CN108324945B - Inhibitor for inhibiting nano-drug particles from penetrating placenta barrier - Google Patents
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Abstract
The invention relates to a method for inhibiting a nano-drug particle cross-placental barrier model. The specific method is to apply the inflammatory factor inhibitor and the phagocytic pathway inhibitor at the same time and investigate the change of the quantity of the nano-drug particles across the placenta barrier model. A96-well cell culture plate is adopted, an inflammatory factor inhibitor and a phagocytic pathway inhibitor are incubated with cells for a period of time, fluorescent-labeled nanoparticles are added, and the condition that the nanoparticles are taken up by the cells is inspected by an ELISA method. The invention has strong innovation, and various added reagents are easy to obtain, thereby having important significance for reducing potential embryo toxic and side effects of the nano-drug particles.
Description
Technical Field
The invention relates to a nano-drug particle, in particular to an inhibitor for inhibiting the nano-drug particle from penetrating a placenta barrier.
Background
The phagocytosis pathway of nanoparticles, the mathematical model of the uptake process and related parameters are gradually being recognized and established[1]. The uptake of nanoparticles is mainly performed through endocytosis (endocytosis) route, the size, shape, charge, material formed by the nanoparticles, surface modification group and the like all influence the entry of the nanoparticles into phagocytes, and the entry mechanism of the nanoparticles is not consistent at present. Possible endocytic pathways include macropinocytosis (macropinocytosis), pinocytosis (pinocytosis), clathrin-dependent endocytosis (clathrin-dependent endocytosis), foveolin-dependent endocytosis (caveolin-dependent endocytosis), and actin-dependent phagocytic pathway (phag)ocytosis), and the like. Researches show that almost all endocytic signal paths are involved in the process of the superparamagnetic iron nanoparticles entering RAW264.7 macrophage[2]. The ultra-small paramagnetic iron oxide and the ultra-paramagnetic iron oxide nano-particles enter human giant cells through clathrin-mediated and scavenger receptor-mediated endocytosis[3]. On the other hand, research shows that the nano particles enter the body as foreign matters to activate inflammatory reaction pathways and cause inflammatory cell factor secretion[4]The relation between inflammatory reaction and NF-kB (nuclear factor kB) signal channel activation has been proved, and inflammatory factors TNF- α and IL-1 before the NF-kB signal channel can be activated by Lipoprotein (LPS) which is a microbial product to mediate the generation of inflammation.
The drug delivery in the gestational period is related to the safety risk of the mother and the fetus, and the nano-drug carrier/delivery system has great potential in the drug delivery direction in the gestational period due to the characteristics of slow/controlled release, targeting and the like, and can generate toxicity to the fetus through a placenta barrier, thereby limiting the deep research and development application of the nano-drug in the perinatal medicine field to a certain extent; whether the nano-drug carrier can penetrate through the placenta barrier to enter the fetus body to circulate to generate toxicity or not is of great significance to the research on how to penetrate through the placenta barrier and other related problems.
The placental barrier is the barrier between placental villus tissue and the uterine antrum, a special barrier that regulates mass exchange between the mother and the fetus. The model for researching the penetration of the nano particles through the placenta barrier at home and abroad comprises a human choriocarcinoma cell BeWo cell model, a human placenta in-vitro perfusion model, in-vivo research by applying rodent, and the like. BeWo cells of human choriocarcinoma cells can form trophoblast monolayer cells and are placenta barrier in-vitro models for effectively evaluating the intake, discharge and transportation of nutrients and medicines[5-7]. Cartwright et al[8]The BeWo model is optimized, a Transwell diffusion cell is utilized to establish a model, and the condition that the polystyrene nano particles penetrate through the placenta barrier is effectively observed by applying a transmission electron microscope, a laser confocal instrument, a photon correlation spectroscopy and the like. The human placental perfusion model was successfully used for nanoparticle crossing placental barrier studies[9]NanoparticlesExperimental conditions for trans-placental transport can be achieved, reproducible results can be obtained, and placental perfusion models can be standardized for assessing trans-placental transport of nanoparticles, but this placental barrier height is highly dependent on the gestational cycle. Using this model, researchers have investigated polystyrene nanoparticles, Cd, Te, Si, TiO2And placenta transport of gold nanoparticles[10]. In the domestic world, research on in vitro placental perfusion models is in the infancy. Cellular molecular mechanisms by which more and more nanoparticles penetrate the placental barrier are also being revealed, studies have shown that the pathways by which nanoparticles may pass through the placental barrier are diffusion, membrane vesicle transport, and trophoblastic channel systems, related to the properties of the nanoparticles such as particle size, charge, and functionalization[10-11]. Simple diffusion is rapid and vesicle trafficking involves through clathrin-dependent endocytosis and caveolin-dependent endocytosis, among others.
Pullulan (pulullan) is a water-soluble neutral linear polysaccharide, and the unique connection mode thereof endows pullulan with some unique physicochemical properties, so that the pullulan is attracted by more and more researchers in the aspect of medicine[12]. The inventor is involved in a plurality of researches on nano delivery systems taking pullulan as material[13-15]And certain results are obtained. Hydrophobic modification is carried out on pullulan polysaccharide to synthesize acetyl Pullulan (PA) and prepare acetyl pullulan nano Particles (PANs), and the stability, safety and slow release functions of the PANs are investigated[14]And research results show that: the preparation process of the PANs is simple and regular in shape, the particle size is 200-300nm, and the Zeta potential absolute value is less than 5; the particle size and the surface potential can be kept in the aqueous solution for at least two months without obvious change, and the stability is better; the compound preparation is administered to mice by single intravenous injection of 200mg/kg, and no obvious acute toxicity is seen; the injection is given to rats by intravenous injection, and shows a certain slow release effect on the encapsulated drug. However, studies on whether it is possible to influence the permeation of PANs through the placental barrier by the above inhibitors have not been reported.
On the basis of earlier researches, the inventor simultaneously applies inflammatory factors and phagocytic pathway inhibitors to inhibit PANs from crossing placenta barrier cells so as to reduce the quantity of nanoparticles penetrating through a placenta barrier model, thereby reducing the influence on embryos and providing scientific basis for realizing the application of nano-drugs in the field of perinatal medicine, and the researches do not see any literature or patent reports.
Disclosure of Invention
The invention aims to provide a novel combined inhibitor for inhibiting the transport of nano-drug particles across placenta barriers, which comprises effective amounts of an inflammatory factor inhibitor and a phagocytic pathway inhibitor, and preferably comprises effective amounts of the inflammatory factor inhibitor and the phagocytic pathway inhibitor; conventional auxiliary ingredients, such as pharmaceutical adjuvants or excipients, may also be included. The nano-drug particles are drug particles carried by the following nano-particles: acetyl pullulan nano-particles and other nano-particles which are synthesized and prepared by taking polysaccharide as a raw material.
The phagocytosis pathway inhibitor is one or more of the following inhibitors: macropinocytosis inhibitors such as Amiloride (AMR), pinocytosis pathway inhibitors such as colchicine (Colchicines, COL), clathrin-dependent endocytosis inhibitors such as Chlorpromazine (CPZ), caveolin-dependent endocytosis, and actin-dependent phagocytosis pathway inhibitors such as Nystatin (NY), and the like.
The inflammation factor inhibitor is one or more of the following inhibitors: NF-kB signal channel specific inhibitors such as tetrahydropyrrole dithiocarbamate (PDTC) and dexamethasone (DEXAMETHASONEM, DEX).
The invention has unique thinking and easily obtained added reagents, and has important significance for reducing the transportation of the nano particles across the placenta barrier, effectively reducing the distribution of the nano particles in the placenta and the embryo and reducing possible toxic and side effects of the embryo.
By adopting the technology of the invention, when the nano-drug is administered, the inhibitor of the inflammatory factor and the inhibitor of the nano-particle trans-BeWo cell transfer are applied, so that the nano-drug can be expected to be reduced to permeate the placenta barrier, thereby reducing the distribution of the nano-drug in the placenta and the embryo, reducing the potential toxic and side effects of the embryo, and having clinical application prospect.
Drawings
FIG. 1 shows the inhibition of nanoparticle uptake by BeWo cells by phagocytic inhibitors and combination inhibitors.
Detailed Description
The NF-kB signal channel specific inhibitor and the phagocytic pathway inhibitor are simultaneously applied to BeWo cells to take up the nano particles, so that the effect of the combined inhibitor is verified. In-vitro test method is adopted, a 96-hole cell culture plate is applied, an inflammatory factor inhibitor and a phagocytic pathway inhibitor are incubated with cells for a period of time, nanoparticles are added, and the condition that the pullulan nanoparticles PANs are taken up across the BeWo cell membrane is investigated by a fluorescence spectrophotometry method.
EXAMPLE 1 inhibition of uptake of PANs by BeWo cells from NF-kB signaling pathways and phagocytic pathways
BeWo cells: is a gift from professor Erik rytinging, university of Texas, and can also be purchased from Beijing collaborating cell resource center.
The inhibitor is prepared, and the final concentration is 70 mu g/mL of Chlorpromazine (CPZ), 500 mu M of Amiloride (AMR), 500 mu g/mL of Nystatin (NY), 100 mu g/mL of Colchicine (COL), 100 mu M of PDTC and 10 mu g/mL of Dexamethasone (DEX).
According to the reference, the plates cultured BeWo cells for 24 hours, 1 ten thousand per well of plate; absorbing and removing the culture medium, washing with PBS for 3 times, adding 200 mu L of inhibitor, setting a cell-free culture medium control group, a cell culture medium control group and a non-inhibitor control group in 6 compound holes of each group, incubating for 1 hour, washing with PBS for 3 times, adding 100 mu L (0.25mg/mL) of fluorescein isothiocyanate labeled acetylpullulan nanoparticles (PA-FITC) containing the same amount of inhibitor, incubating for 2 hours, absorbing and removing the supernatant, washing with PBS for 3 times, adding 0.25% triton lysate, lysing for 1 hour at room temperature, blowing once every 10 minutes, observing under a light microscope until the cells are completely lysed, and keeping the process away from light; the lysate is placed in a microplate reader to detect the fluorescence intensity, the excitation wavelength is 494nm, and the inhibition percentage of the inhibitor is calculated according to the measured OD value, and the result is shown in Table 1 and figure 1.
Percent inhibition (%) - (1-ODt/ODc). times.100%
As can be seen from table 1 and fig. 1, the NF-kB signaling channel inhibitor PDTC can significantly reduce nanoparticle uptake. Thus, NF-kB signaling channel inhibitors are able to effectively inhibit the uptake of PANs across BeWo cells. When PDTC and CPZ, AMR, COL or NY inhibitors are added simultaneously, the uptake inhibition rate of the PANs is further increased, thereby showing that the synergistic inhibition effect is generated by simultaneously applying the NF-kB signal channel inhibitor PDTC and the phagocytic pathway inhibitor chlorpromazine, amiloride or nystatin.
TABLE 1 inhibition of PA-FITC uptake by BeWo cells by inhibitors (%)
The following documents are incorporated in part or in whole into this patent specification as an integral part of this patent specification.
[1]Lunov O,Zablotskii V,Syrovets T,
C,Tron K,Nienhaus GU,SimmetT.Modeling receptor-mediated endocytosis of polymer-functionalized iron oxidenanoparticles by human macrophages.Biomaterials[J].2011；32(2):547-55.
[2] Grain Jingli, Xuhaifei, Korea and so on, superparamagnetic iron sesquioxide nanoparticles enter a phagocyte RAW264.7, the pathway, metabolism, homing and biological effects [ J ] Chinese science, Life sciences, 2011; 41(8):626-39.
[3]Di Gioacchino M,Petrarca C,Lazzarin F,et al.Immunotoxicity ofnanoparticles.Int J Immunopathol Pharmacol.2011；24(1Suppl):65S-71S.
[4]Nicolete R,dos Santos DF,Faccioli LH.The uptake of PLGA micro ornanoparticles by macrophages provokes distinct in vitro inflammatoryresponse.Int Immunopharmacol.2011；11(10):1557-63.
[5] Gouo, songhe, songhua rong. BeWo cell model and its use in the study of placenta transport mechanism [ J ]. chinese traditional medicine journal, 2012; 37(21):3193-3197.
[6] Sun grain rhyme, wuhui, zhang and so on, research progress of human placenta drug permeability experiments [ J ]. journal of pharmacology and toxicology of china, 2011; 25(3):327-329.
[7]Castro AS,Alves CM,Angeloni MB,Gomes AO,Barbosa BF,Franco PS,SilvaDA,Martins-Filho OA,Mineo JR,Mineo TW,Ferro EA.Trophoblast cells are able toregulate 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 transportstudies[J].Int J Nanomedicine.2012；7:497-510.
[9]Buerki-Thurnherr T,von Mandach U,Wick P.Knocking at the door ofthe 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.Transportof 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,DienerPA,Zisch A,Krug HF,von Mandach U.Barrier capacity of human placenta fornanosizedmaterials[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,LiuX,Zhang Q.Stability,Pharmacokinetics,Biodistribution and Safety Assessment ofFolate-Conjugated Pullulan Acetate Nanoparticles as Cervical Cancer TargetedDrug 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,ZhangQQ*.Stability and in vivo evaluation of pullulan acetate as a drugnanocarrier[J].Drug Deliv.2010；17(7):552-558.
[15] Preparation, stability and in vitro release of pullulan-based tumor targeting nanoparticles [ J ] chinese tissue engineering study, 2012; 16(34):6326-30.
Claims (1)
1. The application of a combined inhibitor consisting of an inflammatory factor inhibitor and a phagocytic pathway inhibitor in the preparation of a medicament for inhibiting the transport of nano-drug particles across the placental barrier,
the inflammation factor inhibitor is tetrahydropyrrole dithiocarbamate;
the phagocytic pathway inhibitor is nystatin;
the nano-drug particles are acetyl pullulan nanoparticles.
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