CN102940651B - A kind of method and application thereof utilizing tumor-targeting bacterium activation prodrug - Google Patents
A kind of method and application thereof utilizing tumor-targeting bacterium activation prodrug Download PDFInfo
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Abstract
The invention belongs to biological technical field, be specifically related to a kind of method and the application thereof that utilize tumor-targeting bacterium activation prodrug, the method utilizes tumor-targeting bacterium to activate instrument as a kind of natural prodrug, tumor-targeting bacterium can express endogenic pro-drug activation enzymes gene in composing type ground, thus prodrug can be activated at tumor tissue specificity, produce antitumous effect, the method can be used in the treatment of tumour.
Description
One, technical field:
The invention belongs to biological technical field, be specifically related to a kind of method and the application thereof that utilize tumor-targeting bacterium activation prodrug.
Two, background technology:
Killing tumor cell and avoiding injures the important directions and focus that the neoplasm targeted therapy of organism normal cell is oncotherapy research always specifically.Enzyme prodrug treatment (Gene-DirectedEnzymeProdrugTherapy, GDEPT) of gene mediated a kind of important means for the treatment of as tumor-targeting is at kinds of tumors animal model or show good therapeutic efficiency clinically.Enzyme/prodrug the therapy system developed at present mainly contains: herpes simplex virus thymidine kinase/gancyclovir (HSV-TK/GCV), Isocytosine deaminase/5-flurocytosine (CD/5-FC), purine nucleotides Phosphoric acid esterase/6-methyl purine-2-deoxyribosyl nucleosides (PNP/6MePdR) etc.These enzymes that can be used for activating prodrug mainly come from bacterium or virus, and are not expressed in normal mammalian cell.People utilize virus vector, bacteria carrier, antibody that the enzyme spcificity activating prodrug is transported to tumor tissues; make pro-drug activation enzymes specific expressed in tumour cell or tissue; after such injection prodrug; prodrug is just converted into the medicine of killing activity specifically in tumor tissues; and avoid the injury (XuG etc. to normal body; 2001, ClinCancerRes.7 (11): 3314-3324).But there is following shortcoming in the GDEPT treatment depending on expression vector: tumor-targeting is not good, tumor cell transfection efficiency is not enough, body internal stability is bad, involve great expense.
Purine nucleotides Phosphoric acid esterase/6-methyl purine-2-deoxyribosyl nucleosides (PNP/6MePdR) system equals exploitation in 1994 by SorscherEJ, it utilizes intestinal bacteria PNP gene (purine nucleotides Phosphoric acid esterase) can transform adenosine (Desoxyadenosine) for VITAMIN B4 and ribose one phosphoric acid (ribodesose one phosphoric acid), and the purine nucleotides Phosphoric acid esterase of normal mammalian cell not this activity, can not the cracking (SorscherEJ etc. of catalysis adenosine (Desoxyadenosine), 1994, GeneTher1:233-238).PNP/6MePdR system has the antitumous effect of wide spectrum, and scholars utilize various targeting vector to attempt to realize the expression of PNP gene at the efficient target of tumour, but is still faced with the above-mentioned various technical barriers depending on the enzyme prodrug treatment of carrier.
Some facultative anaerobic bacterias as Salmonellas, clostridium etc. specificly can copy in neoplasm necrosis district, grow, metabolism and breeding, there is higher tumor-targeting.These bacteriums, in addition after attenuation transformation, are widely used in the transport agent of oncotherapy or therapy of tumor.The intravenous injection attenuation salmonella of American I phase in 2002 clinical display single dose does not show good antitumous effect (TosoJF etc., 2002, JClinOncol20:142-152.), therefore single tumour bacterize still also exists the problems such as curative effect is not remarkable, be badly in need of a kind of new strategy of exploitation and system to strengthen the curative effect of tumour bacterize, minimizing side effect.
Three, summary of the invention:
Object of the present invention is exactly for above Problems existing and deficiency, solve the various technical barriers existed in aforementioned prodrugs and bacterize, set up and realize efficient enrichment pro-drug activation enzymes specifically in tumor tissues, develop and a kind of there is good therapeutic efficiency, and simple to operate, tumor-targeting bacterium/prodrug Activiation method with low cost.
In order to achieve the above object, the invention provides a kind of method utilizing tumor-targeting bacterium to activate prodrug, it is characterized in that tumor-targeting bacterium to activate instrument as a kind of natural prodrug, described tumor-targeting bacterium can for attenuated salmonella typhimurium or other there is the bacterium of cancer target performance; Described prodrug can for 6-methyl purine-2-deoxyribosyl nucleosides (6MePdR) or other can be the compound of active antineoplastic medicine by Bacterial Transformation.
Further, the invention provides a kind of tumor-targeting bacterium with prodrug Activation Activity itself, it is characterized in that the process LAN without any genetic modification or foreign gene, but utilize the constructive expression of bacterium own endogenous in bacterium born of the same parents, activation that the enzyme with pro-drug conversion activity of pericentral siphon, inner membrance or adventitia realizes prodrug.
Further, the invention provides a kind of bacterium pro-drug activation enzymes gene by bacterium oneself expression, it is characterized in that the process LAN without any genetic modification or foreign gene, but utilize the constructive expression of bacterium own endogenous in bacterium, realize conversion and the activation of prodrug.This bacterioid pro-drug activation enzymes gene is guarded at bacterium camber, and such can be purine nucleotides phosphatase gene, cytosine deaminase gene, thymidine kinase gene.
Further, the invention provides a kind of prodrug Activiation method of bacteria mediated, it is characterized in that the instrument of bacterium as pro-drug conversion, and the cancer target ability that described bacterium also must have.
Further, the invention provides a kind of prodrug Activiation method, it is characterized in that the transformation utilizing the pro-drug activation enzymes gene of bacterium self as prodrug, such prodrug can be gancyclovir (GCV), 5-flurocytosine (5-FC), 6-methyl purine-2-deoxyribosyl nucleosides (6MePdR).
Further, 6-methyl purine-2-deoxyribosyl nucleosides (6MePdR) prodrug is activated for attenuated salmonella typhimurium, prodrug 6MePdR can be converted into efficient antitumour drug 6-methyl purine (6MeP) by attenuated salmonella typhimurium, in murine melanoma model, tumour multiple growth time was by 5.54 days of 6MePdR group, 8.72 days of bacterium group, are increased to 19.58 days of 6MePdR/ bacterium group.
Compared with existing prodrug Activiation method or bacterize strategy, innovation of the present invention and special character are:
(1) a kind of tumor-targeting bacterium/prodrug Activiation method has been invented, it utilizes the pro-drug activating gene of tumor-targeting bacterium and own endogenous thereof to activate prodrug, and on murine melanoma model, bacterium/prodrug group tumor control rate is significantly higher than single bacterium group and single prodrug administration group.
(2) invented a kind of prodrug bacterium active mode, which directly utilizes bacterium to transform prodrug, utilizes which to activate prodrug with can be implemented in tumor tissue specificity.
(3) invent the therapeutic strategy of a kind of bacterium/prodrug combined utilization, utilize this strategy greatly can improve the antitumor efficiency of bacterium.
In sum, the present invention establishes a kind of brand-new tumor therapeuticing method, tumor-targeting bacterium is combined with prodrug by the method, the bacterium being enriched in tumor tissues is utilized directly to activate prodrug, and do not need to introduce or the ectogenic pro-drug activating gene of process LAN in bacterium, obtain good therapeutic action.
Four, accompanying drawing explanation
Fig. 1, attenuated salmonella typhimurium VNP20009 tumor-targeting are analyzed
Because liver and spleen are the healthy tissuess that Multiple drug resistance is maximum, the therefore titre of bacterial detection in liver, spleen and tumor tissues (* * * P < 0.001): 1, tumour; 2, spleen; 3, liver.
Fig. 2, attenuated salmonella typhimurium prodrug Activation Activity are analyzed
(2A) Salmonella typhimurium and intestinal bacteria PNP gene sequencing and tetraploid rice.
(2B) expression of PNP gene in Salmonella typhimurium VNP20009 and intestinal bacteria Top10: 1, Salmonella typhimurium VNP20009; 2, intestinal bacteria Top10.
(2C) after bacterial injection, the expression of PNP gene in each tissue: 1, spleen; 2, liver; 3, tumour; 4, lung; 5, kidney.
Fig. 3, attenuated salmonella typhimurium activate prodrug analysis
HPLC analyzes the prodrug Activation Activity of Salmonella typhimurium VNP20009 and intestinal bacteria Top10: 1, prodrug substrate 6MePdR standard substance; 2, active result 6MeP standard substance; 3, Top10+6MePdR; 4, VNP20009+6MePdR; 5, intestinal bacteria Top10; 6, Salmonella typhimurium VNP20009.
Fig. 4, the antitumor efficiency analysis of bacterium/prodrug
(4A) administration is after 2 weeks, tumor size: 1, PBS contrast; 2, prodrug 6MePdR; 3, Salmonella typhimurium VNP20009; 4, Salmonella typhimurium VNP20009+ prodrug 6MePdR.
(4B) tumor growth curve (* * P < 0.01, * * * P < 0.001): 1, PBS contrast; 2, prodrug 6MePdR; 3, Salmonella typhimurium VNP20009; 4, Salmonella typhimurium VNP20009+ prodrug 6MePdR.
(4C) tumour multiple growth time, namely from 1000mm
3to 2000mm
3required number of days (* P < 0.05, * * * P < 0.001): 1, PBS contrast; 2, prodrug 6MePdR; 3, Salmonella typhimurium VNP20009; 4, Salmonella typhimurium VNP20009+ prodrug 6MePdR.
(4D) tumour time of lag, namely tumour grows to 1000mm
3required number of days (* * P < 0.01, * * * P < 0.001): 1, PBS contrast; 2, prodrug 6MePdR; 3, Salmonella typhimurium VNP20009; 4, Salmonella typhimurium VNP20009+ prodrug 6MePdR.
Five, embodiment:
With the attenuated salmonella typhimurium with cancer target performance for prodrug activates instrument, 6-methyl purine-2-deoxyribosyl nucleosides is prodrug (6MePdR), and treatment mouse B16F10 melanoma tumor model is embodiment:
1, the tumor-targeting of bacterium and prodrug Activation Activity are analyzed and are detected:
(1) foundation of B16F10 murine melanoma subcutaneous model:
It is 5 × 10 that B16F10 cell PBS is suspended into concentration
6individual/ml, then every C57BL6 right side of mice dorsal sc subcutaneous injection 100 μ L (5 × 10
5cell), note the growing state observing tumour, greatly about about one week, tumor in situ size grows to 30-50mm
3time, according to every mouse 10
5the dosage abdominal injection attenuated salmonella typhimurium VNP20009 of colony-forming unit (cfu).
(2) tumor-targeting analysis:
Within 5 days, get spleen, liver and tumour upon administration, weigh, and according to PBS: the ratio homogenate of tissue=5: 1 (volume ml: weight g).Take out the dilution that 100 μ l carry out 10 times of gradients after homogenate, tumor tissues generally dilutes 10000-100000 doubly, and liver only needs dilution 100-1000 doubly, and it is dull and stereotyped to take out 100 μ l coating LB, incubated overnight in 37 degree of incubators.Within second day, carry out plate count, calculate and statistical study with the quantity of every gram of tissue bacterial cfu.
(3) bioinformatic analysis:
The intestinal bacteria purine nucleotides Phosphoric acid esterase (PNP) and Salmonella typhimurium PNP that are used to prodrug activation are traditionally carried out alignment and homology analysis.Intestinal bacteria PNP sequence is: matphinaemgdfadvvlmpgdplrakyiaetfledarevnnvrgmlgftgtykgr kisvmghgmgipscsiytkelitdfgvkkiirvgscgavlphvklrdvvigmgact dskvnrirfkdhdfaaiadfdmvrnavdaakalgidarvgnlfsadlfyspdgemf dvmekygilgvemeaagiygvaaefgakaltictvsdhirtheqttaaerqttfnd mikialesvllgdke, Salmonella typhimurium PNP sequence is: matphinaemgdfadvvlmpgdplrakhiaetflenvrevnnvrgmlgftgtykgr kisvmghgmgipcssiytkelitdfgvkkiirvgscgavrmdvklrdvvigmgact dskvnrirfkdhdfaaiadfdmvrnavdaakalgvdarvgnlfsadlfyspdgemf dvmekygvlgvemeaagiygvaaefgakaltictvsdhirtheqttaaerqttfnd mikialesvllgdke.
(4) PNP expression analysis in attenuation salmonella VNP20009:
Adopt Westernblotting technical Analysis tumor-targeting attenuation salmonella VNP20009 to the expression analysis of PNP, collect 1 × 10
9cfuVNP20009, utilizes ultrasonication bacterium, adds sample-loading buffer and boils 5 minutes, make sample, carry out 12%SDS-PAGE electrophoresis.Then semidrying is used to be transferred on PVDF (polyvinylidenefluoride) film by albumen in SDS-PAGE glue, 10 volts of constant voltage electricity turn 1 hour, then the film after transfer printing is placed in freshly prepared 5% skim-milk (PBST preparation) and closes, close for 4 DEG C and spend the night or room temperature effect 1h.Close after terminating, according to antibody illustrate with containing the PBST solution dilution primary antibodie of 5% skim-milk to best effort concentration, film to be coated in primary antibodie incubated at room 1 hour or to be placed in 4 DEG C of effects and spend the night.Then film PBST is placed on shaking table and sways washing gently 5 times, each 5-10 minute.Wash rear bag to be resisted by two, the PBST solution of two of horseradish peroxidase-labeled anti-use containing 5% skim-milk has been diluted by 1: 2000, jointly hatches 1 hour with film, wash 5 times with PBST equally, each 5-10min.Finally, drip on pvdf membrane according to description of product preparation luminous substrate solution (ECL chemical luminous substrate), develop photographic film, judge the expression of results of albumen according to exposure band.
(5) bacterium prodrug Activation Activity is analyzed:
High performance liquid chromatography (HPLC) is adopted to analyze the activation capability of bacterium to 6MePdR, respectively by 1 × 10
9cfu attenuation salmonella VNP20009 and 1 × 10
9intestinal bacteria Top10 and the 100 μM of prodrug 6MePdR of cfu was incubated at room 72 hours, after hatching end, centrifugal 10 minutes of 12000rpm, is then used for HPLC and analyzes, and contrast with the prodrug substrate 6MePdR of standard, active result 6MeP appearance time by supernatant.
2, PNP gene test in tumor tissues:
Treat that tumor growth is to 100mm
3time, according to every mouse 10
6cfu dosage injection VNP20009.After administration 7 days, get the tissues such as liver, spleen, lung, kidney, add PBS and homogenate according to 0.2g/ml, after centrifugal, add RIPA cell pyrolysis liquid, cracking on ice 30 minutes, then centrifugal and quantitatively, after adding sample-loading buffer, make sample, adopt Westernblotting to analyze the expression of PNP in tissue.
3, the antitumor efficiency analysis of coupling attenuation salmonella VNP20009 and 6MePdR:
Treat that tumour grows to 100mm
3time, mouse is divided into 4 groups at random according to often organizing 8, is respectively PBS control group, bacterium group (VNP), prodrug group (6MePdR) and bacterium and adds prodrug group (VNP+6MePdR).Then bacterium group and bacterium add prodrug group according to 1 × 10
6the dosage abdominal injection tumor-targeting Salmonellas VNP20009 of cfu/mice; After bacterial injections the 5th day, prodrug group and bacterium added the dosage abdominal injection prodrug 6MePdR of prodrug group according to 15mg/kg, and are administered once every day, successive administration 5 days; The PBS of PBS control group abdominal injection same volume (0.1ml).According to following formulae discovery gross tumor volume: gross tumor volume=length × wide
2× 0.52, and by regression equation calculation tumor growth curve.
The embodiment of the present invention utilizes the feature of the purine nucleotides Phosphoric acid esterase (PNP) of attenuated salmonella typhimurium VNP20009 high tumor targeting and bacterium self constructive expression, by the titre of bacterial detection in tumor tissues (Fig. 1: 1), spleen (Fig. 1: 2), liver (Fig. 1: 3), verify its cancer target performance.Then by alignment and homology analysis, find that the PNP enzyme of Salmonella typhimurium and the intestinal bacteria PNP enzyme homology of PNP/6MePdR prodrug Activiation method are 96% (Fig. 2 A), and PNP enzyme is all constructive expression in VNP20009 (Fig. 2 B:1) and intestinal bacteria Top10 (Fig. 2 B:1), after general gives bacterium, the PNP enzyme of its intracellular expression is enriched in tumor tissues by Salmonella typhimurium VNP20009, what make PNP enzyme spcificity is only expressed in tumor tissues interior (Fig. 2 C:3), and at spleen (Fig. 2 C:1), liver (Fig. 2 C:2), the organs such as lung (Fig. 2 C:4) and kidney (Fig. 2 C:5) all do not detect the expression of PNP enzyme.
In order to verify that bacterium activates the characteristic of prodrug further, adopt HLPC method, by contrasting with substrate 6MePdR (Fig. 3: 1) and product 6MeP (Fig. 3: 2) standard substance appearance time, determine, after VNP20009 (Fig. 3: 3) and Top10 (Fig. 3: 4) and prodrug 6MePdR are hatched, all 6MePdR to be converted into 6MeP completely.
Then on mouse B16F10 subcutaneous melanoma model, evaluate the antitumor efficiency of bacterium/prodrug Activiation method, in administration after 14 days, gross tumor volume (Fig. 4 A:4 of prodrug 6MePdR+ bacterium VNP20009 group; 4B:4) significantly than PBS control group (Fig. 4 A:1; 4B:1) (p < 0.001), single prodrug group (Fig. 4 A:2; 4B:2) (p < 0.001) and single bacterium group (Fig. 4 A:3; 4B:3) (p < 0.01) is little; The tumour multiple growth time of PBS control group is 5.05 days (Fig. 4 C:1), the tumour multiple growth time of single prodrug group is 5.54 days (Fig. 4 C:2), the tumour multiple growth time of single bacterium group is 8.72 days (Fig. 4 C:3), and the tumour multiple growth time of prodrug+bacterium group is 19.58 days (Fig. 4 C:4); (volume is to 1000cm time of lag for PBS control group tumour
3required time) be 6.72 days (Fig. 4 D:1), single prodrug group tumour time of lag is 8.21 days (Fig. 4 D:2), single bacterium group tumour time of lag is 11.33 days (Fig. 4 D:3), and prodrug+bacterium group tumour time of lag is 23.44 days (Fig. 4 D:4).As can be seen here, bacterium provided by the invention/prodrug Activiation method has the oncotherapy effect of highly significant, after coupling tumor-targeting Salmonella typhimurium and prodrug 6MePdR, compared with alone bacterium or alone prodrug, gross tumor volume significantly reduces, and tumor growth rate significantly slows down.
We are simultaneously according to aforesaid research (Chen Guo etc., 2009, CancerScience100:2437-2443; Jia Lijun etc., 2007, CancerScience98:1107-1112), attempted different bacterium medication (intravenously administrable, intraperitoneal administration, oral administration) and prodrug combination therapy, result can both produce good therapeutic action.
We utilize the cytosine deaminase gene of bacterium self to carry out activation and the conversion of 5-flurocytosine simultaneously, equally also create the antineoplaston effect of certain tumor-targeting.
In sum, the invention provides a kind of utilize tumor-targeting bacterium and own endogenous pro-drug activating gene thereof to activate prodrug method and application, this bacterium/prodrug Activiation method make use of two natural characteristics of bacterium: the endogenous pro-drug activation enzymes characteristic of constructive expression in the tumor-targeting of height and born of the same parents.After administration bacterium, pro-drug activation enzymes is enriched in tumor tissues by bacterium naturally, and the tomour specific realizing enzyme is expressed.After coupling bacterium and prodrug, compared with single bacterium administration or single prodrug administration, can significantly Tumor suppression growth.
The inventive method and exogenous pro-drug activation enzymes is incorporated in bacterium by expression vector artificially, realizes the method difference that prodrug transforms in vivo or activate and be in the past: the work of the exogenous pro-drug activation enzymes gene clone of default, expression vector establishment, transform bacteria, the more important thing is, when allogenic gene can produce extra load to bacterium thus affect the growth of bacterium during high expression level in bacterium, result can affect on the contrary and weaken result for the treatment of.The inventive method then overcomes the method for the conventional exogenous pro-drug activation enzymes high expression level of dependence, thus easier, easy, and result for the treatment of is more remarkable.
Above-described specific embodiment; object of the present invention, technical scheme and beneficial effect are further described; be understood that; the foregoing is only specific embodiments of the invention; be not limited to the present invention; within the spirit and principles in the present invention all, any amendment made, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (6)
1. utilize tumor-targeting bacterium to activate a method for prodrug, it is characterized in that tumor-targeting bacterium to activate instrument as a kind of natural prodrug, described tumor-targeting bacterium is the bacterium VNP20009 with cancer target performance; Described natural prodrug activates instrument and refers to that pro-drug activation enzymes is that bacterium itself has but not introduces through genetically engineered and obtain; Described prodrug is the compound being converted into anti-tumor activity medicine by pro-drug activation enzymes.
2. a kind of method utilizing tumor-targeting bacterium to activate prodrug according to claim 1, it is characterized in that the tumor-targeting bacterium VNP20009 itself with prodrug Activation Activity, without the process LAN of any genetic modification or foreign gene, utilize constitutive expression in bacterium born of the same parents, activation that the pro-drug activation enzymes with pro-drug conversion activity of pericentral siphon, inner membrance or adventitia realizes prodrug.
3. a kind of method utilizing tumor-targeting bacterium to activate prodrug according to claim 1, it is characterized in that the tumor-targeting bacterium VNP20009 itself with prodrug Activation Activity, without the process LAN of any genetic modification or foreign gene, utilize constitutive expression in bacterium born of the same parents, the pro-drug activation enzymes with pro-drug conversion activity of pericentral siphon, inner membrance or adventitia is on tumor tissue specificity ground, independently activate prodrug.
4. a kind of method utilizing tumor-targeting bacterium to activate prodrug according to claim 1, it is characterized in that the tumor-targeting attenuation salmonella bacterium VNP20009 itself with prodrug Activation Activity, without the process LAN of any genetic modification or foreign gene, utilize constitutive expression in bacterium born of the same parents, the pro-drug activation enzymes with pro-drug conversion activity of pericentral siphon, inner membrance or adventitia activates instrument as a kind of natural prodrug, described prodrug is 6-methyl purine-2-deoxyribosyl nucleosides or gancyclovir or 5-flurocytosine.
5. a kind of method utilizing tumor-targeting bacterium to activate prodrug according to claim 4, is characterized in that tumor-targeting attenuation salmonella bacterium VNP20009 can express endogenic pro-drug activation enzymes gene purine nucleotides Phosphoric acid esterase or Isocytosine deaminase, thymidine kinase composing type.
6. a kind of method utilizing tumor-targeting bacterium to activate prodrug according to claim 1 is preparing the application in antitumor drug.
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| "Optimization of tumor-targeted gene delivery by engineered attenuated Salmonella typhimurium";Mei S, et al.;《Anticancer Research》;20021231;第22卷(第2A期);摘要，第3261页右列第2段,第3263页图1 * |
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