A kind of enzyme-sensitive nano system targeting T cells and its preparation method and application
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An enzyme-sensitive and systematic technology, applied in the field of medicine, to achieve high drug loading and good drug loading capacity
Active Publication Date: 2021-12-10
SHANGHAI WEI ER BIOPHARM TECH CO LTD +3
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At present, there is no degradable polypeptide nanosystem that targets T cells, and there is no drug delivery system that simultaneously intervenes with CD28 and PD-1 as dual targets. Nanosystems acting on pathways to relieve immunosuppression and restore tumor-killing effects of immune cells
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Embodiment 1
[0057] Example 1: Synthesis of Stearoyl Modified Polypeptides
[0058] The stearyl-modified polypeptide: stearyl-HHHRRRRPPLGLAGK-Mal, was synthesized by Zhejiang Hongtuo Co., Ltd. using the peptide solid-phase synthesis method and named sHRP. The synthesized sHRP was purified by preparative high-performance liquid chromatography, and its purity reached more than 95%. Wherein HRP is a polypeptide, and the amino acids are connected by peptide bonds to form 15 peptides ( figure 1 , figure 2 ).
Embodiment 2
[0059] Example 2: Method for co-loading chemical drugs and antibodies in sHRP micelles
[0060] Dissolve sHPR in water and CH223191 in dichloromethane. The volume ratio of water and dichloromethane is 1:5. After mixing and stirring for 2 hours, open the cover and keep stirring to volatilize the dichloromethane completely. Prepare CH-sHRP micelles. The obtained micellar solution was mixed with the thiolated CD28 antibody solution, the mass ratio of micelles to antibody was 1:10, and the reaction was sealed in the dark for 24 hours to obtain co-sHRP. Average particle size results and potential see image 3 , 4 . The particle size results are consistent with the TEM images.
Embodiment 3
[0061] Example 3: Investigation of the in vitro release characteristics of CH223191
[0062] Dialysis bag method was used to further evaluate the release degree of CH-sHRP with and without MMP. A dialysis bag with a relative molecular mass of 1000 was selected, and the dialysis medium was PBS solution with pH=7.4. Put MMP-treated CH-sHRP and untreated CH-SHRP into dialysis bags, put them in 50mL of dialysate, 100r / min, at 2, 4, 6, 8, 10, 12, 24, 36, 48h At the time point, 1 mL of external fluid was taken, and 1 mL of dialysate was added, the concentration was measured by HPLC, and the in vitro release curve was drawn. Such as Figure 6 It is shown that in the presence of MMP, the release of CH223191 is faster, which is because the fragmentation of the MMP-sensitive peptide in the structure of the carrier leads to a decrease in the particle size of the nanostructure, thereby accelerating the release.
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Abstract
The invention relates to the technical field of medicine, in particular to an enzyme-sensitive nano system targeting T cells and its preparation method and application. The enzyme-sensitive nanosystem targeting T cells provided by the present invention is based on a polypeptide carrier and can be loaded with hydrophobic therapeutic drugs. The end of the polypeptide is modified with a functional group and can be connected with a functional antibody targeting T cells. The polypeptide carrier includes a hydrophobic segment and a hydrophilic segment, which can self-assemble into micelles and have good drug-loading capacity; the end of the polypeptide introduces a maleimide group, which can be connected to functional antibodies such as antibodies targeting T cell surface proteins. substance. The present invention provides a new nano system for drug delivery, which can target T cells to deliver hydrophobic therapeutic drugs and antibody drugs, restore the function of immune cells, thereby promoting the apoptosis of prostate cancer cells, and is a new method of immunotherapy for prostate cancer. An efficient and low toxicity nanoscale delivery system.
Description
technical field [0001] The invention relates to the technical field of medicine, in particular to an enzyme-sensitive nano system targeting T cells and its preparation method and application. Background technique [0002] Tumor is one of the most common causes of morbidity and death in humans at present. The current treatment methods for tumor mainly include chemotherapy, radiotherapy and so on. In recent years, with the in-depth study of tumor immunology, immunotherapy has gradually become an important method of tumor treatment. In the tumor microenvironment, most T cells are in a state of exhaustion due to long-term stimulation of immune cells by tumor antigens and cannot exert anti-tumor effects. T cells and tumor cells express a variety of inhibitory immune checkpoint molecules, such as PD-1, CTLA-4, etc., which mediate immune suppression and immune escape. The current immunotherapy is mainly immune checkpoint therapy, which uses related antibodies to block the immunos...
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