
Folate-Conjugated Pullulan Acetate Nanoparticles as Cervical Cancer Targeted
Drug Carriers[J].J Nanosci Nanotechnol.2015；15(9):6405-12.
[14]Tang HB,Li L,Chen H,Zhou ZM,Chen HL,Li XM,Liu LR,Wang YS,Zhang
QQ*.Stability and in vivo evaluation of pullulan acetate as a drug
nanocarrier[J].Drug Deliv.2010；17(7):552-558.
[15] Tang Hongbo, Chen Hongli, Zhou Zhimin, Zhang Tong, Liu Lingrong, Zhang Qiqing Propiram base tumor-targeting nanoparticles
Preparation, stability and release in vitro [J] the China Tissue Engineering Study .2012 of son；16(34):6326-30.
Claims (9)
1. a kind of inhibitor for inhibiting Nano medication particle to be transported across placental barrier, including a effective amount of inflammatory factor inhibitor,
The inflammatory factor inhibitor is one or more in following inhibitor：NF-kB signal paths specific inhibitor with
And other inflammatory factor inhibitor；
The drug particle that the Nano medication particle is contained by following nano-particle：Acetyl pullulan nano-particle and other with
Polysaccharide is nano-particle prepared by Material synthesis.
2. a kind of combined depressant for inhibiting Nano medication particle to be transported across placental barrier, while including a effective amount of inflammatory factor
Inhibitor and phagocytosis approach restrainer,
The inflammatory factor inhibitor is one or more in following inhibitor：NF-kB signal paths specific inhibitor with
And other inflammatory factor inhibitor；
The phagocytosis approach restrainer is one or more in following inhibitor：Giant cell drinks inhibitor, pinocytosis, clathrin
Dependence endocytosis inhibitor, small recessed protein dependent endocytosis and the phagocytosis approach restrainer for relying on actin.
3. inhibitor according to claim 2, wherein：The phagocytosis approach restrainer be amiloride, colchicin,
Chlorpromazine or Nysfungin.
4. inhibitor according to claim 1 or 2, wherein：The inflammatory factor inhibitor is two sulphur of tetrahydropyrrole
For carbamate or dexamethasone.
5. inhibitor according to claim 1 or 2, wherein：The inflammatory factor inhibitor is two sulphur of tetrahydropyrrole
For carbamate and dexamethasone.
6. combined depressant according to claim 2, while including a effective amount of tetrahydropyrrole aminodithioformic acid
Ester and amiloride.
7. combined depressant according to claim 2, while including two thio ammonia of a effective amount of effective quantity tetrahydropyrrole
Carbamate and chlorpromazine.
8. combined depressant according to claim 2, while including a effective amount of tetrahydropyrrole aminodithioformic acid
Ester and Nysfungin.
9. combined depressant according to claim 2, including a effective amount of Pyrrolididine dithio-carhamate and
Colchicin.
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Cited By (1)
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| CN114304064A (en) * | 2021-12-16 | 2022-04-12 | 首都医科大学 | Method for establishing animal model with head deformity accompanied with nerve-dyskinesia |
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