CN111358960A - Double-targeting polypeptide and application thereof in resisting tumors and inhibiting tumor angiogenesis - Google Patents
Double-targeting polypeptide and application thereof in resisting tumors and inhibiting tumor angiogenesis Download PDFInfo
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- CN111358960A CN111358960A CN201911213634.4A CN201911213634A CN111358960A CN 111358960 A CN111358960 A CN 111358960A CN 201911213634 A CN201911213634 A CN 201911213634A CN 111358960 A CN111358960 A CN 111358960A
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Abstract
The invention discloses a double-targeting polypeptide and application thereof in resisting tumors and inhibiting tumor angiogenesis, belonging to the technical field of biology, wherein the double-targeting polypeptide is formed by combining a fluorescent unit, namely, a pyrene (BP) with an aggregation luminescence effect, an amino acid sequence capable of self-assembling into β -sheet nanofiber and an amino acid sequence capable of targeting and identifying CD105 protein.
Description
Technical Field
The invention relates to a double-targeting polypeptide and application thereof in resisting tumors and inhibiting tumor metastasis. The invention belongs to the field of biotechnology.
Background
Renal cancer occupies the first ten malignant tumors in developed countries, accounting for 3.7% of all new cancer cases. Worldwide incidence rates continue to rise and prognosis is poor. Renal clear cell carcinoma is the most common type of carcinoma, accounting for approximately 80% of all cases, with high vascular density and high metastatic characteristics, with metastasis occurring in approximately 30% of patients at the time of diagnosis. Kidney cancer has become a prominent problem endangering human health.
The tumor stem cells are a cell subset with high malignancy degree in the tumor, have extremely strong metastatic capacity, can promote the tumor cells to generate distant metastasis in a paracrine mode, and are regarded as an initiating factor of the tumor metastasis at present. Meanwhile, in the aspect of tumor angiogenesis, because endothelial cells are rapidly proliferated, the development of tumor blood vessels is not mature, and the gaps among the endothelial cells are relatively large, so that the tumor cells can easily enter blood circulation through the blood vessels to further perform tumor metastasis. The high permeability of the tumor's new blood vessels opens the door for tumor metastasis. Therefore, the simultaneous inhibition of renal cancer stem cells and tumor vessels has great significance for antagonizing the proliferation and metastasis of renal cancer.
CD105 is specifically and highly expressed on the cell membranes of the renal cancer stem cells and the neovascular endothelium, and is a common biomarker for tumor neovessels and renal cancer stem cells. Therefore, the invention constructs a polypeptide which can be targeted and identified and combined with CD105 and is named as TDS (transformed double-inhibited system), wherein the TDS has double targeting effects on renal cancer stem cells and tumor vascular endothelial cells, can form water-insoluble nano fibers through allosteric and living body self-assembly to be retained outside cell membranes for a long time, and has double effects of resisting tumors and inhibiting angiogenesis.
Disclosure of Invention
The invention aims to provide a dual-targeting polypeptide and application thereof in resisting tumors and inhibiting tumor metastasis.
In order to achieve the purpose, the invention adopts the following technical means:
the invention relates to a double-targeting polypeptide (named TDS) capable of recognizing and combining CD105 protein to form water-insoluble nanofiber, which consists of the following three parts:
1) an amino acid sequence which can be self-assembled into β -sheet nano fiber, wherein the amino acid sequence is shown in SEQ ID NO.1 (FFVLK), and the FFVLK peptide base sequence derived from β amyloid protein can be self-assembled into β -sheet water-insoluble nano fiber with a secondary structure due to the interaction of hydrogen bonds;
2) an amino acid sequence for identifying the CD105 protein in a targeted way, wherein the amino acid sequence is shown as SEQ ID NO.2 (AHKHVHHVPVRL); a sequence that can target recognition of the CD105 protein, which acts as a target head in TDS, specifically binds to the target CD 105;
3) the fluorescent unit is Bispyrene (BP). Bispyrene is a typical AIE effect (aggregation induced emission) fluorescent molecule and can be used for observing TDS aggregation, self-assembly and allosteric processes.
Wherein, preferably, the polypeptide has a structure shown as the following formula:
the double-targeting polypeptide TDS can target and identify CD105 protein on a tumor stem cell membrane, self-assemble and destruct on the surface of a tumor stem cell to form stable water-insoluble nanofiber, adhere to the surface of the tumor stem cell and destroy the tumor stem cell, and further play a role in inhibiting the proliferation and metastasis of tumors. Experiments prove that the sternness of the renal cancer stem cells is inhibited by the double-target polypeptide TDS by 68 +/-9.3%. The metastasis and infiltration capacity of the renal cancer stem cells are respectively inhibited by 55.5 +/-1.8 percent and 62.7 +/-7.2 percent; on the other hand, the TDS can identify CD105 protein on a tumor neogenesis vascular endothelial cell membrane in a targeted manner, and the nano fiber which is stable and insoluble in water is formed by allosteric and living body self-assembly on the surface of the vascular endothelial cell and is adhered and encapsulated on the surface of the vascular endothelial cell, so that the density of the tumor blood vessel with strong permeability is enhanced, and the tumor cells are prevented from generating cancer metastasis by penetrating the endothelial cell. Meanwhile, in vivo and in vitro experiments also prove that the double-targeting polypeptide TDS has stronger anti-angiogenesis effect. Experimental data show that the double-targeting polypeptide TDS reduces the permeability of vascular endothelial cells by 33.0 +/-4.7 percent and inhibits angiogenesis by 38 +/-4.0 percent. Therefore, the double-targeting polypeptide TDS can play an anti-cancer role through two aspects of anti-tumor and anti-tumor angiogenesis.
Furthermore, the invention also provides application of the double-targeting polypeptide in preparing an anti-tumor medicament, wherein the tumor is a tumor with a CD105 membrane surface marker.
Wherein, preferably, the tumor comprises renal cancer, oral cancer and ovarian cancer. More preferably, the tumor is renal cancer.
Preferably, the dual-targeting polypeptide has the effects of resisting tumor cell proliferation and metastasis.
Furthermore, the invention also provides the application of the double-targeting polypeptide in preparing a medicament for inhibiting tumor angiogenesis, and when the double-targeting polypeptide is used for inhibiting tumor angiogenesis, the targeted tumor can be a tumor with a CD105 membrane surface marker or a tumor without the CD105 membrane surface marker.
Preferably, the dual-targeting polypeptide has the effects of reducing the permeability of tumor neovessels and inhibiting tumor angiogenesis.
Wherein, preferably, the tumor comprises renal cancer, oral cancer and ovarian cancer. More preferably, the tumor is renal cancer.
Compared with the prior art, the invention has the beneficial effects that:
the invention relates to a double-targeting polypeptide (named as TDS), which is formed by combining a fluorescent unit, namely, a pyrene (BP), an amino acid sequence and an amino acid sequence, wherein the fluorescent unit has an aggregation luminescence effect, the amino acid sequence can be self-assembled into β -sheet nanofiber, and the amino acid sequence can be used for identifying CD105 protein in a targeted manner.
In addition, the invention focuses on the practical problem of clinical transformation application, and human-derived peptide molecules are used as materials for design and construction, so that the TDS has strong biological safety and great clinical application potential.
Drawings
FIG. 1 shows the molecular structures of polypeptide TDS and polypeptide TDS-C of control group;
a) molecular structure pattern diagram of TDS, b) molecular structure pattern diagram of TDS-C;
FIG. 2 shows that polypeptide TDS can be destructurized and self-assembled in CD105 protein water solution to form hydrophobic nanofibers;
a) the TDS solution is subjected to transmission electron microscopy at 0h and 12h after the CD105 protein is added, and b) the TDS-C solution is subjected to transmission electron microscopy at 0h and 12h after the CD105 protein is added. A scale: 50 nm;
FIG. 3 is a confocal microscope image and ThT fluorescence detection of polypeptide TDS and TDS-C incubated with renal Cancer Stem Cells (CSCs) and vascular endothelial cell membranes;
a) confocal microscopy images and ThT fluorescence detection after co-incubation of TDS and TDS-C with HUVEC cells, b) confocal microscopy images and ThT fluorescence detection after co-incubation of TDS and TDS-C with CSCs cells. A scale: 20 um;
FIG. 4 shows the killing effect and biological safety of polypeptide TDS on renal Cancer Stem Cells (CSCs) and vascular endothelial cells;
a) killing effect of TDS and TDS-C on CSCs cells, b) killing effect of TDS and TDS-C on HUVEC cells, and C) toxicity of TDS and TDS-C on main organs of mice. A scale: 100 um.
FIG. 5 shows the ability of polypeptide TDS to inhibit the balling, migration and infiltration of renal cancer stem cells;
a) influence and quantitative analysis of TDS and TDS-C on renal cancer stem cell balling capacity, scale: 50 um. b) Influence and quantitative analysis of TDS and TDS-C on renal cancer stem cell migration ability, scale: 20 um. c) Influence and quantitative analysis of TDS and TDS-C on the invasiveness of the renal cancer stem cells. A scale: 20 um. Note: TDS compared to TDS-C, <0.05, < 0.01;
FIG. 6 shows the effect of polypeptide TDS and TDS-C on vascular endothelial cell permeability and vascular mimicry formation;
a) influence of TDS and TDS-C on vascular endothelial cell permeability, b) influence and quantitative analysis of TDS and TDS-C on vascular mimicry. A scale: 20 um. Note: TDS compared to TDS-C, <0.05, < 0.01;
FIG. 7 shows polypeptide TDS distribution and metabolism;
FIG. 8 shows the results of co-localization of polypeptide TDS and TDS-C with tumor blood vessels and inhibition of tumor angiogenesis;
a) co-localization of TDS and TDS-C with mouse tumor vessels, b) inhibition of TDS and TDS-C against mouse tumor vessels. A scale: 100 um;
FIG. 9 shows the inhibition of tumor growth by polypeptide TDS and TDS-C in vivo.
a) Effect of TDS and TDS-C on mouse tumor proliferation, b) quantitative analysis of mouse tumor weight, C) quantitative analysis of mouse tumor volume, d) effect of TDS and TDS-C on mouse tumor metastasis.
Detailed Description
The invention will be further described with reference to the following examples, which are to be understood as being illustrative only and in no way limiting.
Example 1 preparation of Dual targeting Polypeptides and molecular Structure
1. Preparation of double targeting polypeptide TDS (BP-FFVLK-AHKHVHHVPVRL)
Can recognize and combine with CD105 protein to form water-insoluble nanofiber, and the double targeting polypeptide consists of the following three parts:
1) an amino acid sequence which can be self-assembled into β -sheet nano fiber, wherein the amino acid sequence is shown in SEQ ID NO.1 (FFVLK), and the FFVLK peptide base sequence derived from β amyloid protein can be self-assembled into β -sheet water-insoluble nano fiber with a secondary structure due to the interaction of hydrogen bonds;
2) an amino acid sequence for identifying the CD105 protein in a targeted way, wherein the amino acid sequence is shown as SEQ ID NO.2 (AHKHVHHVPVRL); a sequence that can target recognition of the CD105 protein, which acts as a target head in TDS, specifically binds to the target CD 105;
3) the fluorescent unit is Bispyrene (BP). To observe the process of TDS aggregation, self-assembly, and allosterism, we selected bi-pyrene molecules as fluorescent signal molecules, bi-pyrene being a typical AIE effect (aggregation induced emission) fluorescent molecule.
2. Non-allosteric self-assembled control polypeptide TDS-C (BP-AHKHVHHVPVRL)
Both TDS and TDS-C were prepared by solid phase synthesis.
The molecular structure pattern of polypeptide TDS and TDS-C is shown in FIG. 1.
Example 2 allosteric, self-assembly of Water-insoluble nanofibers following binding of Dual-targeting Polypeptides to CD105
CD105 reagent was added to the TDS and TDS-C polypeptide solutions and the TDS and TDS-C polypeptide solution samples were observed using transmission electron microscopy at 0 hours and 12 hours, respectively. The results are shown in FIG. 2. From this result, it can be seen that polypeptide TDS was allosteric and self-assembled in CD105 protein aqueous solution to form hydrophobic nanofibers, while TDS-C was not allosteric and self-assembled in CD105 protein aqueous solution to form hydrophobic nanofibers.
Example 3 cell assay
1. Method of administration
TDS and TDS-C polypeptide are dissolved in DMSO solvent, and a polypeptide nano-material solution with the solution concentration of 4mM is prepared. The experimental cells with good state and logarithmic growth are adopted and randomly divided into TDS, TDS-C and PBS (phosphate buffer solution) groups, TDS-C and PBS solutions are slowly dripped into a culture medium at the concentration of 100uM, and the influence of the TDS, TDS-C and PBS solutions on the cell survival state is verified respectively.
2. The polypeptide generates fiber transition on the surfaces of vascular endothelial cells and renal cancer stem cells
HEK293 (human embryonic kidney cell), human tumor renal cancer stem cell, HUVEC (human umbilical vein vascular endothelial cell) 105Cells were incubated in Petri dishes for 12 hours TDS, TDS-C and PBS solutions at 37 ℃ for 12 hours and 24 hours, followed by 3 washes with PBS for laser scanning confocal microscopy measurements, samples were examined by immersion of the objective lens with 40 × under a 405nm laser, and 10 at the same time4The cells were cultured in a 96-well plate for 12 hours, and then added with TDS, TDS-C or PBS solution and cultured for 24 hours. Three washes were performed with PBS. Thioflavin t (tht) was then added for 30 min and washed three times with PBS. The fluorescence intensity was measured under a fluorescent microplate reader.
The results are shown in FIG. 3. From this result, it can be seen that the polypeptide TDS can recognize aggregates on the surfaces of renal Cancer Stem Cells (CSCs) and vascular endothelial cell membranes.
Example 4 killing effect and biosafety of Dual-Targeted Polypeptides on vascular endothelial cells and renal cancer Stem cells
1. Cell administration method
The same as in example 3.
2. Human tumor renal cancer stem cell harvesting
The human clear cell carcinoma tissue specimen is cut into 1mm3The cubic block is enzymolyzed into single cells. Then, CD105 was separated using anti-CD 105 antibody-coupled magnetic beads+A cell. Culturing CD105 in CCRCC stem cell culture medium+A cell. Finally, the cells were placed in a cell incubator at 37 ℃ and 5% CO2 at saturated humidity.
3. Killing effect and biosafety of polypeptide on vascular endothelial cells and renal cancer stem cells
HEK293 (human embryonic kidney cell) with good state and logarithmic growth, kidney cancer stem cell derived from human tumor, and HUVEC (human umbilical vein blood vessel)Endothelial cells) at 8 × 10 per well3Adding each cell and 100 mu l of the total volume into a 96-well plate, placing the plate in a 37-degree incubator, randomly dividing the cells into TDS, TDS-C and PBS groups after 24 hours, respectively adding TDS, TDS-C and PBS solutions at the concentrations of 10 mu M, 20 mu M, 50 mu M, 100 mu M and 200 mu M, placing the plate in the 37-degree incubator, removing the culture medium after 24 hours, adding the prepared CCK-8 solution, placing the plate in the 37-degree incubator for 1-4 hours, and measuring the absorbance. Three groups of mice were administered TDS and TDS-C, PBS once every 2 days, intravenously administered 7 times, and then taken out, organ specimens were taken and subjected to H&E, staining and checking.
The results are shown in FIG. 4. From the results, the TDS has a killing effect on the human tumor-derived renal cancer stem cells and HUVEC, and H & E staining examination results of organ specimens show that three groups of mice have no significant difference, which indicates that the TDS and the TDS-C have biological safety.
Example 5 inhibition of Balling, infiltration, migration of renal cancer Stem cells by Dual targeting Polypeptides
1. Cell administration method
The same as in example 3.
2. Human tumor renal cancer stem cell harvesting
The same as in example 4.
3. Inhibition effect of double-targeting polypeptide on balling, infiltration and migration of renal cancer stem cells
The human tumor renal cancer stem cells which are in good state and grow logarithmically are placed in a DMEM/F12 culture medium containing 20ng/ml EGF, 20ng/ml FGF and B27 to be cultured for 7-10 days to obtain tumor stem cell balls, the cell balls are collected by a gravity method, and enzymolysis is carried out for 10-15min to obtain single tumor stem cells. Then, the cells are paved in a low-viscosity six-well plate at a density of 5000 cells per well for stem cell culture, TDS-C and PBS solution are added every two days, and the number of cell balls larger than 50nm is counted after 7 days. In migration and invasion experiments, the upper chamber of a Transwell (8 μm pore size, polycarbonate filter, 6.5 mm diameter; corning) was coated or uncoated with matrigel (BD bioscience, Franklin lake, N.J., USA) to verify invasion and migration of cells, respectively. The cells were placed in culture medium containing TDS, TDS-C or PBS solution, respectively. 1ml of DMEM/F12 medium containing 50ng/ml Epidermal Growth Factor (EGF) was placed in the lower chamber. After incubation at 37 ℃ for 48h, the lower layer of invaded cells was counted by staining.
The results are shown in fig. 5, and it can be seen from the results that polypeptide TDS has a function of significantly inhibiting proliferation, migration, and infiltration of renal cancer stem cells.
Example 6 inhibition of vascular endothelial permeability and angiogenesis by dual targeting polypeptides.
The cell administration method was as in example 3. Human umbilical vein endothelial cells HUVEC with good state and logarithmic growth are adopted, 10 per hole4Adding the cell concentration of the cells into a Transwell upper chamber paved with 50ul of matrix glue in advance, placing the cells in an incubator at 37 ℃ for incubation, after the cells are fused into a single layer, washing the upper and lower chambers of the Transwell by PBS, sucking out the PBS, adding culture solution containing TDS-C, TDS and PBS solution into the upper chamber respectively, after incubation in the incubator for 24 hours, sucking out the liquid in the upper chamber, washing the liquid in the upper chamber by PBS, adding 200ul of FITC-Dextran (fluorescein isothiocyanate-Dextran) into the upper chamber, adding 200ul of PBS solution into the lower chamber, after incubation in the incubator for 3 hours, taking 100ul of each of the upper and lower chambers, placing the upper and lower chambers in a 96-well plate, and detecting the permeability of endothelial cells by using a fluorescence microplate reader. Meanwhile, HUVEC, which is a good logarithmically growing human umbilical vein endothelial cell, was used at 10 per well4The cell concentration of (A) was added to a 96-well plate previously plated with 50ul of matrigel, cells were randomly divided into TDS, TDS-C and PBS groups, TDS-C and PBS solutions were added at 100uM, respectively, placed in a 37 ℃ incubator, photographed after 24 hours for observation and statistically analyzed using image J.
The results are shown in FIG. 6. From the results, it can be seen that polypeptide TDS can reduce vascular endothelial cell permeability and inhibit proliferation thereof.
Example 7 Dual targeting Polypeptides distribution, metabolism in mice.
Balb/c nude mice are adopted in the experiment, and tumor tissue cells of a patient with metastatic renal cancer are inoculated on the right shoulder of the mice. When the tumor volume reaches 50mm3Mice were injected with 100. mu.l of TDS (400. mu.M/mouse), TDS-C (400. mu.M/mouse), PBS (400. mu.M/mouse), respectively, by intravenous infusion.Fluorescence imaging of mice was monitored 1,12,24,48 hours post injection using a multi-spectral fluorescence small animal in vivo imaging system.
The results are shown in FIG. 7. From the results, the TDS polypeptide is mainly distributed around the tumor tissues, which shows that the TDS polypeptide has good targeting property and can be metabolized by the body.
Example 8 co-localization of Dual-targeting Polypeptides with mouse tumor vessels and inhibition of tumor angiogenesis.
Balb/c nude mice are adopted in the experiment, and tumor tissue cells of a patient with metastatic renal cancer are inoculated on the right shoulder of the mice. When the tumor volume reaches 50mm3Mice were injected with 100. mu.l of TDS (400. mu.M/mouse), TDS-C (400. mu.M/mouse), PBS (400. mu.M/mouse), respectively, by intravenous infusion. And taking the tumor for immunofluorescence and immune group detection 12 hours after injection, and verifying the co-localization of the dual-targeting polypeptide and the tumor blood vessel of the mouse and the inhibition effect on the tumor blood vessel.
The results are shown in FIG. 8. From this result, it can be seen that the polypeptide TDS can co-localize with tumor blood vessels and inhibit tumor angiogenesis.
Example 9 Dual targeting Polypeptides inhibit tumor growth and Lung metastasis in mice
Balb/c nude mice are adopted in the experiment, and tumor tissue cells of a patient with metastatic renal cancer are inoculated on the right shoulder of the mice. When the tumor volume reaches 50mm3Mice were injected with 100. mu.l TDS (400. mu.M/mouse), TDS-C (400. mu.M/mouse), PBS (400. mu.M/mouse) by intravenous infusion once every 2 days, and administered intravenously 7 times. During the experiment, tumor volume and body weight were measured every 2 days. Taking out the specimen, and performing immunohistochemistry and lung metastasis determination.
The results are shown in FIG. 9. From this result, it can be seen that the polypeptide TDS is capable of inhibiting tumor proliferation as well as angiogenesis and metastasis in vivo.
Sequence listing
<110> Harbin university of medicine
<120> double-targeting polypeptide and application thereof in tumor resistance and tumor angiogenesis inhibition
<130>KLPI190478
<160>2
<170>PatentIn 3.5
<210>1
<211>5
<212>PRT
<213>artificial sequence
<400>1
Phe Phe Val Leu Lys 5
<210>2
<211>12
<212>PRT
<213>artificial sequence
<400>2
Ala His Lys His Val His His Val Pro Val Arg Leu 12
Claims (10)
1. A dual-targeting polypeptide, wherein the polypeptide is targeted to recognize and combine with CD105 protein to form water-insoluble nanofiber, and the dual-targeting polypeptide is composed of the following three parts:
1) an amino acid sequence which can be self-assembled into β -sheet nano fiber, wherein the amino acid sequence is shown as SEQ ID NO. 1;
2) the amino acid sequence of the targeting recognition CD105 protein is shown as SEQ ID NO. 2;
3) the fluorescent unit is Bispyrene (BP).
2. The dual targeting polypeptide of claim 1, wherein said polypeptide has the structure of formula:
3. the use of the dual targeting polypeptide of claim 1 or 2 for the preparation of an anti-tumor medicament, wherein said tumor is a tumor having a surface marker of CD105 membrane.
4. The use of claim 3, wherein the neoplasm comprises renal cancer, oral cancer, ovarian cancer.
5. The use according to claim 4, wherein the neoplasm is renal cancer.
6. The use of any one of claims 3-5, wherein said dual targeting polypeptide has anti-tumor cell proliferation and metastasis effects.
7. Use of the dual targeting polypeptide of claim 1 or 2 for the preparation of a medicament for inhibiting tumor angiogenesis.
8. The use of claim 7, wherein the dual targeting polypeptide has the effects of decreasing tumor neovascular permeability and inhibiting tumor angiogenesis.
9. The use according to claim 7 or 8, wherein the neoplasm comprises renal cancer, oral cancer, ovarian cancer.
10. The use according to claim 9, wherein the neoplasm is renal cancer.
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