CN114225047A - Immune escape nano preparation, preparation method and application - Google Patents
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Abstract
The invention relates to an immune escape nano preparation, and belongs to the technical field of biological medicines. The immune escape nano preparation comprises nano micelles and an anti-tumor drug encapsulated in the nano micelles, wherein the nano micelles are formed by connecting polypeptide MSP and micelle material Mal-PEG-PCL, the polypeptide MSP is designed on the basis of a crystal structure formed by the interaction of beta 2M and LILRB1, the amino acid sequence is Cys-GPLGVRGTLSQPKIVKWDRDM, the nano micelles can be phagocytosed by active escape macrophages after being coupled with the Mal-PEG-PCL, and the anti-tumor drug is encapsulated in the nano micelles to obtain the immune escape nano preparation which can be phagocytosed by the active escape macrophages and can be ingested by tumor-related macrophages.
Description
Technical Field
The invention relates to an immune escape nano preparation, a preparation method and application, and belongs to the technical field of biological medicines.
Background
In recent years, nanoparticle-based drug delivery platforms have become an important vehicle to overcome the pharmacokinetic limitations of traditional pharmaceutical formulations. The rationally designed nano preparation has the advantages of good circulation time, targeting property, biocompatibility and the like. For example, the nano-preparation adriamycin liposome which is marketed has good long-circulating effect in vivo, and compared with a patient treated by a conventional preparation, the cardiotoxicity is reduced after the adriamycin liposome is used. Another nano-formulation, paclitaxel micelle, has also been approved for clinical treatment of tumors.
Clinical application of a nano delivery platform (such as nano preparations of adriamycin and paclitaxel) improves the medication safety of patients and relieves symptoms. However, the targeted delivery of the nano-preparation is not ideal, and only 1% of nano-drug in the intravenous dose can be effectively delivered to the tumor site, and more than 99% of nano-drug is accumulated and eliminated in non-target tissues. This is because the nano-delivery platform faces a complex series of biological barriers that severely limit the bioavailability at a particular site and make it difficult to achieve the desired therapeutic results. For example, these barriers include protein adsorption in the blood, opsonization and subsequent clearance by the mononuclear phagocyte system, nonspecific distribution, effects of blood rheology, pressure gradients, intracellular internalization, endosomal/lysosomal escape, drug efflux, and the like. Among the most important barriers is the clearance of nanoparticles by the mononuclear phagocyte system. The mononuclear phagocyte system consists of phagocytes in the spleen, lymph nodes and liver, by which the nanoparticles are immediately captured after intravenous injection. The capture process begins with conditioning of the nanoparticles, and plasma proteins are rapidly adsorbed onto the surface of the circulating nanoparticles, forming a "protein corona" around the nanoparticles. After protein adsorption, the nanoparticles are recognized and phagocytized by specific receptors on the surface of phagocytic cells, and finally are rapidly cleared from the body. Therefore, if the recognition of the nano-preparation by the mononuclear phagocyte system can be reduced, the elimination of the nano-preparation can be effectively reduced.
Studies have shown that phagocytosis by the mononuclear phagocyte system is dependent on the recognition of phagocytic or anti-phagocytic signals by phagocytes. In organisms, there are various phenomena of immune clearance escape, such as certain microorganisms, red blood cells, tumor cells and the like, which can escape recognition of immune cells in human bodies through various anti-phagocytic signal molecules. For example, CD47 is a transmembrane glycoprotein in the immunoglobulin superfamily, which acts as a marker of anti-phagocytosis function and binds to the signal-regulating protein sirpa on phagocytes, thereby inhibiting phagocytosis by macrophages. Rodriguez et al modified the nanospheres with CD47, which allowed escape Clearance of the mononuclear phagocyte system in vivo for long-term circulation (Rodriguez PL, Harada T, Christian DA, Pantano DA, Tsai RK, Discher DE. Minimal "Self" Peptides, at least Inhibit pharmaceutical research and Enhance Delivery of nanoparticules. science.2013; 339(6122): 971-5.). However, the current design of nano-formulations based on the CD47 pathway has the following problems: (1) CD47 not only binds to SIRP alpha on phagocytes, but also acts with various intracellular and extracellular proteins such as integrin, thrombospondin 1(TSP1), and participates in the regulation of various signal pathways, and CD47 is used to realize Immune escape and influence related signal transduction, causing adverse effects (Kale A, Rogers NM, Ghimire K.Thrombospondin-1CD47 Signalling: From Mechanism to medicine. int J Mol Sci.2021; 22(8): 4062; Logetenberg MEW, Scheeren FA, Schumacher TN.the CD47-SIRPa Immune checkpoint.Immunity.2020; 52(5): 742-752); (2) it has been found in experiments that some cancer subtypes develop resistance to this treatment (Barkal AA, Weiskopf K, Kao KS, Gordon SR, Rosential B, Yiu YY, et al. engage element of MHC class I by the inhibition receptor LILRB1 supples tumors and is a target of cancer establishment. Nat Immunol.2018; 19(1):76-84.) in some solid tumors, Tumor-associated macrophages constitute the plasticity of the Tumor Microenvironment (TME) and 50% of the heterogeneous cell population (Meta I, Manic G, Coussens LM, et al. macromolecules and Tumor in Tumor environment. cell 2019; 30: 36-50) and Tumor-associated macrophages are also expressed by the Tumor receptor Ab 6754, graft Ab. on the uptake of Tumor-associated macrophages by the Tumor microenvironment (CD 34, 7-32. Ab. on the uptake of Tumor-20. Ab. by the Tumor-20. Ab. A. the Tumor-3. Ab. the Tumor-2. on the Tumor-associated macrophages Scanand J Immunol, 2014; 80(1):22-35.).
A second "don't eat me" signal was reported in 2018 (Barkal AA, Weiskopf K, Kao KS, Gordon SR, Rosent B, Yiu YY, et al. engage element of MHC class I by the inhibition receptor LILRB1 subunit antigens and is a target of cancer immunological therapy. Nat Immunol.2018; 19(1):76-84.), namely β 2 microglobulin (β 2M), β 2M being the light chain of a Major Histocompatibility Complex (MHC) -class I molecule highly expressed by tumor cells, sending an "do eat me" signal by binding to the macrophage expressed receptor LILRB1, resulting in loss of immune monitoring. However, whether the anti-phagocytosis effect similar to that of CD47 is generated by applying beta 2M to the nano-carrier is not reported, and the process is complex and the cost is high when the beta 2 microglobulin is used as the nano-carrier.
Disclosure of Invention
The invention aims to solve the defects of the prior art and provides an immune escape nano preparation which can actively escape macrophage phagocytosis and can be taken up by tumor-related macrophages.
The invention also aims to provide a preparation method of the immune escape nano preparation.
The invention designs a section of polypeptide (Cys-GPLGVRGTLSQPKIVKWDRDM) based on a crystal structure of beta 2M and LILRB1(LIR1) interaction, couples the polypeptide to a polymer micelle material PEG-PCL to form a polymer micelle capable of actively escaping phagocytosis of macrophages, and adopts a peptide segment GPLGVRG which can be enzymolyzed by the metalloproteinase 2 as a bridge connecting micelle and a peptide segment TLSQPKIVKWDRDM according to the high expression of the metalloproteinase 2 in tumor tissues to construct a nano-micelle system with immune escape function and tumor microenvironment response type at the same time.
Technical scheme
An immune escape nano preparation comprises a nano micelle and an anti-tumor drug entrapped in the nano micelle, wherein the nano micelle is formed by connecting polypeptide MSP and micelle material Mal-PEG-PCL, and the amino acid sequence of the polypeptide MSP is Cys-GPLGVRGTLSQPKIVKWDRDM.
Further, the anti-tumor drug is paclitaxel, adriamycin or photodynamic therapy drug.
Further, the micelle material Mal-PEG-PCL is Mal-PEG2000-PCL 2000.
The preparation method of the immune escape nano preparation comprises the following steps:
(1) dissolving a micelle material Mal-PEG-PCL in a solvent, then dripping the solution into PBS buffer solution with pH7.4, stirring uniformly, and dialyzing to obtain a micelle solution;
(2) performing solid-phase synthesis on polypeptide MSP according to the sequence of the polypeptide MSP, then adding the polypeptide MSP into the micelle solution obtained in the step (1), stirring and reacting at room temperature, transferring reaction liquid to a dialysis bag after the reaction is finished, and dialyzing overnight by using deionized water to obtain nano micelles;
(3) freeze-drying the nano micelle, dissolving the nano micelle and the anti-tumor drug in a solvent to obtain a mixed solution, adding the mixed solution into deionized water, uniformly stirring, performing ultrasonic treatment by using a probe in an ice bath, and finally dialyzing to obtain the immune escape nano preparation.
Further, in the steps (1) and (3), the solvent is dimethyl sulfoxide (DMSO).
Further, in the step (2), the molar ratio of the polypeptide MSP to the micelle material Mal-PEG-PCL is (1-2):1, and more preferably 1.2: 1.
The application of the immune escape nano preparation in preparing a medicament for treating tumors.
The invention has the beneficial effects that:
the invention provides an immune escape nano preparation, which comprises nano micelles and an anti-tumor drug encapsulated in the nano micelles, and the nano preparation can be phagocytosed by actively escaping macrophages and can be taken up by tumor-related macrophages, so that the targeting effect is improved.
Drawings
FIG. 1 is the NMR spectrum of Mal-PEG-PCL;
FIG. 2 shows the NMR spectrum of polypeptide MSP;
FIG. 3 is the NMR spectrum of nanomicelle MSP-PEG-PCL prepared in example 1;
FIG. 4 is a transmission electron microscope image of the immune escape nano-formulation prepared in example 2;
FIG. 5 is a result of phagocytosis effect test of macrophage on the immune escape nano-preparation prepared from mixed micelle composed of mPEG-PCL and nano-micelle MSP-PEG-PCL;
FIG. 6 shows the result of macrophage phagocytosis effect test on the immune escape nano-preparation prepared from mixed micelle composed of mPEG-PCL and disrupted MSP;
fig. 7 is a result of a phagocytosis effect test of tumor-associated macrophages on an immune escape nano-preparation prepared from mixed micelles composed of mPEG-PCL and disrupted MSP.
Detailed Description
The technical solution of the present invention is further explained with reference to the accompanying drawings and specific embodiments.
EXAMPLE 1 preparation of nanomicelle MSP-PEG-PCL
The preparation method of the nano micelle MSP-PEG-PCL comprises the following steps:
(1) weighing Mal-PEG2000-PCL 200020 mg, dissolving in 2ml DMSO, dripping into PBS buffer solution with pH7.4, stirring uniformly, and dialyzing overnight to obtain micelle solution;
(2) the amino acid sequence of polypeptide MSP is: Cys-GPLGVRGTLSQPKIVKWDRDM, performing solid phase synthesis on polypeptide MSP according to the sequence, adding 11mg of polypeptide MSP into the micelle solution obtained in the step (1), stirring at room temperature for 24 hours for reaction, transferring the reaction solution into a dialysis bag (MWCO3500Da), and dialyzing with deionized water for 24 hours to remove unreacted polypeptide, thereby obtaining nano micelle MSP-PEG-PCL.
Fig. 1 is a nuclear magnetic resonance hydrogen spectrum of Mal-PEG-PCL, fig. 2 is a nuclear magnetic resonance hydrogen spectrum of polypeptide MSP, fig. 3 is a nuclear magnetic resonance hydrogen spectrum of nanomicelle MSP-PEG-PCL prepared in example 1, and in fig. 1 and 3, a-f are characteristic peaks of Mal-PEG-PCL, wherein the characteristic peaks of PCL are δ a ═ 1.38ppm, δ b ═ 1.65ppm, δ c ═ 2.33ppm, δ e ═ 4.08 ppm; the characteristic peak of PEG is delta d which is 3.66 ppm; the characteristic peak for the maleimide (Mal) group is δ f ═ 6.69 ppm; it can be seen that MSP-PEG-PCL shows the same characteristic peaks of PEG and PCL as PCL-PEG-Mal, and the characteristic peaks of MSP (delta 1.14, delta 3.18, delta 4.30, delta 4.65, delta 7.10, delta 7.22 and delta 7.4) also appear, and it can be seen in the figure that the characteristic peak (delta 6.69) of Mal-PEG-PCL polymer Mal disappears in the MSP-PEG-PCL polymer, indicating that MSP is successfully grafted to Mal-PEG-PCL.
Example 2
The photosensitizer Ce6 is used as an antitumor drug and is encapsulated in the nano micelle MSP-PEG-PCL prepared in the example 1, and the method is as follows: freeze-drying the nano-micelle MSP-PEG-PCL prepared in example 1, dissolving 10mg and 0.5mg of photosensitizer Ce6 in 0.5mL of solvent DMSO to obtain a mixed solution, adding the mixed solution into 3mL of deionized water, stirring for 1h, performing ultrasonic treatment on an ice bath probe for 5min, and finally transferring the mixed solution into a dialysis bag (MWCO3500Da) to dialyze the mixed solution with deionized water to obtain the immune escape nano-preparation.
The transmission electron microscope image of the immune escape nano preparation prepared in example 2 is shown in fig. 4, and as can be seen from fig. 4, the appearance of the immune escape nano preparation loaded with Ce6 is in a sphere-like structure, and the surface is smooth and complete.
Example 3
The photosensitizer Ce6 is used as an antitumor drug and is encapsulated in the nano micelle MSP-PEG-PCL prepared in the example 1, and the method is as follows: after the nano micelle MSP-PEG-PCL prepared in the embodiment 1 is freeze-dried, 10mg and 0.8mg of photosensitizer Ce6 are dissolved in 0.5mL of solvent DMSO to obtain a mixed solution, the mixed solution is added into 3mL of deionized water, the mixed solution is stirred for 1h, ultrasonic treatment is carried out on the mixed solution for 5min by a probe under ice bath, and the mixed solution is transferred into a dialysis bag (MWCO3500Da) and dialyzed by the deionized water to obtain the immune escape nano preparation.
Example 4
The photosensitizer Ce6 is adopted to replace an anti-tumor drug to be encapsulated in the nano micelle MSP-PEG-PCL prepared in the example 1, and the method is as follows: after the nano micelle MSP-PEG-PCL prepared in the embodiment 1 is freeze-dried, 10mg and 1.0mg of photosensitizer Ce6 are dissolved in 0.5mL of solvent DMSO to obtain a mixed solution, the mixed solution is added into 3mL of deionized water, the mixed solution is stirred for 1h, ultrasonic treatment is carried out on the mixed solution for 5min by a probe under ice bath, and the mixed solution is transferred into a dialysis bag (MWCO3500Da) and dialyzed by the deionized water to obtain the immune escape nano preparation.
The immune escape nano-formulations prepared in examples 2 to 4 were tested for drug Loading (LD), Encapsulation Efficiency (EE) and PDI (polydispersity index), and the results are shown in table 1:
table 1 LD, EE and PDI test results for immune escape nano-formulations of examples 2-4
As can be seen from Table 1, when Ce6 is 0.8mg (example 3), the drug loading and encapsulation efficiency of the nano-micelle are maximum, the drug loading is 6.10 + -0.49%, and the encapsulation efficiency is 83.49 + -2.78%. The particle size and the distribution of the Ce 6-loaded micelle are measured by a dynamic light scattering method (DLS), the average particle size is 172.6nm +/-2.3 nm, the PDI is 0.208 +/-0.02, and the zeta potential is-13.5 mv +/-0.46 mv. The prepared immune escape nano preparation can realize the targeting effect depending on the EPR effect and has better stability in vivo.
Example 5 phagocytic Effect of macrophages on Nanopropreparations
To investigate the effect of MSP polypeptides on macrophage phagocytosis, mixed micelles carrying Ce6 were prepared with mPEG-PCL and MSP-PEG-PCL at different molar ratios, separately incubated with macrophages (induced by human leukemia monocytes, reference: Genin M, clinical F, Fattacioli A, et al, M1 and M2macrophages derived from THP-1cells under the responsive model of cancer cell to eoside. BMC cancer.2015; 15: 577; human leukemia monocytes from Wuhan Prod. Life technologies Co., Ltd.) and tested for macrophage phagocytosis effect on the nanoformulation by:
experimental groups (mPEG: MSP-PEG-PCL ═ 1:1, mPEG: MSP-PEG-PCL ═ 4:1, mPEG: MSP-PEG-PCL ═ 8: 1): taking 10mg of a carrier material mPEG-PCL and the nano-micelle MSP-PEG-PCL prepared in the embodiment 1 after freeze drying (the molar ratio of the mPEG-PCL to the nano-micelle MSP-PEG-PCL is 1:1, 4:1 and 8:1 respectively), dissolving the carrier material mPEG-PCL and the nano-micelle MSP-PEG-PCL in 0.5mL of solvent DMSO to obtain a mixed solution, adding the mixed solution into 3mL of deionized water, stirring for 1h, performing ultrasonic treatment on a probe under ice bath for 5min, transferring the mixed solution into a dialysis bag (MWCO3500Da) and dialyzing with the deionized water to obtain the nano-micelle MSP-PEG-PCL.
Control group (mPEG-PCL micelle): dissolving 10mg of carrier material mPEG-PCL and 0.8mg of photosensitizer Ce6 in 0.5mL of solvent DMSO to obtain a mixed solution, adding the mixed solution into 3mL of deionized water, stirring for 1h, carrying out ultrasonic treatment on an ice bath probe for 5min, transferring the mixed solution into a dialysis bag (MWCO3500Da) and dialyzing the dialyzed solution with the deionized water to obtain the finished product.
The phagocytosis of the micelles of the experimental group and the control group is quantitatively analyzed by flow cytometry: the differentiated macrophages were first seeded in 12-well plates at a density of 1.5X 105cells/well, 37 ℃ 5% CO2Culturing overnight under the condition, then removing the culture medium, adding the micellar solutions of the experimental group and the control group diluted by the culture medium, wherein the concentration of Ce6 is 5 mug/mL; at 37 deg.C, 5% CO2Continuously incubating for 1h under the condition, then removing redundant micelle solution, washing for three times by using precooled PBS to remove non-ingested micelles, transferring the digested micelles to a centrifuge tube at 1200r/min after trypsinization, centrifuging for 5min, removing supernatant, and washing for three times by using precooled PBS; finally, resuspend the cells with 0.5mL PBS and place them in a flow loading tube, and detect the fluorescence intensity of the cells by a flow cytometer.
Fig. 5 is a result of testing phagocytic effect of macrophages on the immune escape nano preparation prepared from the mixed micelle composed of mPEG-PCL and nanomicelle MSP-PEG-PCL, wherein n is 3 and P is less than 0.001, and it can be seen that the phagocytic amount of macrophages on the immune escape nano preparation prepared from the mixed micelle composed of mPEG-PCL and nanomicelle MSP-PEG-PCL is significantly reduced, and the mixed micelle molar ratio is 1:1 and 4:1, which has similar phagocytic amount of cells and the lowest phagocytic amount.
Example 6 Effect of matrix Metalloproteinase-2 on micelle-escaping macrophage phagocytosis
In order to study whether phagocytosis of the micelle by macrophages is increased after MSP is detached from the surface of the micelle, matrix metalloproteinase-2 (MMP-2) is used for carrying out enzyme digestion on the micelle so as to detach MSP polypeptide, and after the MSP polypeptide is prepared into a nano preparation, the nano preparation is incubated with the macrophages. The method comprises the following steps:
MMP-2 was first mixed with 2.5mmol/L Paraminomercuric acetate (APMA) in TCNB buffer (50mmol/L Tris,10mmol/L CaCl)2,150mmol/L NaCl20.05% Brij35, pH 7.5) at 37 ℃ for 1h to activate MMP-2, and then 0.4ml of the mixed micelle solution loaded with Ce6 (molar ratio 4:1, prepared as in example 3) was incubated with 0.2ml of MMP-2 (10. mu.g/ml) solution at 37 ℃ for 3h for an enzymatic cleavage reaction, and after the reaction was completed, a macrophage phagocytosis assay was performed using micelles that had detached MSP polypeptide, as in example 5, with incubation of micelles with macrophages for 1 h. The phagocytosis of micelles was quantified by flow cytometry and the results are shown in FIG. 6.
Fig. 6 is a result of testing phagocytosis effect of macrophage on the immune escape nano preparation prepared by mixed micelle composed of mPEG-PCL and fractured MSP, it can be seen that after the MSP is fractured by adding MMP-2, the micelle is taken up by the macrophage and increased, which indicates that the MSP inhibits the phagocytosis of the macrophage, MMP-2 sensitive peptide is used as the micelle and polypeptide connecting bridge, so that the MSP modification does not affect the taking of tumor parts.
Example 7 uptake by tumor-associated macrophages
Macrophage cells are taken and added with IL-4 with the concentration of 20ng/ml for incubation for 24h, and the macrophage cells are induced to be tumor-associated macrophages. The macrophages were replaced with tumor-associated macrophages, and the remainder were tested in example 6 for uptake of the nanoformulation by tumor-associated macrophages with and without the addition of MMP-2 enzyme. The results are shown in FIG. 7.
Fig. 7 is a result of a phagocytic effect test of tumor-associated macrophages on an immune escape nano-preparation prepared from mixed micelles composed of mPEG-PCL and disrupted MSP, and it can be seen that, after MMP-2 enzyme treatment is added, uptake of the tumor-associated macrophages into the nano-preparation is significantly increased, thereby illustrating that matrix metalloproteinase-2 (MMP-2) sensitive peptide is used as a connecting bridge in the present application, so that the nano-preparation can be efficiently taken up by the tumor-associated macrophages.
Claims (7)
1. The immune escape nano preparation is characterized by comprising nano micelles and anti-tumor drugs entrapped in the nano micelles, wherein the nano micelles are formed by connecting polypeptide MSP and micelle material Mal-PEG-PCL, and the amino acid sequence of the polypeptide MSP is Cys-GPLGVRGTLSQPKIVKWDRDM.
2. The immune escape nano-formulation of claim 1, wherein the anti-tumor drug is paclitaxel, doxorubicin or a photodynamic therapy drug.
3. The immune escape nano preparation as claimed in claim 1 or 2, wherein the micellar material Mal-PEG-PCL is Mal-PEG2000-PCL 2000.
4. The method for preparing the immune escape nano preparation as claimed in claim 1, 2 or 3, which is characterized by comprising the following steps:
(1) dissolving a micelle material Mal-PEG-PCL in a solvent, then dripping the solution into PBS buffer solution with pH7.4, uniformly stirring, and dialyzing overnight to obtain a micelle solution;
(2) performing solid-phase synthesis on polypeptide MSP according to the sequence of the polypeptide MSP, then adding the polypeptide MSP into the micelle solution obtained in the step (1), stirring and reacting at room temperature, transferring reaction liquid to a dialysis bag after the reaction is finished, and dialyzing overnight by using deionized water to obtain nano micelles;
(3) freeze-drying the nano micelle, dissolving the nano micelle and the anti-tumor drug in a solvent to obtain a mixed solution, adding the mixed solution into deionized water, uniformly stirring, performing ultrasonic treatment by using a probe in an ice bath, and finally dialyzing to obtain the immune escape nano preparation.
5. The method for preparing the immune escape nano preparation according to claim 4, wherein the solvent is dimethyl sulfoxide in the steps (1) and (3).
6. The method for preparing the immune escape nano preparation of claim 4, wherein in the step (2), the molar ratio of the polypeptide MSP to the micellar material Mal-PEG-PCL is (1-2): 1.
7. Use of the nano-formulation for immune escape according to claim 1, 2 or 3 for the preparation of a medicament for the treatment of tumors.
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