CN106905277A - It is a kind of131I marks the preparation method and applications of Quercetin - Google Patents

Abstract

The present invention discloses one kind¹³¹I marks the preparation method of Quercetin, and radioiodination is carried out using chloramine-t method, comprises the following steps：(1) by Quercetin in the system of pH=6 8 with KI,¹³¹I and toluene-sodium-sulfonchloramide carry out reacting 5 30min；(2) excessive reductant is added to terminate step (1) reaction；(3) purify, obtain final product.The present invention further discloses described¹³¹I marks application of the Quercetin in treatment thyroid cancer medicine or preparation is prepared.The present invention¹³¹The preparation method of I mark Quercetins is simple, and label stabilization, mark rate is high, is easy to further exploitation.

Description

It is a kind of131I marks the preparation method and applications of Quercetin

Technical field

The present invention relates to biomedicine field.More particularly, to one kind¹³¹I marks the preparation method of Quercetin and its answers With.

Background technology

Thyroid cancer is a kind of common endocrine tumors, accounts for the 1% of whole human tumor, is had been reported that within 2005 aobvious Show, global thyroid cancer incidence is risen with annual 4% amplification, has leapt to women kinds of tumor the 8th.Differentiated thyroid gland Cancer (Differentiated thyroid carcinoma, DTC) includes thyroid papillary carcinoma (Papillary thyroid Carcinoma, PTC) and follicular carcinoma of thyroid (Follicular thyroid carcinoma, FTC), due to tumour cell Remain the partial function of normal thyroid cell and there is dense poly- iodine ability, so most of DTC patients undergoing surgeries cut off+put Penetrating property nucleic¹³¹The replacement of I treatment+thyroid hormones suppresses therapy can cure, prognosis bona.But 30% patient exists¹³¹I is treated During the state of an illness in progressivity change, thyroid cancer and MET gradually lose because of losing points and take the photograph iodine ability.Therefore, research is found Reduce losing points and make the treatment method that the cancer of losing points breaks up again, recovery¹³¹I therapeutic effects, reduce the death of thyroid cancer Rate, has great significance.

Differentiation therapy refers to the growth for suppressing tumour again, losing points and undifferentiated first cancer is regained the function of inhaling iodine Method, at present to the research of existing following several respects for the treatment of of losing points first cancer：1st, vitamin A acid (RA) promotees differentiation therapy again, 2, NIS gene transfers are treated, and 3, NIS Demethylation treatments, 4, anti-vegf treatment.But, several treatment unsatisfactory curative effects of the above and There are the side effects of many, accordingly, it would be desirable to one kind safely and effectively medicine.

Any tumor therapeuticing method is used alone, and the raising of its curative effect is difficult satisfactory, the synthesis of various methods Using that can bring out one's strengths to make up for one's weaknesses, curative effect is improved, reduce toxic and side effect, such as clinically widely used radiotherapy and the connection of chemotherapy Application is closed, the application of radiosensitizer is also the part in complex treatment.Radiosensitizer refers to that can improve ray to tumour Anoxic cell in the lethality of cell, especially tumor tissues, and some little changes are influenceed on the normal cell of exposure Learn material.Have now found that in oncotherapy, simple irradiation treatment, the healing of tumour are carried out with the tolerable dosage of normal structure Rate can only achieve 40% or so, if merging uses hypersitization medicine, cure rate is up to 90%.Oneself obtains some enhanced sensitivity potency at present Medicine very high, and try out in clinic, such as nitro glyoxaline compound, but due to there is obvious nerve toxic and side effect limitation Its application clinically, thus, the tumor radiotherapy sensitive-increasing agent for finding high-efficiency low-toxicity is that current cancer radiotherapy is badly in need of solving Problem, particularly studies in Inner irradiation enhanced sensitivity, domestic and international rarely found research.

Quercetin (quercetin, QU；3,3 ', 4 ', 5,7-5 flavonol) and its derivative be with various biological The flavone compound of activity.It is widely present in the flower and fruit of the various plants of nature.Domestic and foreign scholars research finds Mongolian oak Skin have extremely strong antitumor action, and its mechanism is to suppress tumor cell proliferation by multipath, induces its apoptosis etc..There is many Experiment confirms that the material can make the cell line of many types obtain cancer cell and break up again.

In view of current research situation, inquires into¹³¹I marks Quercetin to intra-tumor radiosensitization, to losing points and undifferentiated first Shape gland cancer plays the role of differentiation therapy again, for the treatment of thyroid cancer provides method and radiation sensitivity to RIT grinds Study carefully and provide fundamental basis.

The content of the invention

It is an object of the present invention to provide one kind¹³¹I marks the preparation method of Quercetin, and the method is simple, label Stabilization, mark rate is high.

It is another object of the present invention to provide one kind¹³¹I marks the application of Quercetin.

To reach above-mentioned purpose, the present invention uses following technical proposals：

It is a kind of¹³¹I marks the preparation method of Quercetin, and radioiodination is carried out using chloramine-t method, comprises the following steps：

(1) by Quercetin in the system of pH=6-8 with KI,¹³¹I and chloramine-T reacted under conditions of 0-37 DEG C 5-30min；

(2) excessive reductant is added to terminate step (1) reaction；

(3) purify, obtain final product.

In a preferred embodiment of the invention, the pH=6 of the system；

Further, the KI and the mol ratio of Quercetin are 0.25-0.75；Preferably 0.25；

Further, it is described¹³¹The consumption of I is 1mg Quercetins and 1.21-1.693m Ci's¹³¹I is reacted；Preferably, It is 1mg Quercetins and 1.529mCi¹³¹I is reacted.

The influence to mark rate such as amount, reaction time, reaction temperature to pH, KI of the invention, and QU pairs¹³¹The load of I The influence of amount is studied, and is as a result shown the amount of pH, KI and is influenceed larger to mark rate, and reaction time and temperature are to mark rate Influence is smaller, finally gives：Work as pH=6-8, KI is that 0.25-0.75 mark rates are higher with the mol ratio of Quercetin；Work as pH=6, KI is 0.25 mark rate highest with the mol ratio of Quercetin；And QU pairs¹³¹The load capacity of I also has material impact, 1mg Quercetins Correspondence is with 1.21-1.693mCi's¹³¹When I is reacted, load capacity and mark rate have reached preferable result, can cause mark Note rate is higher, and does not cause¹³¹A large amount of wastes of I, have saved cost；In addition, in order to time-consuming, the reaction time is preferred Be 5min.

In the preferred embodiment of the invention, the reducing agent is Sodium Metabisulfite or sodium thiosulfate；

In the preferred embodiment of the invention, the purifying is ethyl acetate extraction.

The invention also discloses described¹³¹I marks application of the Quercetin in treatment thyroid cancer medicine or preparation is prepared.

The present invention is by research¹³¹I-QU shows with the interaction of thyroid carcinoma cell：With¹³¹I is compared, and thyroid cancer is thin Born of the same parents couple¹³¹I-QU has high and quickly absorbs, and the holdup time is long；With¹³¹I, QU and¹³¹The suppression that I+QU breeds to neoblast Situation processed is compared,¹³¹I-QU is most strong to the inhibitory action of cancer cell；By mice with tumor intratumor injection¹³¹I-QU is to thyroid cancer Treatment, as a result shows¹³¹I-QU has good therapeutic effect to thyroid cancer, and does not influence body weight.

Beneficial effects of the present invention are as follows：

The present invention¹³¹The preparation method of I mark Quercetins is simple, and label stabilization, mark rate is high, is easy to further exploitation Utilize.In addition, of the invention¹³¹I mark Quercetins effectively increase the inhibitory action to thyroid carcinoma cell, reach and preferably control Therapeutic effect.

Brief description of the drawings

Specific embodiment of the invention is described in further detail below in conjunction with the accompanying drawings.

Fig. 1 shows pH pairs¹³¹The influence of I mark rates；

Fig. 2 shows the amount pair of KI¹³¹The influence of I mark rates；

Fig. 3 shows influence of the reaction time to mark rate；

Fig. 4 shows¹³¹The load capacity of I and the relation of mark rate；

Fig. 5 shows the HPLC results of iodine labeling QU；

Fig. 6 shows the mass spectral analysis at 3.63min；

Fig. 7 shows the mass spectral analysis at 5.81min；

Fig. 8 shows the mass spectral analysis at 6.82min；

Fig. 9 shows¹³¹Stability of the I-QU in physiological saline and PBS (0.01mol/L, pH=7.4)

Figure 10 shows FTC-133 pairs, differentiated thyroid carcinoma cell¹³¹I and¹³¹The intake situation of I-QU；

Figure 11 shows TT pairs, differentiated thyroid carcinoma cell¹³¹I and¹³¹The intake situation of I-QU；

Figure 12 shows DRO pairs, undifferentiated thyroid carcinoma cell¹³¹I and¹³¹The intake situation of I-QU；

Three kinds of thyroid carcinoma cells pair when Figure 13 shows to add excessive QU¹³¹The intake situation of I-QU；

Figure 14 shows fluorescent effect of the Quercetin in thyroid carcinoma cell DRO, wherein, A：The microphoto of cell, B： Cell fluorescence photo, C：Microphoto after cellular uptake Quercetin, D：Fluorescence photo after cellular uptake Quercetin, E：Cell The fusion figure of microphoto and fluorescence photo after intake Quercetin；

Figure 15 is shown in thyroid carcinoma cell DRO¹³¹The outflow situation of I-QU；

Figure 16 shows¹³¹I-QU、¹³¹I、QU、¹³¹I+QU is to thyroid carcinoma cell DRO growth inhibitions situation (when medicine is acted on Between T=24h)；

Figure 17 shows¹³¹I-QU、¹³¹I、QU、¹³¹I+QU is to thyroid carcinoma cell DRO growth inhibitions situation (when medicine is acted on Between T=48h)；

Figure 18 shows¹³¹I-QU、¹³¹I、QU、¹³¹I+QU is to thyroid carcinoma cell DRO growth inhibitions situation (when medicine is acted on Between T=72h)；

Figure 19 shows intratumor injection¹³¹After I-QU, the SPECT imagings of tumor bearing nude mice different time points；

Figure 20 shows treatment group and control group tumor bearing nude mice gross tumor volume size；

Figure 21 shows tumor bearing nude mice changes of weight.

Specific embodiment

In order to illustrate more clearly of the present invention, the present invention is done further with reference to preferred embodiments and drawings It is bright.Similar part is indicated with identical reference in accompanying drawing.It will be appreciated by those skilled in the art that institute is specific below The content of description is illustrative and be not restrictive, and should not be limited the scope of the invention with this.

Test example 1¹³¹I marks the selection of Quercetin (QU) condition

The present invention have studied and be made using chloramine-t method¹³¹During I marks QU, the amount of pH, KI, reaction time, reaction The influence to mark rate such as temperature, and QU pairs¹³¹The influence of the load capacity of I；

1st, influences of the pH to mark rate

The pH of reaction system is adjusted using 1mol/HCl and NaOH, makes pH=2-10, research pH with¹³¹The influence of I mark rates Relation, as a result as shown in figure 1, as a result showing：During pH=6, mark rate highest, up to 82.17%.When pH≤6, mark rate is with pH Increase and increase, during pH >=6, mark rate is reduced with the increase of pH.This may be relevant with the activity of chloramine-T, and chloramine-T exists (pH=6-8) activity highest under neutrallty condition, oxidation effectiveness is best.In addition, pH changes, become QU phenyl ring cloud densities Change, influence¹³¹The mark rate of I.When that can exist as its sodium salt under QU alkalescence conditions, so as to change the water solubility of QU, influence The extraction efficiency of ethyl acetate.

2nd, influence of the KI consumptions to mark rate

1mg is fixed as in the amount of QU, under conditions of pH=6, setting KI/QU (mol/mol)=0,0.25,0.5,0.75, 1.0,1.25,1.5,2.0, determine KI with¹³¹The relation of I mark rates.As a result result as shown in Fig. 2 show：The KI and QU of stabilization When mol ratio is 0.25,¹³¹The mark rate of I is maximum, is 86.78%；Gradually increase with KI and QU mol ratios (is increased by 0.25 It is added to 2.0),¹³¹The mark rate of I is gradually reduced.This is probably because KI amount increases are unfavorable for¹³¹I and KI's vies each other；And work as The amount of KI be 0 when, the mark rate (86.78%) when its mark rate (80.28%) is 0.25 less than KI, this be probably due to¹³¹I Caused by concentration is too low, the KI of appropriate addition stabilization is advantageously reduced¹³¹I's is free, so as to increase mark rate.

3rd, the influence of reaction time and temperature to mark rate

0.3 μm of QU of ol, 0.075 μm of KI of ol, 10 μ L¹³¹I and 0.1 μm of chloramine-T of ol is distinguished under conditions of pH=6 After reaction 5,10,15,20,30min, determine¹³¹The mark rate result of I as shown in figure 3, as can be seen from the figure reaction 5,10, 15th, 20, after 30min¹³¹The mark rate of I is respectively poor between 86.78%, 85.04%, 85.19%, 87.29%, 85.44%, group Different not statistically significant (p ＞ 0.05), illustrates that influence of the reaction time to mark rate is smaller, is one using chloramine-t method mark iodine Individual quick process, reaction 5min can obtain mark rate higher.

The present invention is investigated temperature pair¹³¹The influence of I mark rates, as a result shows, is temperature in 0~37 DEG C of interval in temperature Degree has no significant effect to mark rate.

4th, QU pairs¹³¹The influence of the load capacity of I

In order to inquire into ultimate loads of the QU to radioiodine, the present invention have studied 1mg QU in difference¹³¹Under I dosage Mark rate, experimental result as shown in table 1 and Fig. 4, as can be seen from the figure：When¹³¹When the dosage of I is 0.219-2.477mCi, with ¹³¹I adds the increase of dosage, and 1mg QU are consequently increased to the load capacity of iodine (increases to 1.407mCi/ by 0.163mCi/mg Mg), but¹³¹The mark rate of I but shows the trend for gradually reducing.Illustrate QU pairs¹³¹Although the load capacity of I increased, but with The reduction of mark rate,¹³¹The waste of I increases.

Consider load capacity and¹³¹The mark rate of I, it is considered herein that QU pairs¹³¹The load capacity that I is best suitable for is appeared in Between 0.856-1.125mCi (at such as Fig. 4, A point), at A points¹³¹I additions are 1.529mCi,¹³¹The load capacity of I is about 1.04mCi/mg, mark rate is about 68%.

The radiocounting of the water phase of table 1 and ethyl acetate phase

Test example 2¹³¹I marks the quality testing of QU

1st, HPLC, MS, LCMS-IT-TOF detection label

The present invention judges the mark situations of the KI to QU of stabilization using LC-MS analyses, determines the number of I generation reactions.By Fig. 5 Understand, in the HPLC of the product of the QU of iodine labeling after purification it is main comprising 1.95,2.79,3.63,5.25,5.81,6.82min Six peaks at place, wherein 3.63,5.81, absorbance of three peaks at 6.82min at 360nm it is larger, its content accounts for mark 95.44% (such as table 2) of product.Invention is further analyzed using MS and obtained：Molecular weight difference at 3.63,5.81,6.82min It is 302.0347,427.9328,427.9328 (such as Fig. 6, Fig. 7, Fig. 8).This molecular weight 302.02 with QU, the molecule of 1I-QU Measure 427.9166 consistent.And three time point product proportions are respectively 78.53%, 9.46%, 7.45%.5.81, Molecular weight is identical at 6.82min, is two kinds of isomers of I-QU.

The integral area of the iodine labeling QU each components of table 2

Thus, it is believed that stabilization I to QU mark after, and by extraction purify product be mainly QU and I-QU, account for 95.44%.Therefore think to can be used for the product that QU carries out iodine labeling grinding for follow-up cell and zoopery using chloramine-t method Study carefully.

Although being analyzed from the molecular structure of QU, QU has the parental materials site of multiple iodine, under the conditions of differential responses, I has different parental materials sites.But from LCMS data analyses, only one iodine there occurs substitution reaction.Iodine is anti-with QU Should, iodine most easily replaces the ortho para position of QU phenolic hydroxyl groups, and thus, the reaction equation of the reaction of iodine labeling QU is as follows in the present invention：

2、¹³¹I marks the vitro stability of Quercetin

In the present invention,¹³¹The vitro stability of I-QU is used¹³¹I-QU at 37 DEG C, when being incubated different in different medium Between after radiochemical purity represent.As shown in figure 9,¹³¹I-QU is in physiological saline (0.9% NaCl solution) and PBS In after placement 1,2,4,8,16,24,48h under the conditions of 37 DEG C in (0.01mol/L, pH=7.4), its radiochemical purity presents slow Slow downward trend.

¹³¹The radiochemical purity of I-QU 1h in physiological saline is 91.24% ± 3.25% (means ± sd), after 48h Radiochemical purity still up to 81.62 ± 6.28%, explanation¹³¹I-QU has preferable vitro stability in physiological saline.¹³¹After I-QU is incubated 1h in PBS (0.01mol/L, pH=7.4), its radiochemical purity is 82.25% ± 4.05%, 48h Radiochemical purity 54.48% ± 10.07% afterwards.With¹³¹Stability of the I-QU in physiological saline is compared,¹³¹I-QU is in PBS Stability not as good as stability in physiological saline.

Test example 3¹³¹The interaction of I-QU and thyroid carcinoma cell

1st, thyroid carcinoma cell intake experiment

To probe into¹³¹Can I-QU improve thyroid carcinoma cell to radioactive intake, and present invention research simultaneously compares first shape Gland cancer deferentiative type cells (FTC-133, TT) and undifferentiated type cell (DRO) are right¹³¹I and¹³¹The intake ability of I-QU, as a result as schemed 10th, shown in Figure 11 and Figure 12, as can be seen from the figure：Undifferentiated first cancer cell DRO hardly has intake¹³¹The ability of I, and Differentiated first cancer cell FTC-133, TT have intake¹³¹The ability of I, and it is right¹³¹The intake of I changes over time and shows first to increase The trend of balance, its maximal oxygen taken amount is gradually kept to be both present in 15min or so afterwards.The intake of FTC-133 and TT¹³¹I abilities Difference may be relevant with cytoactive and cell culture algebraically, and differentiated thyroid carcinoma cell may during long-term cultivation Gradually losing points, is embodied in the reduction for taking the photograph iodine ability.

With¹³¹I is compared, FTC-133, TT, DRO couple¹³¹I-QU has intake higher, wherein FTC-133 pairs¹³¹I-QU's Maximal oxygen taken amount is right¹³¹4.2 times of I intakes, TT pairs¹³¹The maximal oxygen taken amount of I-QU is right¹³¹13.1 times of I, DRO pairs¹³¹The maximal oxygen taken amount of I-QU is right¹³¹17.0 times of I.Also, three kinds of cancer cells pair¹³¹The maximal oxygen taken amount of I-QU is both present in 5-7min, illustrates cancer cell pair¹³¹The intake of I-QU compared with¹³¹I is more rapidly.Thyroid carcinoma cell pair¹³¹I-QU high and quickly take the photograph Take, would be even more beneficial to¹³¹Treatments of the I-QU to the growth inhibition effect and thyroid cancer of cancer cell.

Further to inquire into three kinds of thyroid carcinoma cells pair¹³¹The intake of I-QU is mainly attributed to intake of the cancer cell to QU, The present invention has carried out following experiment, i.e., in research cancer cell pair¹³¹During the intake of I-QU, excessive QU is added, in measure cell Radioactivity, and compare cell pair¹³¹I-QU absorbs situation, as a result as shown in figure 13.After excessive QU is added in absorbing experiment, FTC-133, TT, DRO couple¹³¹The intake of I-QU is substantially reduced, and is reduced to about original 1/8.Its reason may be interpreted as QU with¹³¹I- The Competition of QU, intake of the cancer cell to QU, reduces its right¹³¹The intake of I-QU.

Additionally, in view of QU is under ultraviolet light, the fluorescence of green can be sent.The present invention have studied by fluorescence microscope After thyroid carcinoma cell (DRO) is incubated jointly with QU, the fluorescent effect of cell.As shown in figure 14, cell is total to experimental result with QU After being incubated, cell is under fluorescence microscope in green, it was demonstrated that cell can absorb QU really.

Thyroid carcinoma cell pair¹³¹The intake description of test of I-QU, will¹³¹I is tagged on QU, can be made not having originally and be taken the photograph iodine Ability thyroid carcinoma cell DRO intake radioiodine (¹³¹I-QU), so as to reach kill and cytostatic effect；Together Shi Zengjia have take the photograph the cancer cell FTC-133, TT of iodine ability to radioiodine (¹³¹I-QU intake ability), increases thin to its cancer The destruction of born of the same parents.And QU has the effect of radioactivity enhanced sensitivity, and make what losing points and undifferentiated cancer cell broke up again Effect,¹³¹I will be expected to faster kill cancer cell with being used in combination for QU, it is to avoid the generation of losing points, and make to lose points simultaneously Change and undifferentiated cancer cell breaks up again.

2nd, cell outflow experiment

Thyroid carcinoma cell is absorbed¹³¹After I-QU,¹³¹Can I-QU " long-term " exist in the cell, be to influence it to first shape The key factor of adenocarcinoma cell inhibitory action.Therefore, the present invention is determined¹³¹I-QU is in undifferentiated thyroid carcinoma cell DRO Outflow situation, experimental result is as shown in figure 15.¹³¹Half-life period of the I-QU in DRO is about 10min, explanation¹³¹I-QU is in thyroid gland Holdup time in cancer cell with¹³¹Holdup times of the I in melanoma cells is suitable.

3rd, cell growth inhibition test

It is of the invention main using the CCK-8 methods lower undifferentiated thyroid carcinoma cell DRO survival conditions of inspection different pharmaceutical effect, And drug dose, the influence of action time are have studied simultaneously.Study on a cellular level¹³¹I-QU,¹³¹I, QU and¹³¹I+QU is not to The suppression situation of noble cells propagation.Wherein,¹³¹The concentration that the dosage of I is respectively 5,10,20,30,40 μ Ci, QU is respectively 14, 28th, 56,84,112 μm of ol/L, drug treating time is respectively 24,48,72h, experimental result is as shown in Figure 16, Figure 17, Figure 18.

Under same drug dose, the strong and weak order of suppression that four kinds of medicines are bred to DRO is¹³¹I-QU≥¹³¹I+QU ＞ QU ＞¹³¹I, and inhibitory action and drug dose and action time are into dependence.When QU concentration is 112 μm of ol/L,¹³¹I dosage It is 40 μ Ci, when action time is 72h,¹³¹The inhibiting rate of I-QU cell proliferations is up to 86.87 ± 7.15% (mean ± SD) ,¹³¹I+QU, QU and¹³¹I is respectively 83.66 ± 12.11%, 58.43 ± 5.08%, 18.86 to the inhibiting rate of cell ± 6.29%.With same dose¹³¹I is compared,¹³¹I-QU about improves 5 times to the inhibitory action of cell.Its reason can give the credit to DRO The radioactivity sensitization of quick intake and QU to QU.

After QU enters cell, can be embedded into DNA double chain, and be acted on and DNA phosphate groups by covalently or non-covalently key With reference to.Because undifferentiated type first cancer cell DRO can not be absorbed¹³¹I,¹³¹I and¹³¹I+QU mainly suppresses cancer cell by external exposure Growth.With¹³¹I、¹³¹I+QU is compared,¹³¹I-QU can be absorbed by cancer cell, and be embedded into DNA double chain, will greatly increase medicine pair The damage of nucleus and DNA, and accelerate the fragmentation of cell.

From the suppression situation to growth of cancer cells, with¹³¹I+QU groups are compared,¹³¹I-QU groups are to thyroid carcinoma cell DRO The inhibitory action of growth does not have a clear superiority (86.87 ± 7.15%Vs 83.66 ± 12.11%), but comes for entity tumor Say, because anaplastic thyroid carcinoma cell does not possess intake¹³¹The ability of I,¹³¹The therapeutic modality of I+QU will be relatively inaccessible to suppress tumour The effect of growth.

Test example 4¹³¹I-QU is to thyroid cancer inhibitory action and its distribution in vivo

1、¹³¹Distributions and SPECT imaging of the I-QU in mice with tumor body

It is right that the present invention is imaged using SPECT¹³¹I-QU has carried out preliminary point in the holdup time of intra-tumor and whole body distribution Analysis.And by different time¹³¹The distribution situation that I-QU is respectively organized in tumor bearing nude mice, have studied¹³¹I-QU generations in animal body Thank to situation.

SPECT image results show (such as Figure 19), are injected by the radiation of intratumor injection¹³¹Preceding 4h after I-QU,¹³¹I-QU Mainly it is enriched in intra-tumor；After injection medicine 8h,¹³¹I-QU starts to be spread from tumor center to surrounding tissue, injects medicine 24h, After 36h,¹³¹I-QU further spreads to surrounding tissue, and the radioactive dosage of tumor center substantially weakens.

The biodistribution that lotus DRO knurls nude mouse tumor and other each groups knit organ is as shown in table 3.Intratumor injection¹³¹I- After QU 2h,¹³¹I-QU is concentrated mainly on tumor tissues, accounts for 57.99 ± 5.62% (mean ± SD) of injection rate, blood, liver It is dirty to wait tissue to have no that obvious radioactivity is dense poly-；And after injection medicine 8,16,24,48h, intra-tumor¹³¹I-QU accounts for injection respectively 47.22 ± 3.86%, 35.22 ± 5.23%, 18.46 ± 4.54% and 9.03+1.14% of amount.Organized with bone, muscle etc. Compare, liver and kidney have radioactivity higher, further illustrate free¹³¹I is mainly excreted by urine, and with The metabolite of QU mainly passes through CO₂It is consistent with the result of study that fecaluria is excreted.

Table 3¹³¹Biodistributions (%ID/g, mean ± SD, n=4) of the I-QU in knurl nude mouse

2、¹³¹I- Quercetins are observed the therapeutic effect of thyroid cancer

After injection medicine, whether the tumour growth of lotus DRO knurl nude mices is inhibited by judging¹³¹I-QU treats vivo tumor Whether effective most positive evidence.The present invention observes intratumor injection¹³¹PBS (pH=7.4, the 0.01mol/ of I-QU and isodose L) after 0-28 days, the Volume Changes for the treatment of group and nude mice of control group tumour, its result is as shown in table 4 and Figure 20.

Within the observation period of 28 days, control group gross tumor volume constantly increases, at the 28th day, gross tumor volume be 907.65 ± 189.21mm³(mean±SD).Compared with control group, treatment group tumors volume is substantially suppressed after injection medicine, and from the 3rd day Start, there is significant difference (P ＜ 0.05) in treatment group with control group gross tumor volume, and the tumour inhibiting rate of the 28th day is about 66.51%.Knurl Interior injection¹³¹The 7th day after I-QU, treatment group tumors volume reached minimum (by 54.98 ± 5.14mm³It is contracted to 34.93 ± 13.29mm³), subsequent treatment group tumors volume starts gradually to increase.Its reason is probably 1mCi's¹³¹I-QU is not enough to press down completely The growth of tumour processed or¹³¹I-QU falls short of in the holdup time of intra-tumor.In consideration of it, to completely inhibit about 50mm³Tumour Growth, needs to increase¹³¹The dosage of I-QU single-doses or the treatment means using multiple dosing.In addition, can also extend medicine swollen Holdup time in knurl is reaching more preferable therapeutic effect.

The treatment group of table 4 and control group tumor bearing nude mice gross tumor volume size (mean ± SD, n=5)

Additionally, in observation¹³¹While I-QU is to the therapeutic effect of thyroid cancer, the present invention is also carried out to nude mice body weight Investigate, its result is as shown in figure 21.The condition of Experiment on therapy late control group and treatment group nude mice and Experiment on therapy early stage Compared to having weakened, but from nude mice body weight, obvious Body weight loss is had no, and treatment group does not have with nude mice of control group body weight There is significant difference (P ＞ 0.05).

Obviously, the above embodiment of the present invention is only intended to clearly illustrate example of the present invention, and is not right The restriction of embodiments of the present invention, for those of ordinary skill in the field, may be used also on the basis of the above description To make other changes in different forms, all of implementation method cannot be exhaustive here, it is every to belong to this hair Obvious change that bright technical scheme is extended out changes row still in protection scope of the present invention.

Claims (7)

1. a kind of¹³¹I marks the preparation method of Quercetin, and radioiodination is carried out using chloramine-t method, it is characterised in that including Following steps：

(1) by Quercetin in the system of pH=6-8 with KI,¹³¹I and chloramine-T react 5-30min under the conditions of 0-37 DEG C；

(2) excessive reductant is added to terminate the reaction of step (1)；

(3) purify, obtain final product.

2. preparation method according to claim 1, it is characterised in that：The pH=6 of system described in step (1).

3. preparation method according to claim 1, it is characterised in that：The KI is 0.25- with the mol ratio of Quercetin 0.75。

4. preparation method according to claim 3, it is characterised in that：The KI is 0.25 with the mol ratio of Quercetin.

5. preparation method according to claim 1, it is characterised in that：It is described¹³¹The consumption of I is 1mg Quercetins and 1.21- 1.693m Ci's¹³¹I is reacted.

6. preparation method according to claim 1, it is characterised in that：Step (1) reacts 5min under the conditions of 0-37 DEG C.

7. one kind is as described in claim 1-6 is any¹³¹I marks Quercetin in treatment thyroid cancer medicine or preparation is prepared Using.