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CN-121974951-A - Aggregation-induced emission photosensitizer probe with phosphatase specific response and application thereof

CN121974951ACN 121974951 ACN121974951 ACN 121974951ACN-121974951-A

Abstract

The invention relates to an aggregation-induced emission photosensitizer probe with phosphatase specific response and application thereof, belonging to the technical field of biochemistry. The phosphatase-specific responsive aggregation-induced emission photosensitizer probe of the present invention consists of a pyridyl photosensitizer core and a phosphate response-quenching unit. The probe can be specifically activated by phosphatase with high expression in a tumor area, and can realize in-situ aggregation through a dephosphorylation-self-leaving mechanism, so that fluorescence imaging and activation of photodynamic therapy functions are synchronously completed. The probe shows excellent selectivity in vitro and at the cell level, and can effectively distinguish and kill cancer cells. In a living experiment, the tumor can be targeted and enriched and the in-situ treatment guided by imaging can be realized by systemic administration after the tumor is compounded with albumin, so that in-situ tumor, distal tumor and metastasis can be effectively inhibited. The research constructs a new strategy of 'diagnosis-treatment' integration, and provides a new direction for developing an in-situ activated tumor diagnosis and treatment method.

Inventors

  • HE XUEWEN
  • GENG JIANGTAO

Assignees

  • 苏州大学

Dates

Publication Date
20260505
Application Date
20260213

Claims (8)

  1. 1. The aggregation-induced emission photosensitizer probes with phosphatase specific responses are characterized in that the structural formula of the aggregation-induced emission photosensitizer probes with phosphatase specific responses is selected from one or more of the following structural formulas: ; Wherein R 1 、R 2 、R 3 and R 4 are independently selected from H, alkyl, methoxy, Or (b) ; R' is selected from 、 、 Or (b) ; X - is selected from Cl - 、Br - 、I - or PF 6 - .
  2. 2. The phosphatase-specific response aggregation-induced emission photosensitizer probe according to claim 1, wherein the phosphatase-specific response aggregation-induced emission photosensitizer probe is selected from the group consisting of: 。
  3. 3. a pharmaceutically acceptable salt of the phosphatase-specific response aggregation-induced emission photosensitizer probe according to any one of claims 1-2.
  4. 4. A pharmaceutical composition comprising the active ingredient of the phosphatase-specific response aggregation-induced emission photosensitizer probe according to any one of claims 1-2, and a pharmaceutically acceptable salt of the phosphatase-specific response aggregation-induced emission photosensitizer probe according to claim 3.
  5. 5. Use of the phosphatase-specific responsive aggregation-induced emission photosensitizer probe according to any one of claims 1-2, the pharmaceutically acceptable salt of the phosphatase-specific responsive aggregation-induced emission photosensitizer probe according to claim 3, the pharmaceutical composition according to claim 4 for the preparation of a medicament for diagnosing or treating tumor cells.
  6. 6. The use according to claim 5, wherein the tumour cells are selected from one or more of the group consisting of human cervical cancer cell line HeLa, human liver cancer cell line Hep G2, mouse liver cancer cell line Hepa1-6, human breast cancer cell line MCF-7, human triple negative breast cancer MDA-MB-231, mouse breast cancer cell line 4T1, mouse colorectal cancer cell line CT26, human colorectal cancer HCT-116, human non-small cell lung cancer a549, mouse lung cancer cell LLC, human brain astrocytoma cell U87MG, mouse glioblastoma cell GL261, human prostate cancer cell PC-3, human pancreatic cancer cell line PANC-1, mouse pancreatic cancer cell line KPC1245, human esophageal squamous carcinoma cell KYSE-150, human esophageal squamous carcinoma cell TE-11, mouse melanoma cell line B16.
  7. 7. The method according to claim 5, wherein the photosensitizer probe is dissolved in alkaline water, and is complexed with albumin under neutral conditions, and is cleaved by a phosphatase specifically expressed by tumor cells.
  8. 8. The use according to claim 5, wherein the phosphatase is selected from one or more of a lipid phosphatase, a serine/threonine phosphatase, a tyrosine phosphatase, a dual specificity phosphatase, an alkaline phosphatase and an acid phosphatase.

Description

Aggregation-induced emission photosensitizer probe with phosphatase specific response and application thereof Technical Field The invention belongs to the technical field of biochemistry, and particularly relates to an aggregation-induced emission photosensitizer probe with phosphatase specific response and application thereof. Background As a global disease seriously threatening human health, cancer incidence and death rate are high, human life safety is seriously threatened, and comprehensive measures are needed to alleviate the current situation. The traditional cancer treatment methods such as chemotherapy, radiotherapy and the like inevitably damage normal tissues while killing cancer cells, cause a series of side effects and complications, have poor treatment effect on advanced diffusion or metastasis cancers, have higher recurrence risk and are difficult to realize radical treatment. Photodynamic therapy is an emerging accurate tumor treatment technology, has the remarkable advantages of a multi-mode anti-tumor mechanism, minimally invasive and repeatable treatment, the treatment effect depends on the synergistic effect of three key elements of a photosensitizer, a specific wavelength light source and a tissue oxygen environment, the design of the photosensitizer is particularly critical, the activatable photosensitizer can realize the selective activation of a lesion part through a marker (such as alkaline phosphatase, cathepsin and the like) which is specifically identified to be over-expressed in a tumor microenvironment, the treatment targeting is remarkably improved, and meanwhile, the generation level of Reactive Oxygen Species (ROS) can be dynamically controlled by combining the time-space accurate regulation and control of illumination based on the activation characteristic of the dependence of target concentration, so that the tumor treatment effect is optimized. The killing of imaging guidance is an advanced strategy combining medical imaging and accurate treatment, and focus positions, boundaries and treatment responses can be monitored in real time through high-resolution imaging technologies such as magnetic resonance imaging, computed tomography or fluorescence imaging, so that the treatment accuracy is improved, side effects are reduced, and the curative effect is further optimized. Wherein fluorescence imaging guided killing has demonstrated unique value in tumor surgery, drug delivery and minimally invasive therapies by virtue of its high sensitivity, real-time visualization and molecular targeting. Although the traditional fluorescence imaging molecules (such as fluorescein isothiocyanate, rhodamine and Cy series cyanine dyes) are widely applied, the molecules are always in an on state, are easy to accumulate in non-target tissues such as livers, blood vessels and the like, so that high background noise is caused, the phenomenon of fluorescence quenching under high concentration exists, the dynamic change of target enzyme activity or tumor microenvironment can not be accurately reflected, and the aggregation-induced emission type molecules of activatable fluorescence imaging are distinguished in the field by virtue of the intelligent activating characteristic and the ultra-high signal-to-noise ratio. Malignant tumor cells often express a plurality of biomolecules related to tumor progress abnormally and highly, wherein phosphatase (ALP) is in an over-expression state in a plurality of malignant tumors such as osteosarcoma, liver cancer, prostate cancer and the like, the expression level of the phosphatase can be 5-10 times that of normal tissues, the enzyme can generate adenosine through hydrolyzing ATP, the functions of immune cells such as T cells and NK cells are inhibited, the immune escape of tumors is promoted, and meanwhile, the metastasis tendency of tumor bones is further aggravated in the phosphate metabolic process mediated by the enzyme. Therefore, the ALP key biomarker is used as a target point, and an activatable luminous probe or photosensitizer probe is designed to realize dynamic monitoring and in-situ killing of tumor in-situ enzyme activity and microenvironment change, so that the method has become an important development direction of tumor diagnosis and treatment integration under imaging guidance. Although many activatable probes are reported at present, the probes have the defects of low activation specificity and sensitivity, single function, diagnosis and treatment dislocation, poor optical performance and biocompatibility and the like, for example, a pH activated photosensitizer has nonuniform activation effect due to the obvious heterogeneity of the pH value of a tumor microenvironment, and an 'opening' threshold value is not accurate enough, so that false activation can occur in a weak acidic environment of normal tissues. Therefore, the preparation of the aggregation-induced emission photosensitizer probe which can perform in-situ response on a malignant