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Human serum albumin nano-drug based on metabolic checkpoints as well as preparation method and application of human serum albumin nano-drug

A technology of human serum albumin and nano-drugs, applied in the field of biomedicine, can solve the problems of side effects of weak anti-tumor drugs, achieve the effect of improving treatment efficiency, improving stability, and overcoming toxicity challenges

Pending Publication Date: 2022-04-12
SHENZHEN INST OF ADVANCED TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the complexity of the immunosuppressive microenvironment, it is difficult to reactivate T cells only by inhibiting one immunosuppressive pathway, and IDOi has shown weak anti-tumor effects and obvious drug side effects in clinical studies

Method used

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  • Human serum albumin nano-drug based on metabolic checkpoints as well as preparation method and application of human serum albumin nano-drug
  • Human serum albumin nano-drug based on metabolic checkpoints as well as preparation method and application of human serum albumin nano-drug
  • Human serum albumin nano-drug based on metabolic checkpoints as well as preparation method and application of human serum albumin nano-drug

Examples

Experimental program
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Effect test

preparation example Construction

[0042] The preparation method of the double drug coupling prodrug molecule comprises: Fmoc group protected 1-methyl tryptophan (1-MT) and isopropyl-DON are coupled through an amide bond, and the obtained coupling The molecule is detached from the Fmoc group through a hydrolysis reaction to obtain a double-drug coupling prodrug molecule, which specifically includes the following steps:

[0043] (1) Isopropyl-DON and 9-fluorenylmethoxycarbonyl-1-methyltryptophan in benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate In the presence of (HBTU) and diisopropylethylamine, coupled to generate Fmoc-protected IDOi-DON;

[0044] (2) The Fmoc-protected IDOi-DON obtained in step (1) reacted overnight under the action of piperidine to remove the Fmoc protecting group to obtain the target product IDOi-DON;

[0045] The present invention also provides a method for preparing human serum albumin nano-medicines (IDNPs) based on the Tie checkpoint-immune activator prodrug, using the ...

Embodiment 1

[0051] Example 1 Synthesis of IDOi-DON Protected by 9-Fluorenylmethoxycarbonyl

[0052] The specific preparation method is as follows:

[0053] Weigh 880 mg of 9-fluorenylmethoxycarbonyl-1-methyl tryptophan (2.06 mmol, 1.1 equivalents) and 854 mg of HBTU (2.25 mmol, 1.2 equivalents) and dissolve in 14 mL of dry N,N-dimethyl Formamide (DMF), then sequentially added 980 μL of diisopropylethylamine (727 mg, 5.63 mmol, 3 equivalents) and isopropyl-DON (400 mg, 1.88 mmol, 1 equivalent) in dry DMF solution, in an inert gas atmosphere Stirring was continued for 4 hours.

[0054] DMF was removed by rotary evaporation, 100 mL of dichloromethane (DCM) was added, and the resulting organic solutions were washed with 100 mL of saturated sodium bicarbonate (NaHCO 3 ) solution, water, 1mol / L hydrochloric acid (HCl), water and saturated sodium chloride (NaCl) solution, and dried with anhydrous magnesium sulfate. DCM was evaporated and column chromatography (separation solvent: dichlorometh...

Embodiment 2

[0056] Example 2 Preparation of IDOi-DON by removing the carbonyl group of 9-fluorenylmethyloxy group

[0057] Weigh 9-fluorenylmethoxycarbonyl-IDOi-DON (900 mg, 2.07 mmol, 1 equiv) and dissolve in 10 mL of dry DCM, slowly add piperidine (514 μL, 5.17 mmol, 2.5 equiv) dropwise, and then continue at Stir at room temperature for 4 hours.

[0058] The organic solvent was removed by rotary evaporation and vacuum pump, and purified by column chromatography (separation solvent: chloroform / methanol = 30 / 1) to obtain the yellow product IDOi-DON. The synthetic route is shown below.

[0059]

[0060] Characterize the obtained IDOi-DON, its H NMR spectrum is as follows figure 1 As shown, the peak at ~3.7ppm belongs to the -CH on the indole ring 3 , the ~1.3ppm peak is attributed to the two -CH of isopropyl 3 . The mass spectrum of IDOi-DON as figure 2 As shown, wherein 414m / z belongs to the protonation peak of the prepared IDOi-DON.

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Abstract

The invention discloses a human serum albumin nano-drug (IDNPs) based on a metabolic checkpoint as well as a preparation method and an application of the human serum albumin nano-drug. A prodrug molecule IDOi-DON obtained by coupling an indoleamine-2, 3-dioxygenase inhibitor (IDOi) and a metabolic reprogramming agent DON through a chemical bond amidation reaction can be subjected to enzymolysis breakage in a tumor microenvironment, and is externally coated with natural biocompatible serum albumin, so that the stability of the drug can be improved, the toxic and side effects of the drug can be reduced, the drug is enriched at a tumor site, and the drug activity is improved. Through the synergistic effect of the two drugs, the effects of inhibiting IDO activity of tumor cells, inhibiting Treg cell proliferation and activating CD8 + T cells can be achieved, and the anti-tumor immunotherapy effect can be synergistically enhanced.

Description

technical field [0001] The invention relates to the field of biomedical technology, in particular to a human serum albumin nano-medicine based on a metabolic checkpoint and its preparation method and application. Background technique [0002] Tumor immunotherapy is a revolutionary breakthrough in the field of tumors in recent years by stimulating the body's anti-tumor immune response to kill or inhibit tumor growth. However, there is still an important problem that the immune tolerance formed by the tumor microenvironment cannot be overcome. The immune microenvironment caused by the vigorous metabolism of the tumor forms a metabolic inhibition of immune cells, and cannot effectively recognize and kill tumor cells. Therefore, for the metabolic targets of tumor immunosuppression, it is of great significance to develop functional metabolic check regulators that induce controllable immune responses for cancer immunotherapy. [0003] Tumor immunotherapy inhibits tumor progressio...

Claims

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Application Information

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IPC IPC(8): A61K47/42A61K45/06A61K31/405A61P35/00B82Y5/00B82Y40/00
CPCA61K31/405A61K45/06A61K47/42A61P35/00B82Y40/00B82Y5/00
Inventor 蔡林涛黄国俊潘宏郑明彬唐晓帆廖健洪王盟盟张保珍
Owner SHENZHEN INST OF ADVANCED TECH
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