CN101318054B - Microelectro field net guided transfer apparatus for medicament of liver target cell - Google Patents
Microelectro field net guided transfer apparatus for medicament of liver target cell Download PDFInfo
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- CN101318054B CN101318054B CN200810043641XA CN200810043641A CN101318054B CN 101318054 B CN101318054 B CN 101318054B CN 200810043641X A CN200810043641X A CN 200810043641XA CN 200810043641 A CN200810043641 A CN 200810043641A CN 101318054 B CN101318054 B CN 101318054B
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Abstract
The invention provides a drug transfer device in the liver targeting cells led by a micro electric field net and pertains to the medical field. The drug transfer device comprises a drug transfer pipe, which is characterized in that at least two drug input holes and a first electrode group are arranged at the front end of the drug transfer pipe; a second electrode group is arranged out of the liver; the first and the second electrode groups are electrically connected with the impulse output end of a generator with low pressure and micro electric field; and the drug transfer pipe is communicated with the drug transfer device. By providing a multidimensional/three-dimensional low/micro pressure electric field, 'permeability' of cell membrane can be improved obviously, and the acceptance dosage of targeting cells or organs is increased greatly. Not only the targeting cells or organs can not be injured, but also the targeting performance aiming at liver cancer cells is improved to an extreme extent and the side effects to the whole body of a sufferer is lowered. The drug transfer device can be extensively used in the clinic application field of drug/gene treatment.
Description
Technical field
The invention belongs to medical domain, relate in particular to a kind of being used for medicine is sent to intended target and helped to increase the medical treatment device of its permeability.
Background technology
It is prevailing pernicious constitutional liver neoplasm that primary hepatocellular carcinoma (hcc) (calling hepatocarcinoma in the following text) has another name called liver tumor.Hepatocarcinoma is one of three big fatal cancers in many Asia and African country.
According to the Ministry of Public Health statistics, annual about 130,000 people of China die from hepatocarcinoma, account for 40% of global PLC mortality sum.
The hepatocarcinoma onset is concealment, has belonged to middle and advanced stage as obvious clinical symptoms.Can undergo surgery the excision, only account for hepatocarcinoma patient 10-15%, even excised, relapse rate is up to about 60%.Because its early symptom is not obvious, be easy to out in the cold, and once find patients more than half be in, late period.In, the advanced liver cancer patient is not as treating, the average life span had only about 3 months.It is thus clear that hepatocarcinoma is one of the poorest malignant tumor of prognosis.
Supporting/auxiliary treatment means as excision adopts embolic chemotherapy usually.
But the general chemotherapy side effect is big, and like intestines and stomach reaction, bone marrow depression etc., due to illness the people is difficult to tolerate and can only does the treatment of discontinuity; But in the treatment intermission, the growth of tumor cell has surpassed normal cell widely, so weak curative effect, systemic chemotherapy does not have obvious raising to liver cancer patient survival rate and life span.
Getting involved chemotherapy and thromboembolism (Transcatheter Arterial Chemoembolization TACE) is the prefered method of present non-operative treatment; Chemotherapeutic is injected in the supply artery of the tumor; Can make local drug concentration than high tens of times of systemic chemotherapy, the thromboembolism tremulous pulse can make tumor dwindle because of ischemia after the medication.But the drug level in the hepatic tissue of this " property crossed " increases, and can not make that the drug level in the tumor cell rolls up, and only being less than 20% patient's tumor dwindles, and most medicine still gets into the body circulation, and side effect is still very big.
Simultaneously, arterial thrombosis often is directed at vascular occlusion, and can not repeatedly treat, and originality VEGF (Vascular Endothelial Growth Facotr, vascular endothelial cell growth factor) increases in can causing, a large amount of hypertrophy of intratumoral vasculature.Therapeutic effect is still undesirable.
As everyone knows, most anticarcinogens will get into cell and just can work.And all administering modes can only make the 5-15% medicine get in the cell so far.So, for reaching therapeutic effect, must improve drug dose, and must cause the side effect of great part and/or whole body like this.
In order to make more dose get into cell interior, " permeability " problem that improves cell membrane is clearly proposed.
Electroporation is to be employed at most in the method in the past a kind of electricity consumption to increase the permeability method of cell membrane.Electroporation technology is in the prior art allogenic gene to be imported active somatic cell effective method the most, and its genetically modified effectiveness in the live body body will be similar to or be higher than virus and any other method.
Specifically, electroporation is that a kind of electric pulse generator that adopts applies the electric pulse of short time, certain intensity to cell or tissue, and exogenous gene through electric field action, is imported the technology of animal target tissue or organ.
Because this method can effectively import exogenous gene; Can on multiple histoorgan, use, and efficient is higher, the live body electroporation report that is used for transgenic research is on the increase in recent years; Advantage aspect gene therapy is increasingly significant also, is a kind of good live body method of gene introduction.
Its concrete principle is; The electric pulse of electric pulse generator (electricity irritation) can cause cell membrane unstable, forms the hole (or minim channel) of nanoscale size then, and this passage can be kept several milliseconds to several seconds; Recover voluntarily then, present a kind of specific " permeable " state.At this " permeable " state, cell membrane allows DNA, enzyme, antibody and other macromole to get into cell through cell membrane.Electroporation not only makes gene therapy, also makes other field such as transdermal drug delivery and chemotherapy become possibility.
Since twentieth century eighties is early stage, adopted electroporation DNA, RNA, protein, other macromole, liposome, latex beads or whole virus particles to be imported in the living cells as research tool.
Electroporation is usually used in the outer-gene transfection, and existing available a pair of aciculiform of report or plate shape electrode are implemented vivo gene transfer at rodentine tumor, liver, myocardium, but this type of research work is limited.In recent years, just adopt the electroporation conduit with the ductus arteriosus wall of delivery heparin to rabbit and significantly improved drug delivery efficiency.
Open day is on January 31st, 2007, and publication number is the Chinese invention patent application " system and method that is used for transdermal delivery " of CN1905920A, can be used as a kind of example or the guidance of disclosed electroporation technology.
But on the other hand, the electric pulse of the high electric field intensity that existing electric pulse generator is produced can cause cell membrane permanent damage (lysis).According to the knowledge of having grasped at present; The voltage that puts on any kind cell in the specimen cup, full embryo or embryo heart must be up to 200-1500V/cm; And the voltage that any in-vivo tissue is applied when adopting aciculiform or plate shape electrode must be up to 100-200V/cm; If we use electroporation on large animal or human organs (for example human heart), voltage must reach several kilovolts.This will cause a large amount of tissue injurys.Therefore, this technology is not applied to clinical medicine always as yet.
Simultaneously; Because electroporation moment can produce big calorimetric in the part; Therefore in operating process; Exogenous gene or DNA transfection reagent etc. need remain on a lower temperature (for example 4 ℃), need carry out suitable cooling to the electroporation operating position simultaneously, and this has brought certain restriction to its enforcement and application.
Once sent as dermal drug with electroporation device, and adopted 2-6 syringe needle on skin, to implement the high voltage short-time pulse, this system is owing to the direct injury and the high voltage impact of syringe needle have caused significant skin injury and inflammation to limit its application.
Simultaneously, in the actual clinical practice, chemicals or allogenic gene infusion application are in skin, skeletal muscle or the tumor of muroid animal tissue or live body.For the live body transgenic of whole organ, it is to accomplish in the dirty method through direct gene injection and single needle or the insertion of six needle electrodes of rat, mice or Hepar Felis domestica that few studies is only arranged.This method can only be to around the entry needle, the effect of organizing in diameter＜0.8 cm range, and also needle stick injuries is also big, can only be used for body surface at most, can not be used for big organ in the human body, after one's own heart, liver, lung, kidney etc.
So; In medical research and clinical treatment, press for a kind of " permeability " that can either improve cell membrane, increase it and receive dose; Can not damage again, can also reach the interior drug delivery devices of cell that " low dosage, long-time " transmits effect target cell or organ.
Summary of the invention
Technical problem to be solved by this invention provides drug delivery device in the net guided liver target sexual cell of a kind of electric microfield; Its through provide a kind of multidimensional/spatial low/the micro voltage electric field; Can obviously improve " permeability " of cell membrane; Can increase the dose that receives of target cell or organ significantly, can not damage target cell or organ again, the targeting property that has farthest improved to HCC has also greatly reduced the side effect to patient's whole body.
Technical scheme of the present invention is: drug delivery device in the net guided liver target sexual cell of a kind of electric microfield is provided; Comprise the medicine delivery catheter that gets into liver via endoscope or indwelling tube along blood vessel; It is characterized in that:, at least two the medicine input holes and the first electrode group are set at the front end of medicine delivery catheter; In the outside of liver, the second electrode group is set; The described first and second electrode groups are electrically connected with the pulse output end of low voltage micro-electric field generator; Described medicine delivery catheter is communicated with delivery device.
Wherein, its first electrode group is a plurality of ring-types, point-like or strip shaped electric poles.
Its second electrode group is a plurality of strip shaped electric poles or a mesh electrode.
Concrete, its first and/or second electrode group is for being arranged on metallic conduction silk or the conductive foil layer in the insulating thin layer.
Its metallic conduction silk or conductive foil layer are strip or netted being arranged in the insulating thin layer.
Its metallic conduction silk or conductive foil layer with the alternate version of positive and negative electrode, are strip or netted being arranged in the insulating thin layer.
Further, its first and/or second electrode group through being attached thereto and penetrating the conductiving point of insulation film laminar surface, constitutes lattice-like electrode group at the insulation film laminar surface.
Positive and negative electrode in its first and/or second electrode group is through after gathering/confluxing; Respectively with the corresponding electrical connection of positive and negative pulse output end of low voltage micro-electric field generator; Inner at liver surface and/or liver, form multidimensional, spatial, even and intensive electric microfield net.
Compare with prior art, advantage of the present invention is:
1. adopt the first and second electrode groups to combine; At liver surface and/or multidimensional, spatial electric microfield net of the inner formation of liver; Shrouding electric field network even and intensive on liver can be so that temporary structural change takes place in the cell membrane of each cell, and the permeability of cell membrane and affinity increase;
2. adopt low/minute-pressure electric field, kept the integrity of cell membrane largely, can not damage, avoided cells injury target cell or organ;
3. electrode and medicine input pipe are combined; Medicine is transported to each cell of liver organ through blood vessel when; Give impulse wave and increase in the liver organ permeability of cell membrane on each cell; Let medicine pass through cell membrane and get in each cell, get in the cell but the utmost point is beneficial to the help medicine;
4. electrode directly contacts with liver organization, has eliminated the decay of the electric field intensity that the distance of being deposited between electrode and the target cell causes fully;
5. because medicine is directly sent to Target organ, except the high characteristics of drug delivery efficient are arranged, the most important thing is not have the side effect of significantly local and whole body.
Description of drawings
Fig. 1 is the structural representation of the front end of medicine delivery catheter of the present invention;
Fig. 2 is the structural representation of the present invention's second electrode group;
Fig. 3 is the structural representation of electrode and conductiving point joint portion;
Fig. 4 is the structural representations of the first and second electrode groups at the inner electric field net that is produced of liver;
Fig. 5 is the another kind of distributed architecture sketch map of the first electrode group;
Fig. 6 is the another kind of distributed architecture sketch map of the second electrode group,
Fig. 7 is the C portion structure cutaway view Amplified image of Fig. 6.
10 is the medicine delivery catheter among the figure, and 11 is the first electrode group, and 12 is the medicine input hole, and 13 is lead; 20 is insulating thin layer, and 21,22 is the positive and negative electrode that is made up of metallic conduction silk or conductive foil layer, and 23 is conductiving point; 24,25 is busbar, and 30 is liver organ, and 31 is target canceration position; 32 is blood vessel, and 33 is electric field line, and 34 is multidimensional, three-dimensional electric microfield net.
The specific embodiment
Below in conjunction with accompanying drawing and embodiment the present invention is further specified.
Among Fig. 1,, at least two the medicine input holes 12 and the first electrode group 11 are set, connect through lead 13 between each electrode group at the front end of medicine delivery catheter 10.
Its first electrode group is a plurality of ring-types, point-like or strip shaped electric poles, and electrode is a circulus among this figure.
Among Fig. 2, the second electrode group is metallic conduction silk or conductive foil layer 21 and/or 22 that are arranged in the insulating thin layer 20.
Its metallic conduction silk or conductive foil layer are strip or netted being arranged in the insulating thin layer.
Electrodes use list structure among this figure; Its anelectrode 21 and negative electrode 22 alternate settings; After its positive and negative electrode gathers through the busbar 24,25 that is positioned at insulation film 20 two ends, through lead respectively with the corresponding electrical connection of positive and negative pulse output end of low voltage micro-electric field generator.
Visible by figure, metallic conduction silk or conductive foil layer 21 or 22 of formation electrode group through being attached thereto and penetrating the conductiving point 23 on insulating thin layer 20 surfaces, constitute lattice-like electrode group at the insulation film laminar surface.
About the related data of low voltage micro-electric field generator, the Chinese patent of can the REFERENCE TO RELATED people applying for before this 200810036767.4 or 20082005784.2 and International Patent Application PCT/CN2008/001022 in related content, no longer narrate at this.
What should state is, the disclosed content of above-mentioned reference paper should be regarded the application's background information or explanatory data as, and should not regard as certain restriction of the application or define.
Among Fig. 3, constitute metallic conduction silk or the conductive foil layer (among the figure be example with anelectrode 21) of electrode group,, constitute lattice-like electrode group at the insulation film laminar surface through being attached thereto and penetrating the conductiving point 23 on insulating thin layer 20 surfaces.
When actual fabrication, conductiving point can adopt platinum or tungsten gold point, and the method that also can be employed in breakthrough point chemical plating conducting metal (like copper, silver etc.) obtains conductiving point, because of it is a prior art, no longer narrates at this.
Among Fig. 4; The medicine delivery catheter 10 that gets into liver 30 along blood vessel 32 is provided with the first electrode group 10 (being anelectrode here); Outer setting in liver organ has strip or the netted second electrode group 22 (being negative electrode here); When positive and negative electrode with after low voltage micro-electric field generator (not shown) is connected; In its driving and control down, can set up and produce multidimensional, the three-dimensional electric microfield net 34 that is constituted by plurality of electromagnetic line 33 between the positive and negative electrode, target canceration position 31 integral body placed act among the electric field.
For the drawing part electric field line that only drawn for purpose of brevity, in fact, between every pair of positive and negative electrode, all have electric field line among the figure, this is a common practise.
In Fig. 5, the another kind of version of the first electrode group that is positioned at medicine delivery catheter 10 front ends is disclosed, its first electrode group is distributed alternately by anelectrode 11-1 and negative electrode 11-2 and constitutes, and this moment, the first electrode group was the strip shaped electric poles group.
Can also adopt the arranged in form first electrode group of point-like electrode group, its concrete distribution form is no longer narrated at this.
All the other same Fig. 1.
Among Fig. 6, disclose the another kind of distributed architecture of the second electrode group, it is arranged on metallic conduction silk or conductive foil layer 21 and/or 22 in the insulating thin layer 20 and is netted and is arranged in the insulating thin layer.Wherein conductive filament or conductive foil layer 21 are anelectrode, and conductive filament or conductive foil layer 22 are negative electrode, and it forms the electrode dot matrix through conductiving point 23 on the surface of insulation film respectively.
All the other same Fig. 2.
Among Fig. 7, anelectrode 21 and negative electrode 22 cross-distribution are in insulation film 20, and it is respectively through conductiving point 23 and 23 ' at the surface of insulation film formation electrode dot matrix.
All the other are with Fig. 2 or Fig. 3.
Should be noted that; The version of its first and/or second electrode group should only not be confined to above-mentioned several kinds of listed modes; In order to obtain the stack of better Electric Field Distribution effect and/or electric field intensity; The distribution of electrodes shape of various geometric shapes (such as strip, netted, ring-type, irregular curve shape, even some conic section shape) all is attemptable.
For the ease of operation, as a kind of special case, its second electrode group even can directly adopt wire mesh electrode to be covered in to be positioned at the surface at human liver position also can play identical effect.
Because electrode directly contacts with tissue, the decay that this has eliminated the great electric field intensity that the distance of being deposited between electrode and the target cell/tissue causes fully also helps reaching the purpose of increase permeability of cell membrane.
In technique scheme and each embodiment; Why take the distribution of electrodes form of various geometries, its purpose is exactly on liver organ surface or inner, or even in its certain inner target area; More electric field intensity as much as possible superposes; Through high as far as possible effect effect of electric field, the permeability of cell membrane on each cell in the increase liver organ as much as possible helps medicine to get in the cell.And numerous electric microfield intersects, overlapping, intert in tissue, so just no longer need high voltage, also be enough to reach the purpose of increase permeability of cell membrane.Simultaneously, can use continuous a plurality of pulse, for example the string bundle-interval method that replaces the program pulse of (Burst) increases action time.
After adopting technique scheme; Through test; Adopt the pulse voltage of volt level or millivolt level; Also can not produce damage with continuous 5 hours of the method, and 60～70% medicine is got in the cell histiocyte, be far superior to prior art (adopt hectovolt superfine in addition more voltage levels pulse voltage; 5～15% dose is got in the cell) drug delivery efficiency, farthest improved to the targeting property of HCC and greatly reduced side effect patient's whole body.
Each above embodiment is used for explaining and explaining of the present invention; And be not with the qualification of doing the invention scope of claim of the present invention; Those of ordinary skill in the art can make various variations or distortion to the present invention fully under the situation that does not deviate from thinking of the present invention and scope.
Think that especially like those of ordinary skills, with that kind that existing knowledge or designing institute are afterwards seen, the unsubstantiality that the theme that requires to protect is carried out changes, in the scope that drops on the application's claim comparably.
Therefore, those of ordinary skills also should belong in the scope that has defined key element at present or the obvious replacement of knowing afterwards.
Therefore, those of ordinary skill in the art will be appreciated that, as long as in connotation scope of the present invention, to variation or the distortion of above each embodiment, all will drop in the application's the desired protection domain of claim.
The present invention can be widely used in medicine/clinical application of gene therapy field.
Claims (6)
1. drug delivery device in the net guided liver target sexual cell of an electric microfield comprises via endoscope or indwelling tube getting into the medicine delivery catheter of liver along blood vessel, at the front end of medicine delivery catheter, is provided with at least two medicine input holes, it is characterized in that:
At the front end of medicine delivery catheter, the first electrode group is set;
In the outside of liver, the second electrode group is set;
The described first and second electrode groups are electrically connected with the pulse output end of low voltage micro-electric field generator;
Described medicine delivery catheter is communicated with delivery device;
Wherein, the described first electrode group is a plurality of ring-types, point-like or strip shaped electric poles;
The described second electrode group is a plurality of strip shaped electric poles or a mesh electrode.
2. according to drug delivery device in the net guided liver target sexual cell of the described electric microfield of claim 1, it is characterized in that the described first and/or second electrode group, for being arranged on metallic conduction silk or the conductive foil layer in the insulating thin layer.
3. according to drug delivery device in the net guided liver target sexual cell of the described electric microfield of claim 2, it is characterized in that described metallic conduction silk or conductive foil layer, be strip or netted being arranged in the insulating thin layer.
4. according to drug delivery device in the net guided liver target sexual cell of the described electric microfield of claim 3, it is characterized in that described metallic conduction silk or conductive foil layer,, be strip or netted being arranged in the insulating thin layer with the alternate version of positive and negative electrode.
5. according to drug delivery device in the net guided liver target sexual cell of the described electric microfield of claim 1; It is characterized in that the described first and/or second electrode group; Through being attached thereto and penetrating the conductiving point of insulation film laminar surface, constitute lattice-like electrode group at the insulation film laminar surface.
6. according to drug delivery device in the net guided liver target sexual cell of the described electric microfield of claim 1; It is characterized in that positive and negative electrode in the said first and/or second electrode group is through after gathering/confluxing; Respectively with the corresponding electrical connection of positive and negative pulse output end of low voltage micro-electric field generator; Inner at liver surface and/or liver, form multidimensional, spatial, even and intensive electric microfield net.
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| CN200810043641XA CN101318054B (en) | 2008-07-18 | 2008-07-18 | Microelectro field net guided transfer apparatus for medicament of liver target cell |
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| CN200810043641XA CN101318054B (en) | 2008-07-18 | 2008-07-18 | Microelectro field net guided transfer apparatus for medicament of liver target cell |
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| CN101318054B true CN101318054B (en) | 2012-01-25 |
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| CN106823145A (en) * | 2017-03-24 | 2017-06-13 | 长沙普特斯科技有限公司 | A kind of device of use amplitude modulation electric field treatment tumour |
| CN106823125A (en) * | 2017-03-24 | 2017-06-13 | 长沙利星医药科技开发有限公司 | A kind of device of use amplitude modulation electric-field enhancing curative effect of medication |
| CN107362445A (en) * | 2017-08-30 | 2017-11-21 | 东北师范大学 | Anticancer targeting medicine points to electrostatic field resultant vector intensifier |
| CN110464506B (en) * | 2018-05-08 | 2023-09-01 | 柔脉医疗(深圳)有限公司 | Electronic blood vessel capable of introducing medicine in situ, preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6654636B1 (en) * | 1998-07-13 | 2003-11-25 | Genetronics, Inc. | Skin and muscle-targeted gene therapy by pulsed electrical field |
| WO2007120557A2 (en) * | 2006-04-10 | 2007-10-25 | The Regents Of The University Of California | Method and apparatus of low strengh electric field network-mediated delivery |
| CN101119735A (en) * | 2005-03-19 | 2008-02-06 | 加利福尼亚大学董事会 | Ultra low strength electric field network-mediated ex vivo gene, protein and drug delivery in cells |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6654636B1 (en) * | 1998-07-13 | 2003-11-25 | Genetronics, Inc. | Skin and muscle-targeted gene therapy by pulsed electrical field |
| CN101119735A (en) * | 2005-03-19 | 2008-02-06 | 加利福尼亚大学董事会 | Ultra low strength electric field network-mediated ex vivo gene, protein and drug delivery in cells |
| WO2007120557A2 (en) * | 2006-04-10 | 2007-10-25 | The Regents Of The University Of California | Method and apparatus of low strengh electric field network-mediated delivery |
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