CN107929754A - A kind of application of polycation carrier coating recombined adhenovirus in Antioncogene medicine is prepared - Google Patents
A kind of application of polycation carrier coating recombined adhenovirus in Antioncogene medicine is prepared Download PDFInfo
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Abstract
The invention discloses a kind of application of polycation carrier coating recombined adhenovirus in Antioncogene medicine is prepared, wherein, the polycation carrier is the polycation that is polymerized by cyclodextrin, polyethyleneimine folic acid, the Antioncogene medicine for people source interleukin 15 of having transduceed on recombined adhenovirus genomic medicine.On subcutaneous and metastatic malignant melanoma mouse model, H1/rAdv 15 can effectively suppress tumour growth, extend the mice with tumor time-to-live, its curative effect is better than single Adv IL15.The antitumor mechanism of H1/rAdv 15 is mainly：The propagation of activation CD4+, CD8+T cells and NK cells, stimulate its killing activity, suppresses immunosuppressant cell Treg and plays its antitumor activity, and new approaches are provided for the immunization therapy research of malignant mela noma.
Description
Technical field
The invention belongs to antitumor drug applied technical field, and in particular to a kind of polycation carrier coating restructuring gland
Application of the virus in Antioncogene medicine is prepared.
Background technology
Malignant melanoma of skin (disliking black) is the highest tumour of grade malignancy in cutaneum carcinoma.White people are apt to occur in, at me
State, it is relatively low to dislike black incidence, but incidence increase it is very fast.With the arrival of aging society, some scholars are even
It is proposed, following 10 years malignant mela nomas are by as the major issue for influencing public health.Due to region and habits and customs etc. because
Element, Photodermatoses, skin chronic injury etc. is relatively conventional in Yunnan Province, and it is also of a relatively high to dislike black Probability.
Immunogenic properties based on malignant mela noma, immunization therapy have become one kind and treat Advanced Malignant melanin
The important supplemental treatment regimens of knurl.IL-15 is a kind of four-helix bundle cell factor, and their heterotrimer acceptor, except α
Beyond chain, β and γ chains share；The similar and part acceptor of these self structures shares, and the function of IL-15 mainly has stimulation NK
Cell, T cell, the propagation of B cell and activation etc..In terms of immunotherapy of tumors, IL-15 can be thin by activation effect T
Born of the same parents, remember CD8+T cells and NK cells and play significant tumor-inhibiting action.Since quick kidney is removed, to reach and effectively control
Treat dosage, it is still desirable to which heavy dose of duplicate injection IL-15 cell factors, the toxic side effect as caused by this shock therapy and take
With also limit its extensive clinical practice the problems such as costliness.
The content of the invention
The purpose of this part is to summarize some aspects of the embodiment of the present invention and briefly introduce some preferably to implement
Example.It may do a little simplified or be omitted to avoid our department is made in this part and the description of the present application summary and denomination of invention
Point, the purpose of specification digest and denomination of invention obscure, and this simplification or omit and cannot be used for limiting the scope of the invention.
In view of above-mentioned technological deficiency, it is proposed that the present invention.
Therefore, the present invention is therein overcomes the deficiencies in the prior art, there is provided a kind of polycation carrier coating
Application of the recombined adhenovirus in Antioncogene medicine is prepared.
In order to solve the above technical problems, the present invention provides following technical solution：A kind of polycation carrier coating weight
Application of the group adenovirus in Antioncogene medicine is prepared, wherein, the polycation carrier is by cyclodextrin, polyethylene
The polycation that imines folic acid is polymerized, the Antioncogene medicine are people source interleukin of having transduceed on recombined adhenovirus
15 genomic medicine.
As polycation carrier of the present invention coating recombined adhenovirus answering in Antioncogene medicine is prepared
Preferred solution, wherein, the recombined adhenovirus is by the adenovirus vector of vitro recombination generation, including serotype 2 and blood
Clear type 5.
As polycation carrier of the present invention coating recombined adhenovirus answering in Antioncogene medicine is prepared
Preferred solution, wherein, the tumour is melanoma.
As polycation carrier of the present invention coating recombined adhenovirus answering in Antioncogene medicine is prepared
Preferred solution, wherein, the polycation and the adenovirus are pressed into 70nmol：2×106Pfu ratios mix shape
Into polymer.
As polycation carrier of the present invention coating recombined adhenovirus answering in Antioncogene medicine is prepared
Preferred solution, wherein, the genomic medicine, its mode of action is the expression of people source interleukin 15 gene.
Beneficial effects of the present invention：
Present invention research is found, on subcutaneous and metastatic malignant melanoma mouse model, people source interleukin of having transduceed
15 polycation carrier coating recombined adhenovirus (hereinafter referred to as H1/rAdv-15), can effectively suppress tumour growth, extend
Mice with tumor time-to-live, recombined adhenovirus (hereinafter referred to as Adv- of its curative effect better than people source interleukin 15 of individually having transduceed
IL15)。
We have further found that the antitumor mechanism of H1/rAdv-15 is mainly：CD4+ is activated, CD8+T cells and NK are thin
The propagation of born of the same parents, stimulate its killing activity, suppresses immunosuppressant cell Treg and plays its antitumor activity, is malignant mela noma
Immunization therapy research provide new approaches.
Brief description of the drawings
In order to illustrate the technical solution of the embodiments of the present invention more clearly, required use in being described below to embodiment
Attached drawing be briefly described, it should be apparent that, drawings in the following description are only some embodiments of the present invention, for this
For the those of ordinary skill of field, without having to pay creative labor, it can also be obtained according to these attached drawings other
Attached drawing.Wherein：
Fig. 1 is H1 structure diagrams.
Fig. 2 is the structure chart that NMR characterizes H.
Fig. 3 packs ratio the selection result figure for H1/Adv-IL15.
Fig. 4 is B16 cell IL15 expression of results figures.
Fig. 5 is subcutaneous tumor model tumour growth situation map.
Fig. 6 is subcutaneous tumor mice with tumor life span figure.
Fig. 7 is metastatic tumour model mice lung tumor growth figure.
Fig. 8 is metastatic tumour model mice Survival figure.
Fig. 9 is CD4+T cell count figures.
Figure 10 is CD4+T cell representativeness flow cytometry block diagrams.
Figure 11 is CD8+T cell count figures.
Figure 12 is CD8+T cell representativeness flow cytometry block diagrams.
Figure 13 counts figure for NK cells.
Figure 14 is NK cell representativeness flow cytometry block diagrams.
Figure 15 is CD4+CD25+ cell count figures.
Figure 16 is CD4+CD25+ fluidic cells expression figure.
Figure 17 is cytokines express spectra result figure.
Figure 18 is T cell and B cell proliferation activity figure.
Figure 19 is the killing activity figure of NK cells.
Figure 20 is dyed for cancer pathology tissue examination HE and Immunohistochemical detection result figure.
Embodiment
In order to make the foregoing objectives, features and advantages of the present invention clearer and more comprehensible, with reference to specific embodiment pair
The embodiment of the present invention is described in detail.
Many details are elaborated in the following description to facilitate a thorough understanding of the present invention, still the present invention can be with
Implemented using other different from other manner described here, those skilled in the art can be without prejudice to intension of the present invention
In the case of do similar popularization, therefore the present invention is from the limitation of following public specific embodiment.
Secondly, " one embodiment " or " embodiment " referred to herein refers to may be included at least one realization side of the present invention
A particular feature, structure, or characteristic in formula." in one embodiment " that different places occur in the present specification not refers both to
Same embodiment, nor the single or selective embodiment mutually exclusive with other embodiment.
The synthesis of H1, the making of the packaging of Adv-IL15, H1/Adv-15：
Synthesis with cyclodextrin (β-Cyclodextrin) for cross-linked scaffold, connect low molecular weight polyethyleneimine (PEI,
600Da), Poly-cation PEI-CyD- of the coupling with the specific small-molecule drug folic acid (Folate) of cancer target
FA, is named as H1, and structure is as shown in Figure 1, the H1 structure charts of NMR characterizations are as shown in Figure 2.
The packaging of Adv-IL-15：
Employment source Ad-IL-15, Ad-Luciferase adenovirus infects HEK293 cells respectively, and high drop is obtained by expanding
The virus of degree, labeled as Ad-IL15, Ad-Luciferase.
The making of H1/Adv-IL-15：
Adv-Luc is packed using the H1 of different proportion, using highest transfection efficiency ratio-dependent as optimal packaging ratio.
Cell culture：
B16-F10 melanoma cell strains cellar culture is in DMEM (hyclone)+10%FBS+100U/ml
Penicillin, and 100mg/ml streptomycin (Invitrogen) are placed in 37 DEG C, in 50% CO2gas incubator
Culture.After stablizing 3,4 generations of passage, growth period cell of taking the logarithm, is resuspended with serum-free medium after the digestion of 2.5g/L pancreatin and received
Collect cell.
The foundation and packet of animal model：
C57BL/6J mouse 100,18-22g, male, buy from Beijing Hua Bukang bio tech ltd, licensing
Numbering：SCXK (capital) 2014-0004, is raised in Kunming Medical University's Experimental Animal Center.All animal experiment methods obtain
Obtain the approval of the animal welfare committee of Kunming Medical University.
1 experimental animal group of table
Situ tumor model is established：
C57BL/6J mouse 70, dorsal subcutaneous Mice Inoculated malignant mela noma B16-F10 cells 1 × 105, freely drink
Water is fed, daily observation experiment the weight of animals and general status.Reach 50mm or so in tumour, be randomly divided into 5 groups, every group includes
10 mouse.The packet same day, and through giving relative medicine treatment knurl week.Later weekly administration is once.
Lung metastases Animal Model：
C57BL/6J mouse 70, dorsal subcutaneous Mice Inoculated malignant mela noma B16-F10 cells 1 × 105, meanwhile,
Tail vein injection B16-F10 cells 1 × 105；Reach 50mm or so in tumour, be randomly divided into 5 groups, every group includes 10 mouse.
The packet same day, and through giving relative medicine treatment knurl week.Later weekly administration is once.
Administration：
Mouse is once in a week, dead or swollen with tumor-bearing mice into the knurl same day 2 × 106pfu/ relative medicine of tumor-side injection
Knurl volume reaches 1500mm3 (computational methods：0.52* major diameter * wide footpaths 2) it is terminal, treat altogether twice.
Indexs measure：
Reached every other day with vernier caliper measurement into knurl mouse tumorous size with tumor-bearing mice death or gross tumor volume
1500mm3 (computational methods：0.52* major diameter * wide footpaths 2) it is terminal, the mouse that gross tumor volume is reached home is taken entirely according to BD
MultitestTMIMK kit operating procedures use Partec GmbH ultrahigh speed flow cytometry sorting works station (CyFlow
Space, Germany) do immunocyte analysis.
Serum is grasped according to BD Cytometric Bead Array (CBA) Mouse Th1/Th2/Th17Cytokine Kit
Make step and do cytokine analysis using BD Accuri C6 stream type cell analyzers (U.S.),
Knurl body is infiltrated on 10% paraformaldehyde and makes histopathologic slide's (HE dyeing), is seen under olympus inverted microscopes
Examine；Fresh knurl body is tumor-infiltrated using analyzing according to mouse tumor infiltration tissue lymph's cell separation liquid kit (Solarbio)
Lymphocyte, 1640 (hyclone)+10%FBS+1% streptoducin cultures, according to BD Cytometric Bead Array
(CBA) Mouse Th1/Th2/Th17Cytokine Kit operating procedures are (beautiful using BD Accuri C6 stream type cell analyzers
State) detection 24-48 it is small when culture medium in Cytokine profile.
Cell factor result is analyzed with BD FCAP Array v3, and all data use SPSS17.0 statistical softwares
Bag carries out statistical analysis.Comparison between multiple sample averages of completely randomized design uses one-way analysis of variance, between group two-by-two
Compare and use LSD methods.Level of significance test is α=0.05.
Embodiment 1：
The packaging of Adv-IL5 and expression：
Titre is surveyed using TCID50 methods：
Adv-IL5：The titre of virus is (0.7 × 5 × 1010.5) PFU=1.106 × 1011PFU/mL
Adv–Luciferase：The titre of virus is (0.7 × 5 × 1010.41) PFU=9.0 × 1010PFU/mL
The making of H1/Adv-IL15 and detection of expression is determine optimal packaging ratio, we are first by different proportion
H1 packaging Adv-Luc.As shown in figure 3, H1:Adv-Luc=70nmol:2×106Pfu shows highest transfection efficiency, because
This, determines the ratio for optimal packaging ratio and using in experiment afterwards.
The B16 cells as shown in figure 4, H1/Adv-IL15 transduces, high efficient expression IL-15 cells in nutrient solution.
As shown in Figure 5：Compared with control group, Adv-IL15 and HI/Adv-IL15 processing, the speed of growth of gross tumor volume,
It is obvious to reduce, explanation：Above-mentioned treatment substantially inhibits the growth of tumour, wherein, HI/Adv-IL15 processing tumour growths are than independent
Adv-IL15 processing it is slower.
As shown in Figure 6：The median survival time of control group mice with tumor is 18 ± 8 days, and Adv-IL15 treatment groups are 30 ± 4
My god, HI/Adv-IL15 treatment groups are 35 ± 5 days；Compared with control group, Adv-IL15 treatment groups significantly extend mice with tumor survival
Time (student t-t test, n=6, p<0.01)；And compared with Adv-IL15 treatment groups, HI/Adv-IL15, treatment group
Significantly extend mice with tumor time-to-live (student t-t test, n=6, p<0.05).
Therefore, HI/Adv-IL15 inhibits the growth of subcutaneous malignant mela noma, extends the time-to-live of mice with tumor.
Embodiment 2：
HI/Adv-IL15 reduces malignant mela noma Lung metastases tubercle, extends the mice with tumor time-to-live：
As shown in Figure 7：Adv-Luc, H1/Adv-Luc, Adv-IL15 and HI/Adv-IL15 treatment group reduce mouse lung
Node number, wherein HI/Adv-IL15 treatment groups are reduced as substantially, have statistical significance (student t-t test, n
=6, p<0.05).
As shown in Figure 8：Adv-IL15 and HI/Adv-IL15 treatment groups extend the metastatic tumour model mice time-to-live.
Embodiment 3：
HI/Adv-IL15 is treated, and increases peripheral blood CD4+T cell numbers：
We are used in flow cytomery peripheral blood lymphocytes, the number of CD4+T cells, and representative streaming is thin
Born of the same parents analyze block diagram and are shown in Figure 10, statistical result showed such as Fig. 9, with control group HI/Adv-Luc, Adv-Luc, 5%Glu phase
Than HI/Adv-IL15, Adv-IL15 processing, significantly increase peripheral blood CD4+T cell numbers (P<0.05).
Embodiment 4：
HI/Adv-IL15 is treated, and increases peripheral blood CD8+T cell numbers：
We are used in flow cytomery peripheral blood lymphocytes, the number of CD8+T cells, and representative streaming is thin
Born of the same parents analyze block diagram and are shown in Figure 12, statistical result showed such as Figure 11, with control group HI/Adv-Luc, Adv-Luc, 5%Glu phase
Than HI/Adv-IL15, Adv-IL15 processing, significantly increase peripheral blood CD4+T cell numbers (P<0.05).
Embodiment 5：
HI/Adv-IL15 is treated, and increases peripheral blood NK cell number：
We are used in flow cytomery peripheral blood lymphocytes, the number of CD49+NK cells, representative streaming
Cell analysis block diagram is shown in Figure 14；Statistical result showed such as Figure 13, with control group HI/Adv-Luc, Adv-Luc, 5%Glu
Compare, HI/Adv-IL15, Adv-IL15 processing, significantly increase peripheral blood CD4+T cell numbers (P<0.05).
Embodiment 6：
HI/Adv-IL15 treatments suppress peripheral blood lymphocytes Treg subgroups
One week treatment and after two weeks, extracts peripheral blood and does FCM analysis CD4, CD25 double positive cells subgroup respectively.
As a result it is as shown in figure 15：Compared with independent Adv-Luc processing, H1/Adv-15 treatments considerably reduce CD4, and CD25 is double positive thin
Born of the same parents' subgroup.Figure 16 is CD4+CD25+ fluidic cells expression figure.
Embodiment 7：
Cytokines expression treatment after a week, extracts peripheral blood, does cell factor expression pattern analysis, as a result as schemed
Shown in 17：Compared with control group, independent Adv-15 treatments and H1/Adv-IL15 treatments significantly increase IL-2, IL-6, IL-
The expression of 4, IL-17 cell factors；In addition, H1/Adv-IL15 treatments also add expression (student ' the s t- of IFN and TNF
T test, n=3, * p<0.05,**p<0.01).
Embodiment 8：
First week after HI/Adv-IL15 treatments increase mouse T cell and B cell proliferation active treatment, mouse spleen is extracted,
Single cell suspension is made, is stimulated respectively using LPS and CoA, detects lymphopoiesis state, as shown in figure 18：Adv-IL15
With HI/Adv-IL15 treatment groups, mouse boosting cell, apparently higher than control group, illustrates Adv- to the propagation sensitiveness of LPS and CoA
IL15 and HI/Adv-IL15 treatments have activated the proliferation activity of B cell and T cell；Wherein HI/Adv-IL15 treatment groups T cell
Proliferation activity be substantially better than single Adv-IL15 groups.
Embodiment 9：
The killing activity after one week treatment of H1/Adv-IL15 treatment increase NK cells in mice, extraction mouse spleen makes single
Cell suspension, using B16-F10 as target cell, does the experiment of NK cell killing activities.As shown in figure 19：In effect target than 50：When 1, H1/
Adv-IL15 treats the NK cells of mouse, compared with control group (Adv-luc), hence it is evident that add the killing activity of NK cells.
Embodiment 10：
Cancer pathology tissue examination：As shown in figure 20：Typical H1/Adv-15 therapeutic response actual shrinkages, a large amount of tissues
Necrosis, is distributed with CD8+ (PE) CD25+ (FITC) double positive cells in slough, and portion is distributed with remaining tumor tissues
Divide CD49+ (PE) cell；And the tumour of untreated, necrotic zone tissue have no in bleeding, edematous state, residual tumor tissue
Lymphocytic infiltration.
It should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention and it is unrestricted, although with reference to preferable
The present invention is described in detail in embodiment, it will be understood by those of ordinary skill in the art that, can be to the technology of the present invention
Scheme technical scheme is modified or replaced equivalently, without departing from the spirit and scope of technical solution of the present invention, it should all cover in this hair
Among bright right.
Claims (6)
1. a kind of application of polycation carrier coating recombined adhenovirus in Antioncogene medicine is prepared, its feature exist
In：The polycation carrier is the polycation being polymerized by cyclodextrin, polyethyleneimine folic acid, described antitumor
Genomic medicine for people source interleukin 15 of having transduceed on recombined adhenovirus genomic medicine.
2. application as claimed in claim 1, it is characterised in that：The recombined adhenovirus is the adenovirus produced by vitro recombination
Carrier, including serotype 2 and serotype 5.
3. application as claimed in claim 2, it is characterised in that：The tumour is melanoma.
4. the application as described in claims 1 to 3 is any, it is characterised in that：By the polycation and the adenovirus
By 70nmol：2×106Pfu ratios are mixed to form polymer.
5. the application as described in claims 1 to 3 is any, it is characterised in that：The genomic medicine, its mode of action are people sources
The expression of interleukin 15 gene.
6. the application as described in claims 1 to 3 is any, it is characterised in that：People source of having transduceed on the recombined adhenovirus is situated between in vain
The genomic medicine of element 15 is by activating CD4+, and the propagation of CD8+T cells and NK cells simultaneously stimulates its killing activity, suppresses immune
Suppress cell Treg and play its antitumor activity.
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| CN116574748A (en) * | 2023-07-10 | 2023-08-11 | 昆明医科大学 | Chimeric nTCR-T construction method for targeting KRAS high-frequency mutant tumor |
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| CN116574748A (en) * | 2023-07-10 | 2023-08-11 | 昆明医科大学 | Chimeric nTCR-T construction method for targeting KRAS high-frequency mutant tumor |
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