CN109512798A - A pharmaceutical composition nanometer system for anti-tumor immunotherapy - Google Patents
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Abstract
The invention designs a drug combination nano system for anti-tumor immunotherapy, and particularly relates to a drug combination nano system for anti-tumor immunotherapy, which is characterized in that one or more perfluorinated carbon compounds and one or more immune checkpoint inhibitors with effective dose are loaded in an albumin shell as effective components.
Description
Technical field
The invention belongs to field of medicaments, are related to a kind of pharmaceutical composition nanometer system for anti-tumor immunotherapy, tool
Body is related to the pharmaceutical composition nanometer system by opening tumor vessel barrier, increases vascular permeability, promotes immunocyte swollen
Tumor infiltration, inducing antitumor immunity reaction, synergic sensitizion antitumor curative effect.
Background technique
Current cancer is still one of the maximum problem for threatening human health, and the annual whole world suffers from cancered number and is more than
14000000, and the number for dying of cancer is more than 8,000,000, as Cancer Mortality and the death rate increase year by year, malignant tumour
Treatment need is increasing.Operation, radiotherapy, chemotherapy and targeted therapy are the essential therapeutic arsenals of current tumour, but these sides
Method more or less has that side effect is big, is also easy to produce the problems such as drug resistance, and long-term existence is not brought to patients with advanced solid tumors
Benefit.Immunotherapy of tumors has unique advantage in existing treatment of cancer, is looked forward to by more and more research institutions and pharmacy
Booming trend is presented in the favor of industry in recent years.
Programmed cell death molecule (programmed death-1, PD-1) is a kind of receptor on immunocyte T cell surface
Albumen, it can be with the programmed death ligand (Programmed death-ligand 1, PD-L1) of tumor cell surface expression
It has an effect, the two presses down once a kind of negative regulation signal will be transmitted to T cell by combining, and inducing T cell enters quiescent condition
Its Immune discrimination function is made, while mediate T cell own amplification reduces or apoptosis, effectively releases the immune response of body.And PD-
1/PD-L1 inhibitor can block the combination of PD-1 and PD-L1, make T cell activity recovery, to enhance immune response.It is immune
Checkpoint inhibitor is the hot spot of current tumour immunotherapy, and the immunologic test point antibody listed at present mainly has: PD-1 monoclonal antibody
Nivolumab and Pembrolizumab, PD-L1 monoclonal antibody Atezolizumab, CLTA-4 monoclonal antibody Ipilimumab.Although immune
Checkpoint inhibitor can improve the survival rate of patient to a certain extent, bring the antitumor work that comparison is lasting in clinical application
With, however only the patients with solid tumor of 10%-30% can benefit from single therapy.Immunologic test point is being applied alone in patient for a long time
In the process, it also occur that the phenomenon that " response low ", " no response " or " drug resistance ".
A large number of studies show that be largely determined by tumour to the response of immunologic test point blocking treatment micro- for clinical patients
Immune t-cell quantity and its immunologic cytotoxicity activity infiltrated in environment.Therefore increasing infiltration in the tumor of effect cytotoxic T cell is mesh
It is preceding that there is an urgent need to the problem in science of breakthrough.In order to reach ideal immunopotentiation effect, it is anti-to need a kind of safely and effectively auxiliary
Tumour medicine is with the existing immunization therapy of synergy.
Perfluorinate carbons compound is a kind of compound formed after the hydrogen atom in hydrocarbon is replaced by fluorine atoms,
PFC is colorless and odorless under room temperature, and the transparency liquid with strong-hydrophobicity, chemical property is stable and is in biologically inert, biofacies
Capacitive is good.Perfluocarbon have good gas solubility, become good breathing gas vehicle medium, earliest by with
It is widely used in medical domain in blood substitute (PFC emulsion), but present Major medical purposes is still limited in oxygen supply model
Within farmland.
Up to the present, the pharmaceutical composition nanometer system based on perfluorocarbon compound and immunologic test point inhibitor exists
Document patent in terms of enhanced sensitivity anti-tumor immunotherapy has no record and report.
Summary of the invention
The purpose of the present invention is the status for clinical immunization therapy and there are problem, provides a kind of for antitumor
The pharmaceutical composition nanometer system of immunization therapy, the pharmaceutical composition specifically include: one or more perfluors of therapeutically effective amount
Change the one or more immunologic test point inhibitor and albumin shell of carbon compound, therapeutically effective amount.
Wherein, the pharmaceutical composition nanometer system both can increase the immunocyte quantity infiltrated in tumor, and can be effective
The antitumor killing activity of immune cell activated, while there is excellent tumor-targeting and biological safety.
Further, the pharmaceutical composition nanometer system, it is characterised in that the average grain diameter of the nanoparticle is
25nm-400nm, preferably 100nm-250nm.
Further, the pharmaceutical composition nanometer system, it is characterised in that the perfluorocarbon compound is chain
One of shape, ring-type, heterocycle and halogenated or nitrogenous perfluoro-compound or their compositions, wherein it is preferred that perfluorotributylamine,
Perfluor triamylamine and perfluor butyl iodide.
Further, the pharmaceutical composition nanometer system, it is characterised in that the albumin includes but is not limited to blood
Pure albumen, ovalbumin, lactoalbumin, myoalbumin, leucosin and legumelin and other type albumin or it
Combination, preferably human serum albumins.
Further, wherein immunologic test point inhibitor including but not limited to PD-1, PD-L1, CLTA-4, LAG3,
Inhibitor of B7-H3, B7-H4, KIR, TIM3 and combinations thereof.
Further, wherein immunologic test point inhibitor is antibody, comprising soluble fusion protein receptor, peptide, small
Molecule and combinations thereof.
Further, the pharmaceutical composition nanometer system is in use, intravenous formulations or jelly can be made into
Dry powder injection.
Further, the composition also includes one or more pharmaceutically acceptable excipient.
Further, in described pharmaceutical composition nanometer system, it is 0.1mL/ that perfluorocarbon compound, which accounts for total system specific gravity,
ML to 0.5mL/mL, wherein it is preferred that 0.2mL/mL.
Further, in described pharmaceutical composition nanometer system, immunologic test point inhibitor accounts for total system specific gravity and is
0.5mg/mL to 3mg/mL, wherein it is preferred that 1mg/mL.
Further, it includes but is not limited to colon that the pharmaceutical composition nanometer system, which can be used for treating kinds cancer,
Cancer, triple negative breast cancer, malignant mela noma, non-small cell lung cancer, liver cancer, clear-cell carcinoma, prostate cancer, oophoroma or stomach
Cancer.
Compared to the prior art, pharmaceutical composition nanometer system provided by the invention has the advantage that
Pharmaceutical composition nanometer system when in use, can dramatically increase the CD4+T lymphocyte that is infiltrated in tumor tissues and
CD8+T lymphocyte quantity, and effectively facilitate antitumor associated immune cells secretion toxicity killer factor IFN-γ, TNF-α and
The level of IL-6, to more preferably play the effect of killing tumor cell.
Pharmaceutical composition nanometer system of the present invention has good tumor-targeting, can be with specific accumulation to tumour portion
The toxic side effect to other normal tissues is reduced in position.
Pharmaceutical composition nanometer system of the present invention makes its antineoplastic immune drug effect better than one-component shape in the presence of synergistic effect
At nanometer system.
Pharmaceutical composition nanometer system of the present invention can activate tumor immune system, have to immunotherapy of tumors preferable
Synergistic function has great clinical research meaning for the existing malignant tumour for lacking effective therapeutic agent, especially
It is limited to immunization therapy caused by the poor immune microenvironment of tumour and responds low case, is mentioned for the clinical existing immunization therapy of enhanced sensitivity
New thinking and platform are supplied.
Detailed description of the invention
Fig. 1 is the formulation aesthetics figure of pharmaceutical composition nanometer system
Fig. 2 is the vivo biodistribution distribution map of pharmaceutical composition nanometer system
Fig. 3 is pharmaceutical composition nanometer system effect front and back tumor vessel SEM phenogram
Fig. 4 is administration front and back lymphocytes in blood quantity statistics result figure
Fig. 5 is the immunohistochemistry fluorogram of tumor locus lymphocyte infiltration
Fig. 6 is the gross tumor volume and knurl weight of each group mouse in embodiment 7
Fig. 7 is tumour CD3+, CD4+ and CD8+T lymphocyte relative percentage statistics knot of each group mouse in embodiment 8
Fruit figure
Fig. 8 is IFN-γ, TNF-α and IL-6 level statistic result figure in the tumour of each group mouse in embodiment 9
Fig. 9 is that organ-tissue is sliced H&E colored graph in embodiment 10
Figure 10 is the Cytotoxic evaluation of pharmaceutical composition nanometer system
Specific embodiment
The present invention is further illustrated below with reference to example, following implementation only describes this hair by way of example
It is bright.But it is not intended that be limited to the present invention, those skilled in the art are without prejudice to the inventive spirit of the present invention
Under the premise of can also make various equivalent variation or replacement, these equivalent variation or replacement are all contained in the claim of this application
In limited range.It is to be understood that this invention is intended to cover the accommodation and modification that include in the dependent claims.
Embodiment 1: pharmaceutical composition nanometer system (the PFC@PD- of perfluocarbon and the checkpoint PD-L1 inhibitor is contained
L1@Albumin) preparation method
Suitable albumin stoste is measured, is placed in ultrasonic bottle with distilled water configuration albumin solution (10g/200mL)
In, it is premixed with 1mL liquid-transfering gun, adds 1mL perfluor butyl iodide and 500 μ L ethyl alcohol (analysis is pure), be eventually adding 3mg anti-
PD-L1 antibody, sufficiently piping and druming mix.Above-mentioned gained nano-emulsion system is placed in ice-water bath, it is super using cell Ultrasonic Cell Disruptor
3 circulations (ultrasonic power 300W) of sound, each circulation 2 minutes.Each ultrasound terminates for preparation to be statically placed in cooling 1- in 4 DEG C of water-baths
2 minutes.Sample 3500rpm is finally centrifuged 3min, taking supernatant is pharmaceutical composition nanometer system (the PFC@PD-L1@prepared
Albumin), formulation aesthetics are shown in Fig. 1.
Embodiment 2: independent perfluocarbon albumin preparation (PFC@Albumin) preparation method
Suitable albumin stoste is measured, is placed in ultrasonic bottle with distilled water configuration albumin solution (10g/200mL)
In, it is premixed with 1mL liquid-transfering gun, adds 1mL perfluor butyl iodide and 500 μ L ethyl alcohol (analysis is pure), sufficiently piping and druming mixes.It will be upper
It states gained nano-emulsion system to be placed in ice-water bath, using ultrasonic 3 circulations (ultrasonic power 300W) of cell Ultrasonic Cell Disruptor, each
Circulation 2 minutes.Each ultrasound terminates for preparation to be statically placed in 1-2 minutes cooling in 4 DEG C of water-baths.Finally sample 3500rpm is centrifuged
3min, taking supernatant is the independent perfluocarbon albumin preparation (PFC@Albumin) prepared.
Embodiment 3: pharmaceutical composition nanometer system is in the intracorporal bio distribution situation of tumor-bearing mice
It chooses weight and establishes colon cancer (CT26) Subcutaneous transplanted model in the male Balb/c mouse of 18-22g or so, it will
IR775, which is contained into pharmaceutical composition nanometer system, tracks nanoparticle in the intracorporal distribution situation of tumor-bearing mice.Mouse tumor connects
After kind one week, tail vein injection contains the pharmaceutical composition nanometer system (0.1mL/10g) of IR775, taken after administration 1h, 10h,
For 24 hours, 48h and 72h time point anaesthetizes mouse with 2% Nembutal sodium solution, is imaged by small animal living body to each group
Mouse carries out bioluminescence imaging and tracks pharmaceutical composition nanometer system vivo biodistribution distribution situation, sees Fig. 2.The results show that medicine
Compositions nanometer system can be accumulated in tumor locus with efficient targeting.
Embodiment 4: influence of the pharmaceutical composition nanometer system to tumor vessel barrier
Weight is taken to establish colon cancer (CT26) Subcutaneous transplanted model in the male Balb/c mouse of 18-22g or so.To tumour
The bulk grows to~200mm3When, mouse is randomly divided into two groups.PFC@prepared by experimental mice tail vein injection embodiment 1
PD-L1@Albumin (10mL/kg), another set inject same amount of normal saline as control.After 10h is administered, mouse is put to death
And solution takes its tumor tissues, and tumor tissues are lyophilized by freeze dryer, observes tumour blood by scanning electron microscope (SEM)
The hole situation of pipe surface, is shown in Fig. 3.The result shows that pharmaceutical composition nanometer system can significantly increase tumor vascular element surface
Hole, i.e. the pharmaceutical composition nanometer system can effectively open tumor vessel barrier, increase tumor vessel permeability.
Embodiment 5: pharmaceutical composition nanometer system administration front and back lymphocytes in blood variation
It chooses normal Balb/c male mice and is randomly divided into 2 groups: 1. control group: 10mL/kg physiological saline (i.v.)；②
PFC@PD-L1@Albumin (i.v.) prepared by 10mL/kg embodiment 1.It is administered after 10h, eye socket is carried out to each group mouse and is taken
Blood sample is carried out blood routine detection, analyzes the variation of each group mouse blood medium size lymphocyte number by blood.As a result as shown in figure 4, table
Bright pharmaceutical composition nanometer system can dramatically increase periphery blood lymphocyte quantity.
Embodiment 6: pharmaceutical composition nanometer system administration front and back tumor locus lymphocytic infiltration situation
It chooses normal Balb/c mouse solution and takes its spleen, shred spleen with operating scissors, then tissue block is placed in cell
It is transferred in centrifuge tube after being ground into cell homogenates on sieve, 3000rpm is centrifuged 5min.Give up supernatant, remove confluent monolayer cells and adds
Entering erythrocyte cracked liquid (ACK) to crack red blood cell therein, 3000rpm is centrifuged 5min again, it is cleaned 3 times with PBS, point
From lymphocyte can be obtained.Fluorescence preliminary making is carried out to separating obtained lymphocyte with fluorescein based dye CFSE.Separately take male Balb/
C tumor-bearing mice (CT26 model of colon cancer) is randomly divided into 2 groups: 1. control group: 10mL/kg physiological saline (i.v.)；②10mL/kg
PFC@PD-L1@Albumin (i.v.) prepared by embodiment 1.Administration 10h and then tail vein inject equivalent CFSE label respectively
Lymphocyte.Each group mouse is dissected after for 24 hours, takes its tumor tissues that frozen section is made.With DAPI to neoplastic cell nuclei into
Line flag.As a result as shown in Figure 5, it is seen that the lymphocyte number infiltrated in the mouse tumor tissue of pharmaceutical composition nanometer system group
Amount increased significantly.
Embodiment 7: using the antitumor drug effect of CT26 bearing mouse model evaluation pharmaceutical composition nanometer system
The male Balb/c mouse of 6-7 week old is chosen, it is subcutaneous to establish mouse junction cancer (CT26) between 18-22g for weight
Transplantation model is made to assess the immune enhanced sensitivity of the pharmaceutical composition nanometer system (PFC@PD-L1@Albumin) of the preparation of embodiment 1
With.
(tumor size is about 80mm to tumor inoculation after a week3), mouse is carried out to be randomly divided into 4 groups (every group of 8-10 is only):
1. control group: 10mL/kg physiological saline (i.v.)；2. 10mL/kg perfluocarbon albumin nano granular (i.v.)；③10mg/kg
Anti-PD-L1 antibody (i.p.)；4. 10mL/kg pharmaceutical composition nanometer system was administered at the 0th, 2,4,6,8 day respectively, experiment
Continue two weeks.In experimentation, a tumor size is measured daily and records data, each group mouse tumor volume is shown in Fig. 6.
The results show that with anti-PD-L1 antibody monotherapy group ratio, the tumour of pharmaceutical composition nanometer system group mouse
Volume significantly reduces, and shows that drug effect is immunized in pharmaceutical composition nanometer system energy synergic sensitizion.
Embodiment 8: the influence that the treatment of pharmaceutical composition nanometer system infiltrates T cell in tumour
By control group, independent PFC nanoparticle group, independent anti-PD-L1 group and the pharmaceutical composition nanometer in embodiment 7
The mouse tumor tissue of system group is fabricated to 8 μm of slice sample, with anti-mouse CD3-Alexa Fluor antibody
(Biolegend), 594 antibody of anti-CD8a-Alexa Fluor (Biolegend) and anti-CD4-Alexa Fluor
Corresponding CD3+, CD8+ and CD4+T cell of 488 antibody (Biolegend) fluorescent staining, quantifies each group mouse by immunofluorescence
All kinds of T cell relative percentages of infiltration, are as a result shown in Fig. 7 in tumor tissues.The result shows that in combination therapy group mouse tumor tissue
The percentage of CD3+, CD8+ and CD4+T cell of infiltration significantly increases, and the result and its tumor killing effect are with uniformity.
Embodiment 9: pharmaceutical composition nanometer system treats the influence to the immunologic cytotoxicity factor level in tumour
By control group, independent PFC nanoparticle group, independent anti-PD-L1 group and the pharmaceutical composition nanometer in embodiment 7
At cell homogenates, 300g is centrifuged 10min and removes lower layer's cell precipitation the mouse tumor tissue enzymatic hydrolysis of system group, takes supernatant solution point
Not carry out IFN-γ, TNF-α and IL-6 factor level MBP enzyme linked immuno-adsorbent assay (ELISA), testing result is shown in Fig. 8.As a result
Show that the level of IFN-γ, TNF-α and IL-6 in combination therapy group mouse tumor is apparently higher than anti-PD-L1 antibody and is administered alone
Group illustrates that pharmaceutical composition nanometer system can effectively activate tumor immune system, so that the toxicity killer factor of effector T cell
Level significantly rises, enhanced sensitivity antineoplastic immune effect.
Embodiment 10: the Study of cytotoxicity of pharmaceutical composition nanometer system
Good biological safety is the premise of pharmaceutical preparation application, this experiment is using Human umbilical vein endothelial cells
(HUVEC) model investigates PFC@PD-L1@Albumin cytotoxicity prepared by embodiment 1.By HUVEC with 1*104/ mL's is close
Degree is inoculated in 96 orifice plates.After culture for 24 hours, the example 1 drug composition nanometer system solution of gradient dilution is added.Dosing is trained altogether
It supports for 24 hours, the CCK-8 of 10 μ L is added in culture medium in every hole, is incubated for 3h under the conditions of 37 DEG C, measures extinction under 450nm wavelength
Angle value calculates cell survival rate, sees Fig. 9 using untreated cell as reference.The experimental results showed that pharmaceutical composition nanometer system
Do not have toxic side effect to normal cell in vitro.
Embodiment 11: safety evaluatio in pharmaceutical composition nanometer system body
Normal Balb/c mouse is taken to be randomly divided into two groups, PFC@PD- prepared by experimental mice tail vein injection embodiment 1
L1@Albumin solution (10mL/kg), another set inject same amount of normal saline as control.After administration 7 days, two groups of mouse are taken
Normal tissue production H&E pathological section and take pictures, see Figure 10.The result shows that pharmaceutical composition nanometer system normal tissue
There is no toxic side effect, there is good vivo biodistribution safety.
Claims (10)
1. a kind of pharmaceutical composition nanometer system for anti-tumor immunotherapy, it is characterised in that the pharmaceutical composition is by following
At being grouped as: one or more immunologic tests of one or more perfluorocarbon compounds of therapeutically effective amount, therapeutically effective amount
Point inhibitor and albumin shell.
2. pharmaceutical composition nanometer system according to claim 1, it is characterised in that the perfluocarbon is chain, ring
One of shape, heterocycle and halogenated or nitrogenous perfluoro-compound or their compositions, wherein it is preferred that perfluorotributylamine, perfluor three
Amylamine and perfluor butyl iodide.
3. pharmaceutical composition nanometer system according to claim 1, it is characterised in that the immunologic test point inhibitor packet
The inhibitor and combinations thereof for containing but being not limited to PD-1, PD-L1, CLTA-4, LAG3, B7-H3, B7-H4, KIR, TIM3.
4. pharmaceutical composition nanometer system according to claim 1, it is characterised in that the immunologic test point inhibitor is
Antibody includes soluble fusion protein receptor, peptide, small molecule and combinations thereof.
5. pharmaceutical composition nanometer system according to claim 1, it is characterised in that the albumin includes but is not limited to
Seralbumin, ovalbumin, lactoalbumin, myoalbumin, leucosin and legumelin and other type albumin, or
Their combination, preferably human serum albumins.
6. pharmaceutical composition nanometer system according to claim 1, it is characterised in that the perfluorocarbon compound accounts for
Total system specific gravity is 0.1mL/mL to 0.5mL/mL, wherein it is preferred that 0.2mL/mL.
7. pharmaceutical composition nanometer system according to claim 1, it is characterised in that the immunologic test point inhibitor
Accounting for total system specific gravity is 0.5mg/mL to 3mg/mL, wherein it is preferred that 1mg/mL.
8. pharmaceutical composition nanometer system according to claim 1, it is characterised in that it can open tumor vessel barrier,
Increase tumor vessel permeability, promotes one or more of leaching in CD3+, CD4+ and CD8+T lymphocyte with anti-tumor activity
Bar cell it is tumor-infiltrated.
9. pharmaceutical composition nanometer system according to claim 1, it is characterised in that the pharmaceutical composition nanometer body
System can enhance the killing activity of tumour related T-cell, increase the antitumor cytotoxicities killer factor tables such as IFN-γ, TNF-α and IL-6
Up to level.
10. pharmaceutical composition nanometer system according to claim 1, it is characterised in that can be used for treating kinds cancer packet
Include but be not limited to colon cancer, triple negative breast cancer, malignant mela noma, non-small cell lung cancer, liver cancer, clear-cell carcinoma, prostate
Cancer, oophoroma or gastric cancer.
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| CN109806404A (en) * | 2019-04-03 | 2019-05-28 | 南京从一医药科技有限公司 | It is a kind of can twin-stage pass albumin nano granular of oxygen and the preparation method and application thereof |
| CN111214459A (en) * | 2020-03-13 | 2020-06-02 | 南京大学 | Perfluorocarbon albumin nanoparticles and application thereof in preparation of tumor treatment drugs |
| CN113018434A (en) * | 2021-02-01 | 2021-06-25 | 南京大学 | Application of nanoscale coordination polymer Hemin @ Gd-NCPs |
| CN114699537A (en) * | 2022-03-07 | 2022-07-05 | 西安交通大学医学院第一附属医院 | ROS (reactive oxygen species) -responsive anticancer drug for improving curative effect of hypoxia-sensitized PD-1 antibody |
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| CN108114273A (en) * | 2018-02-02 | 2018-06-05 | 南京大学 | A kind of perfluocarbon albumin nano granular and preparation method and application |
| WO2018119313A1 (en) * | 2016-12-23 | 2018-06-28 | The Johns Hopkins University | Tumor and immune cell imaging based on pd-l1 expression |
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| WO2018045239A1 (en) * | 2016-09-01 | 2018-03-08 | Mayo Foundation For Medical Education And Research | Carrier-pd-l1 binding agent compositions for treating cancers |
| WO2018119313A1 (en) * | 2016-12-23 | 2018-06-28 | The Johns Hopkins University | Tumor and immune cell imaging based on pd-l1 expression |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109806404A (en) * | 2019-04-03 | 2019-05-28 | 南京从一医药科技有限公司 | It is a kind of can twin-stage pass albumin nano granular of oxygen and the preparation method and application thereof |
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| CN111214459A (en) * | 2020-03-13 | 2020-06-02 | 南京大学 | Perfluorocarbon albumin nanoparticles and application thereof in preparation of tumor treatment drugs |
| CN111214459B (en) * | 2020-03-13 | 2022-09-23 | 南京大学 | Perfluorocarbon albumin nanoparticles and application thereof in preparation of tumor treatment drugs |
| CN113018434A (en) * | 2021-02-01 | 2021-06-25 | 南京大学 | Application of nanoscale coordination polymer Hemin @ Gd-NCPs |
| CN114699537A (en) * | 2022-03-07 | 2022-07-05 | 西安交通大学医学院第一附属医院 | ROS (reactive oxygen species) -responsive anticancer drug for improving curative effect of hypoxia-sensitized PD-1 antibody |
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