A kind of functional targeting therapeutic degradable biological bracket
Technical field
The present invention relates to a kind of functional targeting therapeutic degradable biological bracket, particularly a kind of by the matrix of the synthetic novel Biodegradable material of high molecular structural design as support, appendix certain drug or radioactive substance on matrix, make behind the support implant into body tube chamber when providing mechanics to support to narrow, block, lesions position slow releasing pharmaceutical such as tumor and carry out radiation treatment.This multi-functional degraded support with comprehensive therapy can be applicable to Wicresoft's interventional therapy clinical medicine domain, for the human organ tube chamber narrow, block or tumor plays significantly and the positive therapeutic effect.
Background technology
Along with the raising of people's living standard and the change of living habit and diet structure, digestive system disease, cardiovascular and cerebrovascular disease etc. is just presenting the trend of rising, and toward becoming younger development.Each organ tube chamber of digestive tract, cardiovascular and cerebrovascular vessel narrow or to block be the common complication of digestive system, blood circulation diseases is divided into optimum and malignant stricture or block two classes.Traditional Drug therapy and surgical operation therapy effect are limited, and implant frame becomes a kind of effective minimally-invasive treatment technology in development in recent years, it is a kind of quick, the effective and comparatively safe medical procedure of treatment digestive tract, cardiovascular and cerebrovascular vessel benign and malignant stenosis or obstruction, do not control or the disease of refractory has been opened up new treatment approach for traditional operation, improved the existence time limit and the quality of life of tumor patient.
Current widely used support mainly is metal and alloy bracket thereof from the angle of material, secondly is plastic rubber bracket.Though these widely used supports have played effective function clinically, also exist problems, such as implanting the back constant pain, have long term complication, treating ratio height or the like again.In addition, metal rack is not because of degrading, be difficult to again take out, finally retain in the body for a long time as a kind of foreign body, can cause gastral chronic injury, in the course of time cause the atrophy of internal layer muscle, aneurysmal formation and reactive neointimal hyperplasia easily, even cause digestive tract and arterial vascular restenosis.So strict to the restriction ratio of metal rack indication clinically, only limit to malignant tumor in general, there is the expert advice metal rack should classify taboo as for benign stricture.So, in fact just influenced this treatment means of inner support scope of application clinically.In addition, metal rack is very expensive, so the main expectation survival period that is fit to is tumor patient more than 3 months or economic condition permission person.
The biological degradability support can decompose after certain treatment cycle finishes in vivo, has exempted the misery of taking out once more, provides a good clinical solution for the digestive tract benign stricture and for the acute obstruction relief of symptoms in order to choosing date for operation.
To study at present and use many degraded macromolecular materials mainly be polylactide (polylactic acid), poly-Acetic acid, hydroxy-, bimol. cyclic ester and copolymer thereof, obtained the polylactic acid-based material of different structure, different performance by selecting different comonomer people.But the synthetic relatively difficulty of polylactic acid, the molecular weight of product that the direct polymerization method obtains is not high enough, and two-step method synthesis technique complexity adds that cost of material is higher, causes the cost of polylactic acid very high, has limited it and has used widely.
The research of China's inner support is started late, and except some support was innovated aspect processing technology, configuration improvement to some extent, quite a few only belonged to the imitation imported product, from material, mainly is nondegradable metal, plastic rubber bracket.
The inventor thinks from the biodegradation support of the own intellectual property of height development of material design, to make China occupy leader status in worldwide interventional therapy material field, not only have very big medical value, and have positive social meaning, huge market prospect.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of degradable is provided and has good mechanics retractility and supportive, and the biological support that can treat wound surface.This support can be widely used in tube chamber in the human organ narrow, block and tumor treatment.
The technical conceive of the innovation invention is, utilize means such as high molecular polymerization, copolymerization, blend Polyalkylcyanoacrylanano to be become to have the porous substrate of excellent mechanical performances for the degradable polymer material preparation on basis, medicines such as recombination line rhzomorph D (dactinomycin), paclitaxel, paclitaxel derivant (as taxotere), five fluorouracil, rapamycin, 5-Fu suppress tumor on porous substrate, simultaneously appendix radioelement on porous substrate
99Tc
m,
192Ir,
125I carries out radiotherapy to tumor, has opened up new treatment approach, has improved the existence time limit and the quality of life of tumor patient.
Technical scheme of the present invention is as follows:
Functional targeting therapeutic degradable biological bracket, comprise base material with degradability and good mechanical performance, and on base material compound antitumor drug layer and radioelement layer, it is characterized in that: the surface of support is also carried and has been covered the rate of release of control slow release putting material with the control antitumor drug.
Described degradability biological support base material be homopolymer with Polyalkylcyanoacrylanano of good biocompatibility and degradability, copolymer and with the blend of other conventional degradable high polymer materials.The chemical constitution expression way of Polyalkylcyanoacrylanano is as follows:
Wherein, R
1, R
2, R
3, R
4Can be different respectively various organic substituents, also can be part or all of identical organic substituent.For each substituent group, known their the various isomers of those skilled in the art also ought to have been comprised.
The sequential structure of Polyalkylcyanoacrylanano macromolecular chain, can be that (n=0 is p=0 simultaneously for the monomeric homopolymer of alkyl cyanoacrylate class, or m=0 while p=0), also can be the monomeric copolymer of two or more alkyl cyanoacrylate class (p=0), can also be the copolymer (p ≠ 0) of one or more alkyl cyanoacrylate class monomers and alkyl acrylate ester monomer.
Described biodegradable timbering material has fine solubility energy and melting behaviour, thereby is easy to be processed into different configurations according to the construction features of each organ tube chamber of digestive system, blood circulation and urinary system.
Described antitumor drug layer is line rhzomorph D (dactinomycin), paclitaxel, paclitaxel derivant (as taxotere), five fluorouracil, rapamycin, 5-Fu or other antitumorigenic substance.Described radiotherapy material is
99Tc
m,
192Ir,
125I or other radioactive element.Antitumor drug and radiotherapy material pass through the mode appendix of chemical bonding or physically trapping in the inside of porous support materials.
Described support base material has good physical and mechanical property, radial support power 〉=5N, and maximum radial support force≤28N, the support of diameter 〉=20mm can be compressed to diameter between 6-9mm; Diameter can be compressed between the diameter 2.5-6mm at the support of 10-20mm.
The degradation rate of described timbering material can carry out accuracy controlling by the micro structure of macromolecular chain and the mesoscopic structure of material, and degradation cycle can be selected arbitrarily between three months to 2 years.
The catabolite of described timbering material Polyalkylcyanoacrylanano is water miscible paracyanogen base acrylic acid, and it is not stored in the tissue, can excrete from urine.Polyalkylcyanoacrylanano copolymer and blend thereof, disintegrate finally reaches the degraded to integral material to its material along with the degraded of Polyalkylcyanoacrylanano composition.
Technique effect of the present invention is as follows:
When a kind of functional targeting therapeutic degradable biological bracket provides mechanics to support to the tube chamber of human lesion organ, can also carry out the medicine chemotherapy and radiation to primary affection, the hypertrophy and even the tube chamber restenosis that suppress inner membrance and fibrous tissue have effectively improved the existence time limit and the quality of life of tumor patient.
Description of drawings
Fig. 1 is the structural representation of functional targeting therapeutic degradable biological bracket of the present invention, and wherein A portion represents the enlarged drawing of support section structure.
Fig. 2 is used for esophagostenosis or the outline drawing of the degradable biological support that blocks.
Fig. 3 is used for duodenal stenosis or the outline drawing of the degradable biological support that blocks.
Fig. 4 is the outline drawing that is used for the narrow or degradable biological support that blocks of arteries.
Fig. 5 is the electron scanning micrograph of the medicine-carried nano particles of particle diameter 220nm.
Fig. 6 is the electron scanning micrograph of the medicine-carried nano particles of particle diameter 105nm.
Fig. 7 is the electron micrograph in the timbering material cross section of appendix medicine-carried nano particles
Reference numeral is as follows:
1. multiporous biological support base material 2. suppresses the tumour medicine layer, and 3. radioactive substance is 4. controlled slow release and put clad.
Specific implementation method
The present invention is described in further detail below in conjunction with accompanying drawing.
The base material Polyalkylcyanoacrylanano homopolymer of functional targeting therapeutic degradable biological bracket and the synthesis technique of copolymer thereof are undertaken by radical polymerization as well known to those skilled in the art or anionic polymerisation.Concrete polymerization comprises polymerisation in bulk, polymerisation in solution, suspension polymerisation, emulsion polymerisation, micro-emulsion polymerization, inverse emulsion polymerization, dispersin polymerization or the like.Preferred emulsion polymerization of the present invention, its major advantage are to obtain very high polymer molecular weight (factor that speed is improved often makes molecular weight reduce) when improving rate of polymerization.The viscosity of emulsion and polymer molecular weight and polymer content relation is little in addition, and system viscosity is little, helps mass-and heat-transfer.
The base material of functional targeting therapeutic degradable biological bracket except the homopolymer and the copolymer thereof of the above Polyalkylcyanoacrylanano, has also comprised the blend of Polyalkylcyanoacrylanano homopolymer and copolymer and common high molecular materials.They comprise: polyacrylic acid, polymethylacrylic acid, polymethyl acrylate, polymethyl methacrylate, polyethyl acrylate, butyl polyacrylate, polystyrene, polyvinyl acetate, poly hydroxy ethyl acrylate, polyvinyl pyrrolidone, and other have the macromolecular compound of monomer polymerizations formation of similar unsaturated structure.Polyalkylcyanoacrylanano homopolymer and copolymer thereof can also form mechanical property and the degradation property of blend to improve material with some known degradable materials, these known degradation materials are polylactic acid, polyglycolic acid, synthesized degradable macromolecular materials such as polylactic acid/hydroxy acetate multipolymer, poe, polyamino acid, natural degradable macromolecular materials such as collagen protein, gelatin, agar, glucosan, chitosan, hyaluronic acid, and natural degradable inorganic material such as hydroxyapatite, calcium phosphate and Corallium Japonicum Kishinouye.
Functional targeting therapeutic degradable biological bracket, its structure is formed as shown in Figure 1, wherein A portion represents the enlarged drawing of support section structure, comprise porous substrate 1 with degradability and good mechanical performance, and on porous substrate compound antitumor drug layer 2 and radioelement layer 3, in addition, the surface of support is also carried and has been covered control slow release putting material 4 rate of release with the control antitumor drug.
The functional targeting therapeutic degradable biological bracket material, have fine solubility energy and melting behaviour, can be processed into different configurations according to the construction features of each organ tube chamber such as digestive system, blood circulation and urinary system, be illustrated in figure 2 as the outline drawing of the degradable biological support that is used for esophagostenosis or blocks, Fig. 3 is used for duodenal stenosis or the outline drawing of the degradable biological support that blocks, and Fig. 4 is the outline drawing that is used for the narrow or degradable biological support that blocks of arteries.
The appendix of the antitumor drug layer of functional targeting therapeutic degradable biological bracket is to be loaded in the space of base material by immersion, lyophilization, antitumor drug is line rhzomorph D (dactinomycin), paclitaxel, paclitaxel derivant (as taxotere), five fluorouracil, rapamycin, 5-Fu, etc.The homopolymer of Polyalkylcyanoacrylanano and copolymer, contain numerous cyano functional group (C ≡ N) on its macromolecular chain, its reactivity is very high, derives many other functional groups easily thereby can make cyano group that a series of subsequent reactions take place according to actual needs.Such as, can obtain carboxyl (COOH) by hydrolysis, carboxyl under weak basic condition (as ammonia, NH
3H
2O) can be converted into amide group (CONH
2), pass through Huffman (hoffman) degraded again and can change amido (NH into again
2), utilize this a series of subsequent reactions can obtain some needed functional groups, obtain a kind of functional surface, come the various medicines of bonding with this then.
Functional targeting therapeutic degradable biological bracket antineoplastic radioelement comprises
99Tc
m,
192Ir,
125I etc., by the surface grafting polymerization that ultraviolet light, plasma etc. cause, the macromolecular chain that will have functional groups is incorporated into the surface of timbering material, forms one deck " polymer brush ".By the above-mentioned radioelement of these functional group chelatings, can realize located irradiation treatment to tumor.
In order to increase the appendix amount of material to chemotherapeutics and radioelement, improving the surface chemistry of material forms, can also improve the space topological structure of material surface on meso-scale by various process meanses, as the degree of roughness on surface, size, quantity and the distribution etc. of hole.The size and dimension that suitable template just can accurately be controlled hole is selected and made to preferred template method of the present invention because formed bore hole size of template and shape determine by template.
The present invention prepares mesoporous nano medicine carrying particle by simple and effective dispersion polymerization process and sol-gel process, regulate continuously in the extensive yardstick of the big I of these particles between 10nm-5 μ m, and particle diameter is very even, near monodispersity, as shown in Figure 5, the diameter of the mesoporous nano medicine carrying particle of preparation is 220nm, and as shown in Figure 6, the diameter of the mesoporous nano medicine carrying particle of preparation is 105nm.The mesoporous nano material of high-ratio surface is as the chemotherapeutics of all kinds of target tumor cell sensitivities of pharmaceutical carrier appendix, utilize the chemotherapeutics of the mesoporous nano material of above-mentioned high-ratio surface as all kinds of target tumor cell sensitivities of pharmaceutical carrier appendix, utilize above-mentioned reaction kinetic that medicament-carried nano mesoporous material appendix is formed lining on the support matrix, as shown in Figure 7, obtain functional targeting therapeutic degradable biological bracket.
The comparison of present technique and prior art:
The Biodegradable high molecular support and the prior art of Polyalkylcyanoacrylanano homopolymer, copolymer and blend are compared, and have following outstanding advantage:
(1) good biocompatibility of timbering material, degradable, safe, nontoxic;
(2) synthesis technique of Polyalkylcyanoacrylanano homopolymer and copolymer thereof is simple, meets the development trend of environmental protection and " Green Chemistry ";
(3) the microcosmic materials chemistry structure designability of Polyalkylcyanoacrylanano homopolymer and copolymer thereof is strong, effectively regulates by the micro structure to its macromolecular chain, can conveniently obtain the support of different mechanical properties, different degradation rates;
(4) integrate that mechanics supports and the treatment function of radiotherapy chemotherapy.
Should be pointed out that the above specific embodiment can make those skilled in the art more fully understand the innovation invention, but limit the innovation invention never in any form.Therefore, although this description has been described in detail the innovation invention with reference to drawings and Examples,, it will be appreciated by those skilled in the art that still and can make amendment or be equal to replacement this utility model; And all do not break away from the technical scheme and the improvement thereof of the spirit and scope of the innovation invention, and it all should be encompassed in the middle of the protection domain of the innovation patent of invention.