CN100496516C - Spirulina composition as well as preparation method and application thereof - Google Patents
Spirulina composition as well as preparation method and application thereof Download PDFInfo
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- CN100496516C CN100496516C CNB200710178556XA CN200710178556A CN100496516C CN 100496516 C CN100496516 C CN 100496516C CN B200710178556X A CNB200710178556X A CN B200710178556XA CN 200710178556 A CN200710178556 A CN 200710178556A CN 100496516 C CN100496516 C CN 100496516C
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- 235000016425 Arthrospira platensis Nutrition 0.000 title claims abstract description 25
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- 229940082787 spirulina Drugs 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 239000003504 photosensitizing agent Substances 0.000 claims abstract description 58
- ONDPHDOFVYQSGI-UHFFFAOYSA-N zinc nitrate Chemical compound [Zn+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ONDPHDOFVYQSGI-UHFFFAOYSA-N 0.000 claims abstract description 22
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
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- RKCAIXNGYQCCAL-UHFFFAOYSA-N porphin Chemical compound N1C(C=C2N=C(C=C3NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 RKCAIXNGYQCCAL-UHFFFAOYSA-N 0.000 description 1
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- YNHJECZULSZAQK-UHFFFAOYSA-N tetraphenylporphyrin Chemical compound C1=CC(C(=C2C=CC(N2)=C(C=2C=CC=CC=2)C=2C=CC(N=2)=C(C=2C=CC=CC=2)C2=CC=C3N2)C=2C=CC=CC=2)=NC1=C3C1=CC=CC=C1 YNHJECZULSZAQK-UHFFFAOYSA-N 0.000 description 1
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to a spirulina composition photosensitizer, the preparation method and the application. The preparation method of the spirulina composition of the invention includes: spirulina, dihydroporphin E6 and zinc nitrate are mixed according to certain mixing ratio, 1000ml of deionized water is added for slow stirring till complete dissolution to prepare the invention. The obtained spirulina composition photosensitizer can be taken by oral administration or intravenous injection, does not cause the light sensitive problem of skin, and does not need to avoid light. In addition, the spirulina composition photosensitizer can carry out local treatment by activation by a laser light emitting instrument, at the same time, a light emitting tube array instrument (light bed) with small power is used for systemic therapy; compared with other photosensitizers, the spirulina composition photosensitizer is more practical and safe, and the overall performance is better than other photosensitizers.
Description
Technical field
The present invention relates to photon dynamics therapy field, be specifically related to a kind of Spirulin composition that can be used as photosensitizer and preparation method thereof and application.
Background technology
Photon dynamics therapy (PDT) is a promising treatment of cancer method, has comprised the use of optical photon and photosensitizer.Photosensitizer is therein as therapeutic agent.Each element of photosensitizer all is harmless, but in case will produce fatal cytotoxic factor when combining with oxygen element, is initially the singlet oxygen form, can stop the development of tumor cell.Owing to have only the sick cell that is acted on photosensitizer, photon and oxygen simultaneously just can be attacked, thereby this photosensitizer has higher selectivity to pathological tissues by cytotoxin.The present pathological tissues of double selection gonosome of PDT therapy is to the preferential picked-up of photosensitizer and illumination is only acted on these photosensitizer that rest on specific diseased tissue area.Porphyrin and relevant ring family are used for photon dynamics therapy (PDT) synthetic of broad research the most.Porphyrin is the aromatic series macrocyclic compound with 18p electronics, and it shows distinctive spectrum and be accompanied by intensive p near (Soret band) about 400nm.-p transition and 4 Q band absworption peaks are arranged in visibility region.Nature obtains solar energy by these optical characteristics of porphyrin, carries out photosynthesis with chlorophyll and bacteriochlorophyll as antenna beam and reaction center pigment.The long wave absorption characteristic of this nature chromophore makes them can be used as photosensitizer in the photon dynamics therapy (PDT).
In sum, photon dynamics therapy (PDT) be with rest on the tumor tissues photosensitizer and with the effect that reacts to each other of optical photon, singlet oxygen (02) is this generally acknowledges to have destructive medium thereby cause producing.The result who reaches thorough destruction tumor tissues needs high singlet oxygen output.Even lacking under the situation that heavy atom replaces and transition metal ions is coordinated, the porphyrin system generally also can satisfy these requirements.Why Here it is all is porphyrin for the employed photosensitizer of clinical assessment of photon dynamics therapy (PDT) recently or has been the molecule of base with the porphyrin.Therefore, a lot of photosensitizer relevant with chlorin arranged in recent years, picture Bacteriochlorin (bacteriochlorins), porphycenes, titanium cyanines color (phthalocyanines), naphthalene titanium cyanines (naphthalocyanines) and expansion porphyrin (expanded porphyrins) all are used to curative effect synthetic and assessment photon dynamics therapy (PDT).But, design meet photosensitizer that photon dynamics therapy (PDT) uses also needs consider following problem, for example whole lipotropys, (being the balance of satisfactory hydrophilic and hydrophobe), pH value, lymph Excretory system and lipoprotein binding, these factors all can influence distribution and the location of photosensitizer in pathological tissues and tumor.Except that synthetic fine water-soluble porphyrin, research all can be paid attention to those molecules aspect the science of promotion and the practical application of humanistic aspect usually.Can stay in a certain specific part of health as porphin, just reflect its application medically.Hemoporphyrin IX can send fluorescence in malignant tissue, the sulfonation tetraphenylporphyrin then can accumulate on the tumor tissues.The main chlorin and the generation of Bacteriochlorin have three kinds of approach.First kind is to improve to form from the porphyrin of molding; Second kind of chlorin and Bacteriochlorin that is to use chlorophyll a as synthetic other kind of raw material.The third approach is to utilize unsettled bacteriochlorophyll a as the Bacteriochlorin of culture medium as synthesizing stable.Each approach all can successfully be used as prepares the requirement that photon dynamics therapy (PDT) photosensitizer uses, and each approach all is to carry out according to synthetic scientific method and meaning biologically.
Porphyrin is easy to combine with multiple metallic element with chlorine system; Metalloporphyrin is numerous transition metals, lanthanide series, and steel series elements and major element are familiar with.These metal composites not only can protect inner nitrogen-atoms away from electrophilic reagent and powerful substrate.And can produce significant macro ring reaction effect.The chemical of the metalloporphyrin of late transition metal element is known the most.The modal geometry of this synthetic is octahedra, and metal ion is positioned at the planar centre position of N4 porphyrin, and metal ligand body is positioned at the lateral attitude.Recently, the chemical of early transition metal element porphyrin is looked back again.
Metalation is attended by the reaction (for example halogenide, hydride, acetylacetonate and carbonic acyl radical) of metallic salt or synthetic usually in organizing solvent, chloroform for example, toluene or N, N dimethyl formamide (DMF).The de-metallization reaction needed is carried out in sour environment, and the requirement of acid concentration is by the stability decision of metal composite.
Having now at the photosensitizer of usefulness such as the happiness pool branch in Canadian Photofrin and Chinese Chongqing all is the hemoporphyrin goods, and this type of photosensitizer adopts quiet notes, needs lucifuge 30-40 days.Activation need be used the bigger laser device of power as the photosensitizer of hematoporphyrin derivative, and only can be used for the local irradiation treatment, otherwise the danger of burned skin is arranged.
In addition, disclose the C-phycocyanin that contains in the spirulina in the prior art and had certain light power photo-sensitive characteristic, still, the free-radical generating efficient of this kind material is lower, is not enough to be detected.And also point out phycocyanin energy enhance immunity systemic-function in other document, still, the precedent that equal in the prior art no-trump spirulina and other photosensitizer are used in combination all is to consider that the complexity of composition may influence the effect of photosensitizer.
Therefore, the inventor finds chlorin E
6Make up the compositions that obtains with spirulina etc. and can overcome the deficiency that existing photosensitizer exists, at first, the photo-sensitive characteristic that has kept enough sensitivities, next spirulina that is added into can also play the effect of enhance immunity systemic-function, effectively alleviate the damage of radiation, make the photosensitizer that makes than chlorin E to cells in vivo
6The zinc compound is more sensitive and nontoxic in the use, is more suitable for human body and uses, in addition, the preparation method of said composition is simple, can directly use the disposable mixing of component, dissolving, method, more original method is more simple and easy to operate, and convenient storage is stable, is convenient to the storage transportation.
Summary of the invention
The objective of the invention is to overcome the deficiency that existing photosensitizer exists, provide a kind of easy to use, the Spirulin composition that can be used as photosensitizer that toxic and side effects is little.
Another object of the present invention provides the preparation method of the photosensitizer that contains above-mentioned Spirulin composition.
Another object of the present invention provides the application of Spirulin composition in preparation photon dynamics therapy photosensitizer.
Spirulin composition of the present invention, its component is: spirulina 10-30 gram, chlorin E
60.05-0.08 gram, zinc nitrate 3-5 gram.
Preferably, Spirulin composition of the present invention is: spirulina 20 grams, chlorin E
60.07 gram, zinc nitrate 4 grams.
The present invention also provides the application of this kind Spirulin composition in preparation photon dynamics therapy photosensitizer.
The present invention also provides the preparation method with above-mentioned Spirulin composition this photosensitizer when the photosensitizer, and this method comprises spirulina, chlorin E
6, zinc nitrate mixes by proportioning, add the 1000mL deionized water and slowly stir, until dissolving fully.
The present invention has following beneficial effect:
1, easy to prepare: each composition all can commerce be buied in the Spirulin composition, carries out proportioning according to consumption of the present invention and can simply make Spirulin composition of the present invention, anyly can operate per capita, and is simple and clear.
2, easy to use: this Spirulin composition is identical with Dihydroporphine E 6 zinc compound, can not cause the photosensitive problem of skin by oral or intravenous injection, does not need lucifuge.In addition, the photosensitizer that this Spirulin composition is made can also activate according to instrument by laser light and carry out topical therapeutic, and also available low power luminous tube array instrument (light bed) is as whole body therapeutic.
3, effect is obvious: point out in the prior art that phycocyanin has certain heliosensitivity in the spirulina, can be used as biochemical tracer, and point out chlorin E
6Or chlorin E
6The zinc compound is sophisticated photosensitizer technology, still, because the optical sensitive degree of phycocyanin own is low, extracts difficulty, is unfavorable for operation, and as the chlorin E of photosensitizer
6The zinc compound also exists preparation process loaded down with trivial details, bio-safety performance shortcoming such as have much room for improvement, and therefore, the inventor is creatively with spirulina directly and chlorin E
6, zinc nitrate makes up; consumption proportion between these compositions is furtherd investigate; discovery can be brought into play the synergism between each composition well in the amount ranges that the present invention asks for protection; having improved optical sensibility, can produce the more freedom base, can have been absorbed by tumor cell well, is the more excellent photosensitiser composition of more existing photosensitizer performance.
4, toxic and side effects is little: the inventor is creatively at the chlorin E as photosensitizer
6Added spirulina in the zinc compound, never it is added in the photosensitizer in the prior art, because spirulina itself has the effect that strengthens body immunity, after the inventor is surprised to find that spirulina is added photosensitizer, more sensitive when making on the one hand as photosensitizer, also further reduced toxic and side effects in addition, made it safer and practical, more be applicable to human body as the Spirulin composition of photosensitizer itself.
Therefore, contrast other photosensitizer, the inventor is the direct and chlorin E with spirulina creatively
6, zinc nitrate, make up; consumption proportion between these compositions is furtherd investigate; discovery can be brought into play the synergism between each composition well in the amount ranges that the present invention asks for protection; not only improve optical sensibility, can produce the more freedom base, can have been absorbed by tumor cell well, secondly, improved the biological safety and the stability of photosensitizer; at last; greatly reduce preparation process, prepared simplely, had great operation possibility and economic interests.
The specific embodiment
Embodiment 1: the preparation of Spirulin composition when being used for photosensitizer
(a) get spirulina 10-30 gram, chlorin E
60.05-0.08 gram, zinc nitrate 3-5 restrain mixing;
(b) add the 1000mL deionized water and slowly stir,, make the Spirulin composition photosensitizer until dissolving fully.
Embodiment 2: the preparation of Spirulin composition when being used for photosensitizer
(a) get spirulina 20 grams, chlorin E
60.07 gram, zinc nitrate 4 grams mix;
(b) add the 1000mL deionized water, slowly stir,, make the Spirulin composition photosensitizer until dissolving fully.
Embodiment 3: pharmacokinetics
Medicine (metabolism) kinetics is distributed in specific organ, tissue, last 30 hours of body fluid and tumor tissues (embriocarcinome).The test Mus: female BALB/c mouse gross weight 20～21 grams, inoculation T36 embryonal carcinoma after 2 weeks, utilizes diode laser ML-662-SP to realize irradiating step at inoculated tumour on the back leg muscle of these mices, before carrying out with the skin unhairing of irradiation area.This research is that the tissue for organ and tumor carries out injecting in the abdomen on the basis of Percin-elmer spectrofluorophotometer, and dosage is 2.5 mg/kg (body weight).
Though given here is the experimental data and the analysis result of the Spirulin composition acquisition of embodiment 2, those skilled in the art should be appreciated that the Spirulin composition in a big way of embodiment 1 all can obtain identical result.
Injection the results are shown in Table 1, this explanation:
A. animal can be born the abdominal part injection that injected dose is the Spirulin composition of 2.5 mg/kg well, any signs of toxicity do not occur, and after 30 hours, the behavior reaction of mice does not all have to influence in injection back and injection immediately.
B. the dosage of being prepared can promptly absorb in blood from abdominal part, and is stored in liver in injection in back one hour.It will exceed 10 to 14 times in its level in blood of the Capacity Ratio in the liver organization.
C. preceding 12 hours after being injected into priming dose, kidney have stored enough dosage (only lack 2-2.5 times than the quantity of liver the inside), yet in fact do not exist in urine.Among the dosage of preparing in ensuing 18 hours was scavenged into blood from renal tissue fully, simultaneously, in whole viewing duration, the secretory function of animal was not affected.
D. in accepting preceding 8 hours of injection back, photosensitizer farthest accumulates on the liver organization, and residue was absorbed rapidly in ensuing 24 hours in the small intestinal.The dynamically lucky gang of the curve of liver curve dynamic and small intestinal.Therefore, farthest gather on the tumor tissues for making injected dose, it is just enough that suggestion injection lack 5～10 times amount than priming dose.
E. in the quantity of spleen and lung tissue than lacking 5～8 times in the aggregate amount of liver and tumor, and pro-had data readings (phone reading) to produce in 24 hours.
F. the aggregate amount curve on skin and muscle is dynamically about the same, and except a difference: the dosage content in the pro-15 hours in the muscle exceeds 1.5 times.
G. tumor progressively rises and reached maximum after 15 hour from when injection once the dosage that accumulates on the tumor.And the time of the accumulative steady statue of maximal dose (12～20 hours) is than having injected the much longer of chlorine e6 synthetic.After the obvious decline at 24 hours ends of pro-, the steady statue time that reaches maximum gathering reading for the second time is noted as 24 to 30 hours.In the test of liver and tumor, " intercepting " effect has been recorded twice.This is an index (reading of tumor rises, and the reading of liver descends) in 12 hours, has more obvious contrast after 24 hours.
Conclusion: after abdominal part absorbs, redistributing and the removing of unnecessary dosage in first 24 hours from blood to the organ, Spirulin composition accumulates in the amount of tumor tissues than high 2.5 times at liver organization, than high 6 times at integumentary musculature and other soft tissue organs.With the dynamic (dynamical) chlorin E of medicine (metabolism)
6The zinc compound is compared, and the monomer in the demonstration has more activity to tumor tissues and in in-house steady chemical structure.
Table 1
| Sequence number/organ | 1 hour | 5 hours | 15 hours | 24 hours | 30 hours |
| 1, blood | 4 | 8 | 5 | 2 | 1 |
| 2, urine | 7 | 0 | 0 | 0 | 0 |
| 3, small intestinal | 98 | 180 | 143 | 87 | 53 |
| 4, liver | 86 | 165 | 70 | 45 | 33 |
| 5, spleen | 11 | 15 | 14 | 13 | 13 |
| 6, kidney | 38 | 60 | 30 | 10 | 7 |
| 7, lungs | 18 | 17 | 25 | 13 | 6 |
| 8, tumor | 8 | 51 | 120 | 90 | 89 |
| 9, skin | 9 | 7 | 15 | 9 | 12 |
| 10, muscle | 25 | 7 | 34 | 5 | 12 |
Annotate: reading and the F11 unanimity relevant in the table with unit.
In addition, use phycocyanin, chlorin E under the same conditions
6The zinc compound carries out control experiment, and the result shows that the effect of the Spirulin composition of 2 parts of weight is better than 1 part of weight phycocyanin and 1 part of weight chlorin E
6The effect of zinc compound add and, this shows that Spirulin composition of the present invention has more activity to tumor tissues and in in-house steady chemical structure, and, in the Spirulin composition of the present invention the combination results of each composition good synergism.
Embodiment 4: toxicity test
Be defined parameters LD10 and LD50, specially prepared three kinds of dosage: 100,125 and 150 mg/kg are used for injection in the one abdomen, the equal normal activity of three treated animals, expression non-toxic reaction.In addition, with Spirulin composition of the present invention and chlorin E
6Zinc compound, phycocyanin carry out the toxicity contrast experiment.Under the situation of administration mice same dose, when administration 180 mg/kg, administration chlorin E
6The mice of zinc compound has respective reaction to injection, and abdominal part swelling occurs and produces temporary staticly, but administration Spirulin composition mice there is no this reaction; When administration 200 mg/kg, the mice of administration phycocyanin has respective reaction to injection, and swelling appears in abdominal part, but administration Spirulin composition mice does not still have this reaction.Show that Spirulin composition has than chlorin E
6Zinc compound and phycocyanin all have better security performance.For a long time genotoxic potential detect same show the more existing photosensitizer of Spirulin composition safer, to being tried the body totally nontoxic.
Embodiment 5: Spirulin composition produces the comparative experiments of singlet oxygen (free radical)
Spirulin composition of the present invention can produce singlet oxygen under illumination, the singlet oxygen output of itself and existing photosensitizer is as shown in table 2.
Table 2
| Photosensitizer | Output f Δ |
| Protoporphyrin | 0.57 |
| Hemoporphyrin | 0.65 |
| Uroporphyrin III | 0.52 |
| TPP | 0.63 |
| Four (3-hydroxy phenyl) porphyrin | 0.46 |
| Bacteriochlorophyll | 0.32 |
| Phycocyanin | 0.22 |
| Chlorin E 6The zinc compound | 0.32 |
| Spirulin composition | 0.56 |
Conclusion: the Spirulin composition photosensitizer is than chlorin E
6Zinc compound and phycocyanin can produce the more sensitive effect that reacts to each other with optical photon when carrying out the photon dynamics therapy, produce the more freedom base, and Spirulin composition of the present invention is more easy than other existing photosensitizer on preparation process, easy operating.This all is that the inventor does not expect at the beginning of experimentizing, and the unexpected experimental result that obtains.
Claims (4)
1, a kind of Spirulin composition is characterized in that the component of said composition is: spirulina 10-30 gram, chlorin E
60.05-0.08 gram, zinc nitrate 3-5 gram.
2, Spirulin composition as claimed in claim 1 is characterized in that the component of said composition is: spirulina 20 grams, chlorin E
60.07 gram, zinc nitrate 4 grams.
3, the application of Spirulin composition as claimed in claim 1 in preparation photon dynamics therapy photosensitizer.
4, the preparation method of the photosensitizer of Spirulin composition as claimed in claim 3 is characterized in that this method comprises spirulina, chlorin E
6, zinc nitrate mixes by proportioning, adds the 1000mL deionized water, slowly stir down at 60 degrees centigrade, until dissolving fully.
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