Engineered platelets of nanogel internally loaded with chemotherapeutic drugs and externally carried with immune checkpoint inhibitors as well as preparation method and application of engineered platelets

A technology of immune checkpoint and nanogel, which is applied in the direction of nanotechnology, nanotechnology, nanomedicine, etc., can solve the problems of high cost, low drug loading of preparations, and inability to target delivery, etc., to achieve high loading efficiency and prolong survival Long-term, high-safety effect

Pending Publication Date: 2021-12-07
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] Specifically, the first object of the present invention is to overcome the shortcomings of chemotherapy drugs and traditional immunosuppressants that cannot be delivered in a targeted manner, and preparations capable of targeted delivery have low drug loading and high cost, and provide a target drug with a high drug loading. A new dosage form for postoperative residual tumors and circulating tumor cells, that is, engineered platelets loaded with chemotherapy drugs and immune checkpoint inhibitor nanogels

Method used

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  • Engineered platelets of nanogel internally loaded with chemotherapeutic drugs and externally carried with immune checkpoint inhibitors as well as preparation method and application of engineered platelets
  • Engineered platelets of nanogel internally loaded with chemotherapeutic drugs and externally carried with immune checkpoint inhibitors as well as preparation method and application of engineered platelets
  • Engineered platelets of nanogel internally loaded with chemotherapeutic drugs and externally carried with immune checkpoint inhibitors as well as preparation method and application of engineered platelets

Examples

Experimental program
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Effect test

Embodiment 1

[0093] Example 1: Preparation method and characterization of aPD-L1 nanogel engineered platelets (PDNGs) loaded with doxorubicin inside and outside.

[0094] Synthesis schematic see figure 1 .

[0095] (1) aPD-L1 nanogels (NGs) as backpacks were prepared by mixing aPD-L1 antibody and NHS-SS-NHS cross-linking agent at a mass ratio of 1:15, stirring at room temperature for 1 hour, Filter the centrifuge tube (molecular weight cut-off 100kDa) and centrifuge at 4000rpm for 15 minutes, and wash with PBS three times to remove excess NHS-SS-NHS. The prepared aPD-L1 nanogel has a uniform particle size distribution of 100-130 nanometers.

[0096] (2) After the platelet-rich plasma was anticoagulated with EDTA, the red blood cells were removed by centrifugation at 200 g for 4 minutes, and the supernatant was taken and prostacyclin was added to inhibit platelet activation. Mix with an equal amount of ACD solution, centrifuge at 800g for 10 minutes, resuspend the platelets in Ren's solut...

Embodiment 2

[0101]Example 2: Effect of PDNGs on B16-F10 cells in vitro.

[0102] First, the adhesion of PDNGs to B16-F10 cells was investigated. In order to avoid the interference of the fluorescence of doxorubicin itself, PNGs were used instead of PDNGs. DiR-labeled PNGs and DiR-labeled platelets were incubated with tumor cells for 1 hour, and confocal fluorescence microscopy showed that PNGs could adhere to the surface of tumor cells ( image 3 A), In addition, there is almost no difference in fluorescence intensity from attached platelets, further indicating that the outer back aPD-L1 nanogel has no significant effect on the physiological engineering of platelets ( image 3 B).

[0103] After incubation of B16-F10 cells with free DOX, PDs and PDNGs for 0.5 h and 2 h, confocal laser scanning microscopy (CLSM) ( image 3 C) Cellular uptake of doxorubicin was examined and quantified by flow cytometry ( image 3 D, 3E). Bioengineered platelets showed higher intracellular fluorescence i...

Embodiment 3

[0106] Example 3: To investigate the ability of PDNGs to target postoperative tumor sites in vivo.

[0107] In order to investigate the ability of PDNGs to target postoperative tumor sites in vivo, the tumors of B16-F10 tumor-bearing C57BL / 6 mice were incompletely excised, and DiR-labeled PDNGs and free DiR solution were injected through the tail vein immediately after surgery at different time points. In vivo imaging, such as Figure 4 As shown in A, DiR-labeled PDNGs showed stronger fluorescent signals at the tumor site and accumulated the most at the tumor site 6 hours after injection. The postoperative tumors and major organs were removed at 6 hours and 48 hours after injection, respectively, and fluorescence imaging showed that the kidneys and spleens of mice given DiR showed high fluorescence signals ( Figure 4 B). At 6 h and 48 h time points, the fluorescence intensity of the tumors administered with PDNGs was 6.78-fold and 3.10-fold higher than that of the tumors ad...

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Abstract

The invention discloses engineered platelets of nanogel internally loaded with chemotherapeutic drugs and externally carried with immune checkpoint inhibitors as well as a preparation method and application of engineered platelets, and belongs to the technical field of drugs. The preparation method of the engineered platelets includes the following steps: crosslinking the nanogel carried with an immune checkpoint inhibitor, to extract and purified the platelets, and loading a chemotherapeutic drug and the nanogel onto the platelets, and the like. The engineered platelets deliver the chemotherapeutic drug and the immune checkpoint inhibitor to postoperative tumor remaining parts by efficiently targeting damaged vascular endothelium, circulating tumor cells are captured and cleared through a high-affinity membrane adhesion receptor, and the engineered platelets are activated in situ on the surfaces of the tumor cells, and the chemotherapeutic drug and the immune checkpoint inhibitor are released to trigger the T-cell-mediated anti-tumor immune response, so that the tumor is ablated, and the postoperative tumor recurrence and metastasis are effectively avoided.

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to an engineered platelet co-carrying chemotherapy drugs and immune checkpoint inhibitor nanogel, its preparation method and its use in treating postoperative malignant solid tumors. Background technique [0002] Melanoma is an aggressive and difficult-to-treat cancer that has seen a surge in incidence over the past few decades. Local excision is the preferred treatment for melanoma, postoperative adjuvant therapy can reduce the risk of recurrence and metastasis, and significantly improve the cure rate. However, due to factors such as limitations of surgical techniques, vascular extravasation of circulating tumor cells, and postoperative inflammation, tumors are prone to recurrence and metastasis. [0003] Recently, cancer immunotherapy has come to the fore. Tumor cells express programmed death ligand 1 (PD-L1), which can bind to programmed cell death protein 1 (PD-1...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/46A61K45/06A61K39/395A61K31/704A61K9/06A61P35/00A61P35/04B82Y5/00B82Y40/00
CPCA61K47/46A61K45/06A61K39/3955A61K31/704A61K9/0019A61K9/06A61P35/00A61P35/04B82Y5/00B82Y40/00A61K2300/00
Inventor 孙进何仲贵路奇叶皓
Owner SHENYANG PHARMA UNIVERSITY
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