CN106390127A - Novel combined inhibitor for phagocytosis of nano-drug particles by liver Kuppfer cells and application of combined inhibitor - Google Patents
Novel combined inhibitor for phagocytosis of nano-drug particles by liver Kuppfer cells and application of combined inhibitor Download PDFInfo
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Abstract
The invention relates to a novel inhibitor composition for phagocytosis of nano-drug particles by liver Kuppfer cells and an application of the inhibitor composition to nano-drugs. The inhibitor composition comprises an effective dose of an inflammatory cell factor inhibitor and a phagocytosis pathway inhibitor, wherein the phagocytosis pathway inhibitor includes one or more of the following inhibitors: a macropinocytosis inhibitor, a pinocytosis inhibitor, a clathrin-dependent endocytosis inhibitor, a caveolin-dependent endocytosis inhibitor and an actin-dependent phagocytosis pathway inhibitor; and the inflammatory cell factor inhibitor includes one or more of the following inhibitors: an NF-kB signal channel specific inhibitor and other inflammatory cell factor inhibitors. The nano-drugs subjected to phagocytosis by the liver KCs (Kuppfer Cells) can be reduced expectedly, so that the circulation time of the nano-drugs in bodies is prolonged, the drug effect is better achieved, and the toxic and side effects are reduced; and therefore, the inhibitor composition has a clinical application prospect.
Description
Technical field
The present invention relates to a kind of new liver withered Fou Shi (Kuppfer) cell phagocytosis Nano medication particle inhibitor combination and its application in Nano medication.
Background technology
Most of nanoscale medicine delivery system (Nano-scale Drug Delivery System, NDDS after) entering in vivo, realizing drug effect, while reducing toxic and side effects, internal mononuclear phagocyte system (Mononuclear Phagocyte System, MPS) main inclusion liver Kupffer's cells (Kupffer Cell, ) and the giant cell etc. of spleen can cause a large amount of nanoparticles to accumulate (list of references [1-2]) in non-target tissue's especially liver and spleen KC, both greatly reduced the distribution in target tissue for the medicine, also it is likely to cause corresponding organs toxicity, limit the application of target medicine carrier.How to reduce medicine-carried nano particles to be removed by the mononuclear phagocyte system such as liver, realize nanoparticle to be more effectively distributed in target tissue is one of key issue urgently to be resolved hurrily in nanoscale medicine delivery system research (list of references [3-4]).This is significant with reduction toxic and side effects for improving targeted nano drug bioavailability, the enhancing targeting to diseased region for the medicine, and then raising curative effect.
Nanoparticle is identified and swallowed by immunocyte, have a strong impact on its effectiveness and toxicity, although current body also not fully aware of, to nanoparticle Immune discrimination and stable mechanism in biological lyase, will become the pith (list of references [5]) of nanoparticle design to the understanding of its recognition mechanism.Design a kind of method (list of references [6]) that aspheric carrier material is very potential escape MPS.Zhou Zhimin assistant researcher's priority reports polylactic acid (PLA) aspherical medicine (epirubicin) carrier (list of references [7]) and the fibrous and bar-shaped aspherical microgranule of Poly(D,L-lactide-co-glycolide (PLGA) (list of references [8]), to designing the carrier being more beneficial for escape MPS.
Impact nanoparticle is also had nano-particles size and surface physicochemical characteristicses such as electric charge, hydrophilic and hydrophobic and surface functional group etc. (list of references [9]) by the factor of endocytosis.Particle diameter easily escapes the identification of MPS in the nanoparticle of below 200nm, and particle diameter reduces, and the phagocytosiss of MPS weaken；Surface charge also can affect the picked-up of MPS, and surface charge absolute value reduces, and its phagocytosis also reduces；By connecting in material, there is hydrophilic material such as Polyethylene Glycol (PEG) (list of references [10]) etc., the dissolubility of lyophobic dust can be improved, specific adsorption is minimized, largely reduce MPS phagocytosis, extend circulation time, and improve fluorescent dye with tumour-specific targeting effect.
In addition, undoubtedly also had for the MPS solving the problems, such as NDDS by Reasonable Regulation And Control cell behavior from immunocyte phagocytosis mechanism angle being of great significance.Increasing researcher is paying close attention to the interaction (list of references [11-12]) of nanoscale medicine delivery system and phagocytosis system, and the phagocytosis approach of nanoparticle, the mathematical model being ingested process and relevant parameter are all just gradually being realized and are setting up (list of references [13]).The picked-up of nanoparticle is mainly carried out by endocytosis (endocytosis) approach, and endocytosis is the complex process that a class is subject to precision control, and it enters born of the same parents' mechanism and there is no consistent conclusion at present.The size of nanoparticle, shape, modification group of electric charge, the material being formed and surface etc. all affect nanoparticle and enter phagocyte.Possible endocytic pathway includes following several：Giant cell drink (macropinocytosis), pinocytosis (pinocytosis), phagocytosis approach (phagocytosis) of clathrin dependency endocytosis (clathrin-dependent endocytosis), little recessed protein dependent endocytosis (caveolin-dependent endocytosis) and dependence actin etc..Gu Jingli etc. (list of references [14]) research finds, almost all of endocytosis signal path has been involved in the process that superparamagnetism Fe nanometer particles (SPION) enter RAW264.7 macrophage, including the many signal paths swallowing and gulping down drink.Lunov seminar (list of references [13]) research shows that extra small paramagnetic iron oxide (USPIO) and Superparamagnetic Iron Oxide (SPIO) nanoparticle are to enter human cytomegalovirus by the endocytosis of clathrin mediation and scavenger receptor mediation.Understand the mechanism of cell endocytic (endocytosis) and particle enter cell approach the problems such as contribute to predicting position in cell for the particle and distribution, provide thinking for limiting phagocyte endocytosis, also provide experimental basis for designing more effective carrier.
On the other hand, research shows that macrophage is secreted and had certain relation (list of references [15]) to the phagocytosis of nanoparticle and inflammatory cytokine, nanoparticle enters body as " foreign body ", activates inflammatory reaction approach, causes inflammatory cytokine to secrete.Inflammatory reaction has been proven (list of references [16]) with the relation of NF-kB signalling channel activation, NF-kB signalling channel Pro-inflammatory mediator TNF-α and IL-1 all can be activated by microbial product lipoprotein LPS, the generation of transmitting inflammation, therefore regulated and controled from NF-kB signalling channel, be that nanoparticle escape phagocytosis provides possibility.
The good biological safety of polysaccharide material makes such nanoscale medicine delivery system have broad application prospects (list of references [17]) in medicine transmission field.Pulullan polysaccharide (pullulan) is a kind of water-soluble, neutral straight-chain polysaccharide, its unique connected mode imparts some unique physicochemical properties of Pullulan, is paid close attention to (list of references [18]) at medical aspect by more and more researcheres.With pulullan polysaccharide as raw material in applicant's previous work, acetyl pullulan (PA) and its Folic Acid zygosome (FPA) are synthesized, it is prepared for form rule, the self-assembled nanometer particle of stable in properties and medicine-carried nano particles, inquire into the slow releasing function (list of references [19-20]) to package-contained medicine epirubicin (EPI) for the carrier, and apply human cervical carcinoma's Hela Nude mice model, investigate the internal distribution characteristicss of FPA medicine-carried nano particles (FPA/EPI).Early-stage Study shows：Such nanoparticle preparation process is simple, and method is reliable, and nanoparticle at least can keep two months particle diameters and surface potential to have no obvious change in aqueous, has preferable stability；Pharmacokinetics in rats test result indicate that, FPA has obvious slow releasing function to package-contained medicine EPI, and substantially change distribution characteristicss in EPI body, FPA/EPI reduces to the gastrointestinal toxicity of animal, its antitumor action time lengthening, has certain cancer target effect, but the phagocytosiss due to liver Kupffer cell, EPI content in liver, apparently higher than free drug group (see Fig. 1), is allowed to application and is restricted.
In existing document, simultaneously application phagocytosis approach restrainer and Nuclear-factor kappa B (NF-kB) signalling channel inhibitor make medicine-carried nano particles escape phagocytosis method there is not been reported.Inventor is on the basis of early-stage Study, application inflammatory cytokine and phagocytosis approach restrainer make FPA/EPI avoid liver KC cell to swallow simultaneously, to realize nanoparticle long circulating in vivo, increase drug effect, reduce toxic and side effects, there is provided scientific basis for realizing the phagocytosis of Nano medication escape immunocyte, above research has no any document or patent report.
Documents below partially or wholly introduces patent specification, as its ingredient.
List of references：
[1]Sheng Y,Liu C,Yuan Y,et al.Long-circulating polymeric nanoparticles bearing a combinatorial coating of PEG and water-soluble chitosan[J].Biomaterials.2009；30(12):2340-8.
[2]Lee H,Lee K,Kim IK,et al.Synthesis,characterization,and in vivo diagnostic applications of hyaluronic acid immobilized gold nanoprobes[J].Biomaterials.2008；29(35):4709-18.
[3]Igarashi E.Factors affecting toxicity and efficacy of polymeric nanomedicines[J].Toxicol Appl Pharmacol.2008；229(1):121-34.
[4]Sanhai WR,Sakamoto JH,Canady R,et al.Seven challenges for nanomedicine[J].Nat Nanotechnol.2008；3(5):242-4.
[5]Karmali PP,Simberg D.Interactions of nanoparticles with plasma proteins:implication on clearance and toxicity of drug delivery systems[J].Expert Opin
Drug Deliv.2011；8(3):343-57.
[6]Christian DA,Cai S,Garbuzenko OB,Harada T,Zajac AL,Minko T,Discher DE.Flexible filaments for in vivo imaging and delivery:Persistent circulation of filomicelles opens the dosage window for sustained tumor shrinkage[J].Mol Pharm.2009；6(5):1343-52.
[7]Zhou Z,Xu J,Liu X,Li X,Li S,Yang K,Wang X,Liu M,Zhang Q.Non-spherical racemic polylactide microarchitectures formation via solvent evaporation method[J].Polymer.2009；50(15):3841-50.
[8]Li R,Li X,Liu L,Zhou Z,Tang H,Zhang Q.High-yield fabrication of PLGA non-spherical microarchitectures by emulsion-solvent evaporation method[J].Macromol Rapid Commun.2010；31(22):1981-6.
[9]Li SD,Huang L.Pharmacokinetics and biodistribution of nanoparticles[J].Mol Pharm.2008；5(4):496-504.
[10]Cheng TL,Chuang KH,Chen BM,Roffler SR.Analytical Measurement of PEGylated Molecules[J].Bioconjug Chem.2012；23(5):881-99.
[11]Braydich-Stolle LK,Speshock JL,Castle A,Smith M,Murdock RC,Hussain SM.Nanosized aluminum altered immune function[J].ACS Nano.2010；4(7):3661-70.
[12]Hueber AJ,Stevenson R,Stokes RJ,Graham D,Garside P,McInnes IB.Imaging inflammation in real time--future of nanoparticles[J].Autoimmunity.2009；42(4):368-72.
[13]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.
[14] Gu Jingli, Xu Haifei, Han Yehua etc. superparamagnetism ferric oxide nanoparticles enter approach, metabolism, home to return to and the biological effect [J] of phagocyte RAW264.7. Chinese science:Life sciences, 2011；41(8):626-39.
[15]Di Gioacchino M,Petrarca C,Lazzarin F,et al.Immunotoxicity of nanoparticles.Int J Immunopathol Pharmacol.2011；24(1Suppl):65S-71S.
[16]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.
[17]Liu Z,Jiao Y,Wang Y,et al.Polysaccharides-based nanoparticles as drug delivery systems[J].Adv Drug Deliv Rev.2008；60(15):1650-62.
[18]Cheng KC,Demirci A,Catchmark JM.Pullulan:biosynthesis,production,and applications[J].Appl Microbiol Biotechnol.2011；92(1):29-44.
[19]Tang HB,Li L,Chen H,Zhou ZM,et al.Stability and in vivo evaluation of pullulan acetate as a drug nanocarrier[J].Drug Deliv.2010；17(7):552-8.
[20] Tang Hongbo, Chen Hongli, Zhou Zhimin, Zhang Tong, Liu Lingrong, Zhang Qiqing *. the preparation of Pullulan base tumor-targeting nanoparticle, stability and release in vitro [J]. Chinese Tissue Engineering Study, 2012,16 (34):6326-30.
Content of the invention
It is an object of the invention to provide a kind of new suppression liver Kupffer's cells swallow the composite restrainer of Nano medication particle, include inflammatory cytokine inhibitor and phagocytosis approach restrainer simultaneously.
It is another object of the present invention to, there is provided a kind of purposes in preparing relevant nanometer drug particle for composite restrainer of liver Kupffer's cells phagocytosis nanoparticle, described composite restrainer includes inflammatory cytokine inhibitor and the phagocytosis approach restrainer of effective dose simultaneously.
To realize foregoing invention purpose by following technical solution.New suppression liver Kupffer's cells of the present invention swallow the composite restrainer of Nano medication particle, including inflammatory cytokine inhibitor and phagocytosis approach restrainer.Specifically：
(1) the phagocytosis approach restrainer described in is one or more of following inhibitor：Giant cell drinks (macropinocytosis) inhibitor such as amiloride (Amiloride, AMR), pinocytosis (pinocytosis), clathrin dependency endocytosis (clathrin-dependent endocytosis) inhibitor chlorpromazine (chlorpromazine, CPZ), little recessed protein dependent endocytosis (caveolin-dependent endocytosis) and phagocytosis approach (phagocytosis) inhibitor relying on actin.
(2) the inflammatory cytokine inhibitor described in is one or more of following inhibitor：NF-kB signalling channel specific inhibitor is Pyrrolididine dithio-carhamate (pyrrolidinedithiocarbamate, PDTC) and other inflammatory factor dexamethasone-the inhibitors etc..
(3) described Nano medication particle contains medicine by following nanoparticle：Acetyl pullulan Folic Acid zygosome nanoparticle, acetyl pullulan nanoparticle and other nanoparticles of being prepared for Material synthesis with polysaccharide.
Thinking of the present invention is unique, and every reagent of addition is easy to get, and for realizing nanoparticle long circulating in vivo, drug effect is better achieved, and reduces toxic and side effects and has great importance.
While giving Nano medication, apply the phagocytosis approach restrainer that inflammatory factor inhibitor and nanoparticle are swallowed by liver cell simultaneously, it is expected realization minimizing Nano medication to be swallowed by liver KC, extend its circulation time in vivo, drug effect is better achieved, reduce toxic and side effects, there is potential applicability in clinical practice.
Brief description
Fig. 1 show each liver after intravenous injection 5mg/kg EPI and FPA/EPI, spleen, lung and kidney epirubicin content (N=5, ng/g)
Specific embodiment
NF-kB signalling channel specific inhibitor and phagocytosis approach restrainer are applied simultaneously to KC picked-up nanoparticle, the secretion situation of examination inflammatory cytokine, verifies the effect of the two-way function inhibitor of the present invention.Using in vitro tests method, Tissue Culture Plate includes 96 orifice plates and/or 6 orifice plates, inflammatory cytokine inhibitor and phagocytosis approach restrainer are incubated a period of time altogether with cell, add medicine-carried nano particles, application ELISA method investigates the situation that liver KC secretes inflammatory cytokine.
[embodiment 1] suppresses KC cell secretion inflammatory factor from NF-kB signalling channel and phagocytosis approach simultaneously
Primary KC, cultured cells 48h are extracted according to list of references, after 0.25% pancreatin/EDTA digestion, adjusts cell density to be inoculated in 96 orifice plates, in 37 DEG C, 5%CO2Cultivate in incubator, when the fully adherent fusion rate of cell reaches 80%, inhale and abandon culture medium, add inhibitor, suppression agent dose is as follows：Chlorpromazine (CPZ) 7 μ g/mL, amiloride (AMR) 50 μM/mL, nysfungin (NY) 50 μ g/mL, Pyrrolididine dithio-carhamate (pyrrolidinedithiocarbamate, PDTC) 10 μM/mL.37 DEG C of incubation 24h, suction is washed 3 times with PBS after abandoning inhibitor solution, adds FPA/EPI nanoparticle suspension (preparing according to list of references 20), 37 DEG C of incubation 2h, each hole takes supernatant 100ul to add ELISA Plate, measures cytokine levels according to ELISA kit description；Smudge cellses, after extraction, fluorescent quantitation surveys nanoparticle phagocytosis EPI content, judges the suppression phagocytosiss of inhibitor according to OD ratio (inhibition percentage=(1-ODt/ODc) × 100%).
From Tables 1 and 2, NF-kB signalling channel inhibitor PDTC can substantially reduce the secretion of inflammatory factor and the picked-up of nanoparticle.Thus illustrate, NF-kB signalling channel inhibitor can effectively suppress liver Kupffer's cells phagocytosis Nano medication particle.When being simultaneously introduced PDTC and CPZ, two kinds of inhibitor of AMR or NY, cytokine levels reduce further, KC phagocytosis FPA/EPI picked-up inhibition percentage increases further, reach as high as 85.39%, substantially reduce nanoparticle and swallowed entrance Kupffer's cells, thus illustrate, application NF-kB signalling channel inhibitor PTDC and phagocytosis approach restrainer chlorpromazine, amiloride or nysfungin create collaborative depression effect simultaneously.
Table 1NF-kB signalling channel inhibitor and the phagocytosis impact to KC inflammatory factor level for the inhibitor (pg/mL,)
Table 2NF-kB signalling channel inhibitor and phagocytosis inhibitor swallow, to KC, the impact (%) that FPA/EPI absorbs inhibition percentage
Fund information
Beijing's Natural Science Fund In The Light, the effect of targeted nanometer delivery system FPA/EPI escape Kupffer cell phagocytosis and Mechanism Study (7132064)
Claims (6)
1. a kind of suppression liver Kupffer's cells swallow the composite restrainer of Nano medication particle, include effectively simultaneously
The inflammatory cytokine inhibitor of amount and phagocytosis approach restrainer：
Described phagocytosis approach restrainer is one or more of following inhibitor：Giant cell drink inhibitor, pinocytosis,
Clathrin dependency endocytosis inhibitor, little recessed protein dependent endocytosis and the phagocytosis approach relying on actin
Inhibitor；
Described inflammatory cytokine inhibitor is one or more of following inhibitor：NF-kB signalling channel
Specific inhibitor and other inflammatory factor inhibitor；
Described Nano medication particle contains medicine by following nanoparticle：Acetyl pullulan Folic Acid zygosome nanoparticle
Son, acetyl pullulan nanoparticle and other nanoparticles of being prepared for Material synthesis with polysaccharide.
2. composite restrainer according to claim 1, wherein：Described phagocytosis approach restrainer be Ah
Meter Luo Li, chlorpromazine or nysfungin.
3. composite restrainer according to claim 1, wherein：Described inflammatory cytokine inhibitor
For Pyrrolididine dithio-carhamate.
4. composite restrainer according to claim 1, wherein：Described Nano medication particle is general by acetyl
Shandong orchid Folic Acid zygosome nanoparticle contains medicine epirubicin.
5. composite restrainer according to claim 1, includes tetrahydropyrrole dithiocarbamates first simultaneously
Acid esters and chlorpromazine or amiloride or nysfungin, described Nano medication particle is even by acetyl pullulan Folic Acid
Fit nanoparticle contains medicine epirubicin.
6. purposes in preparing relevant nanometer drug particle for the composite restrainer described in any of the above claim.
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| CN114848644A (en) * | 2022-04-20 | 2022-08-05 | 深圳市龙华区人民医院 | Nano-targeting sustained-release drug, and preparation method, device and application thereof |
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| CN114848644A (en) * | 2022-04-20 | 2022-08-05 | 深圳市龙华区人民医院 | Nano-targeting sustained-release drug, and preparation method, device and application thereof |
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