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CN113173955A - Two-photon diagnosis and treatment prodrug with targeted Golgi pH response and preparation thereof - Google Patents

Two-photon diagnosis and treatment prodrug with targeted Golgi pH response and preparation thereof Download PDF

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CN113173955A
CN113173955A CN202110264905.XA CN202110264905A CN113173955A CN 113173955 A CN113173955 A CN 113173955A CN 202110264905 A CN202110264905 A CN 202110264905A CN 113173955 A CN113173955 A CN 113173955A
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颜梅
卫先哲
张晶
杨小凤
朱彤
李成芳
于京华
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Abstract

本发明公开了一种靶向高尔基体pH响应的双光子诊疗前药及其制备方法，所述的诊疗前药化合物结构如式Ⅰ所示。该前药分子在肿瘤细胞因跨膜蛋白165缺乏而导致高尔基体酸化的情况下，通过异常变化的pH敏感地触发裂解反应，不仅激活荧光基团在细胞成像中生成双光子荧光，还释放了活性阿霉素用于癌症治疗。优势在于，pH激活的前药为体内癌症诊断和靶向高尔基体抗癌化疗提供了新的平台，成功应用于体内追踪药物的释放以及异种移植肿瘤小鼠模型的治疗。The invention discloses a two-photon diagnosis and treatment prodrug targeting the pH response of the Golgi body and a preparation method thereof. The structure of the diagnosis and treatment prodrug compound is shown in formula I. The prodrug molecule sensitively triggers the cleavage reaction through abnormal pH changes when tumor cells are acidified in the Golgi apparatus due to lack of transmembrane protein 165, which not only activates the fluorophore to generate two-photon fluorescence in cell imaging, but also releases the Active doxorubicin is used in cancer treatment. The advantage is that pH-activated prodrugs provide a new platform for in vivo cancer diagnosis and Golgi-targeted anticancer chemotherapy, and are successfully applied to track drug release in vivo and treat xenograft tumor mouse models.

Description

Two-photon diagnosis and treatment prodrug with targeted Golgi pH response and preparation thereof
Technical Field
The invention relates to a fluorescent diagnosis chemotherapy prodrug compound activated by abnormal microenvironment in tumor organelles, in particular to a prodrug compound which releases anticancer drug adriamycin after being activated by pH based on targeted Golgi apparatus and simultaneously performs two-photon fluorescence imaging matched with tumor diagnosis and treatment and preparation, belonging to the field of pharmaceutical analytical chemistry.
Background
Past studies have shown that cancer cells are significantly different in energy metabolism from normal tissues, and that most cancer cells maintain a high glycolytic rate, catalyzing the reversible conversion of carbon dioxide and water to carbonic acid and diffusing out of the cell membrane, resulting in H, regardless of the oxygen supply being sufficient+Accumulate in the cancer microenvironment. At the same time, cancer cells have a lower extracellular pH than normal cells, and this difference provides a basis for selective treatment of cancer. Based on this pH difference, prodrugs sensitive to pH can be developed to target cancer cells, thereby increasing drug concentration at tissue sites and thus improving drug efficacy. The pH homeostasis of the golgi body affects many different physiological processes and studies have shown that the absence of transmembrane protein 165 (TMEM 165) in tumor cells leads to abnormal golgi glycosylation by interfering with the pH homeostasis of the golgi body. Due to the lack of effective tools for real-time monitoring of golgi pH, there is still a lack of evidence for the involvement of TMEM165 in H in the golgi+Evidence of transport.
Chemotherapy, which utilizes drugs to inhibit tumor growth, is the primary treatment for cancer. However, conventional chemotherapy often results in low therapeutic efficacy and large toxic side effects due to the disadvantages of low bioavailability and inability to specifically accumulate in tumors. Therefore, a key challenge in new cancer chemotherapies is to enhance selectivity for tumor cells and improve therapeutic efficacy. One of the strategies to solve the above problem is to use molecular prodrugs, which have the ability to modulate drug release, which can be selectively activated by the unique tumor microenvironment at low pH. Prodrugs are generally non-toxic to normal cells and have high toxicity in tumor cells through specific activation. Another benefit of this approach is that the prodrug can be used in conjunction with a fluorescent reporter gene (primarily a fluorescent dye) to achieve tumor-targeted fluorescent diagnosis and to monitor the activation of the prodrug in real time. Several fluorescent nanoparticle-based pH-responsive prodrug systems have been developed to monitor intracellular doxorubicin (Dox) release via Foster Resonance Energy Transfer (FRET). However, due to the strict requirements on the length and rigidity of the linkage and the correct matching of fluorophores, the FRET method can hardly be applied to a single molecule prodrug system to directly monitor the drug release, so we choose the ICT mechanism for the construction of the single molecule prodrug system.
The invention discloses a two-photon diagnosis and treatment prodrug with targeted Golgi pH response and a preparation method thereof. The prodrug molecule combines an L-cysteine group targeting a Golgi apparatus, anticancer drug adriamycin (DOX) and a two-photon fluorophore, and under the condition that tumor cells are acidified by the Golgi apparatus due to the lack of transmembrane protein 165, the abnormally changed pH sensitively triggers a cleavage reaction, so that not only is the fluorophore activated to generate two-photon fluorescence in cell imaging, but also the active adriamycin is released for cancer treatment. The pH activated prodrug provides a new platform for in vivo cancer diagnosis and targeted Golgi anticancer chemotherapy, and is successfully applied to in vivo tracking of drug release and treatment of xenograft tumor mouse models.
Disclosure of Invention
The technical problems to be solved by the invention are as follows: the prodrug compound has the advantages of simultaneously carrying out two-photon fluorescence imaging diagnosis and drug release treatment on cancer. Secondly, a fluorescence diagnostic reagent is provided to effectively, accurately and in-situ measure the pH value of the Golgi apparatus. Thirdly, the prodrug compound is provided, which has the advantage of high-efficiency drug release after pH activation. And fourthly, the application of tracking the drug release in vivo and treating in a mouse model of the xenograft tumor is provided.
In order to solve the technical problems, the technical scheme is as follows:
the invention provides a two-photon diagnosis and treatment prodrug with targeted Golgi pH response, which has the following molecular structural formula:
Figure 861226DEST_PATH_IMAGE001
compound NGD
The invention also provides a preparation method of the two-photon diagnosis and treatment prodrug with targeted Golgi pH response, which comprises the following steps:
(1) dissolving 4-bromo-1, 8-naphthalic anhydride (1 eq), beta-alanine-Boc (1-1.5 eq) and DMAP (1-1.5 eq) in an ethanol solution, stirring and heating a reaction mixture under reflux for 20-24 hours, cooling to room temperature, and filtering to obtain a white solid compound 1; (b) dissolving the compound 1 (1 eq) and p-phenylenediamine (9-10 eq) in ethylene glycol monomethyl ether, stirring the mixture and refluxing for 7-10 hours, cooling to room temperature, and then carrying out column purification (dichloromethane/ethanol) to obtain a yellow solid compound 2;
Figure 194119DEST_PATH_IMAGE002
(2) (c) dissolving the compound 2 (1 eq) and 4- (2-N-Boc-hydrazino) benzoic acid (1-1.5 eq) in an absolute ethanol solution, adding EDC & HCl (1 eq) and NHS (0.4-0.6 eq) to the solution, reacting the mixture at room temperature for 22-26 hours, and purifying the mixture by a column to obtain a solid compound 3; (d) compound 3 was dissolved in dichloromethane, added TFA and stirred in an ice bath for 30-40 minutes to remove the Boc group to give compound 4; (e) DOX hydrochloride (1 eq) and compound 4 (3-3.2 eq) were dissolved in methanol solution, trifluoroacetic acid (0.5-1 mL) was added, the solution was stirred at room temperature for 22-26 hours in the dark, concentrated and crystallized with acetonitrile, the red solid was isolated by centrifugation, the mixture was purified by filtration using a solvent in a volume ratio of 1: (8-12) washing the methanol-acetonitrile mixed solution, and drying in vacuum to obtain a compound 5;
Figure 195442DEST_PATH_IMAGE003
(3) (f) adding compound 5 to a volume ratio of 1: (1-1.5) TFA-DCM, stirring for 2-4 h, adding ether, filtering the precipitate, and washing with ether to obtain compound 6; (g) under the protection of nitrogen, compound 6 (1 eq) is dissolved in dimethylformamide, triethylamine (1-1.5 mL) is added dropwise, DCC and DMAP are added, the mixture is stirred for 10-20 minutes, L-cysteine (1-1.5 eq) is added, the mixture is stirred for 20-24 hours, and the compound NGD is obtained by column purification (ethyl acetate/ethanol).
Figure 17904DEST_PATH_IMAGE004
The invention has the advantages that:
the prodrug molecules of the invention have the advantages of monitoring the biodistribution and the treatment effect of chemical drugs.
The prodrug molecules of the present invention, comprising the anticancer drug Doxorubicin (DOX) and a two-photon fluorophore, can be used for in situ monitoring of golgi pH activity and antitumor therapy.
The prodrug molecule of the invention shows quite high activity and has obvious inhibition effect on tumor growth.
The prodrug molecule provided by the invention integrates the advantages of two-photon fluorescence imaging-assisted cancer diagnosis, high drug loading capacity, controllable drug release and the like.
Therefore, the invention is a drug release and diagnostic tool which is non-invasive, realizes the sustained release of DOX in tumor cells, is accompanied by continuous two-photon fluorescence emission, and can effectively inhibit the tumor growth. Has wide application prospect in the field of pharmaceutical chemistry analysis and detection.

Claims (4)

1. A preparation method of a two-photon diagnosis and treatment prodrug with targeted Golgi pH response is characterized in that the structure of the compound is shown as a formula I:
Figure DEST_PATH_IMAGE001
formula I;
the preparation method comprises the following steps:
(1) dissolving 4-bromo-1, 8-naphthalic anhydride, beta-alanine-Boc and DMAP in an ethanol solution, stirring and heating a reaction mixture under reflux for 20-24 hours, cooling to room temperature, and performing column purification to obtain a white solid compound 1; (b) dissolving the compound 1 and p-phenylenediamine in ethylene glycol monomethyl ether, stirring the mixture, refluxing for 7-10 hours, cooling to room temperature, and performing column purification to obtain a yellow solid compound 2;
Figure 273341DEST_PATH_IMAGE002
(2) (c) dissolving the compound 2 and 4- (2-N-Boc-hydrazino) benzoic acid in an absolute ethanol solution, adding EDC & HCl and NHS, reacting at room temperature for 22-26 hours, and purifying by a column to obtain a solid compound 3; (d) compound 3 was dissolved in dichloromethane, added TFA and stirred in an ice bath for 30-40 minutes to remove the Boc group to give compound 4; (e) dissolving DOX hydrochloride and the compound 4 in a methanol solution, adding trifluoroacetic acid, stirring the solution at room temperature in the dark for 22-26 hours, concentrating, crystallizing by using acetonitrile, centrifugally separating red solid, washing by using a methanol-acetonitrile mixed solution, and drying in vacuum to obtain a compound 5;
Figure DEST_PATH_IMAGE003
(3) (f) adding compound 5 to a mixed solution of TFA and DCM, stirring for 2-4 hours, adding ether, filtering the precipitate and washing with ether to give compound 6; (g) under the protection of nitrogen, dissolving the compound 6 in dimethylformamide, dropwise adding triethylamine, adding DCC and DMAP, stirring the mixture for 10-20 minutes, adding L-cysteine, stirring the mixture for 20-24 hours, and purifying by a column to obtain the compound NGD
Figure 409924DEST_PATH_IMAGE004
。
2. The method for preparing the two-photon prodrug of medical treatment targeting golgi pH response according to claim 1, wherein the two-photon prodrug of medical treatment targeting golgi pH response comprises the following steps: in the step (1) (a), the molar ratio of 4-bromo-1, 8-naphthalic anhydride, beta-alanine-Boc and DMAP is 1: (1-1.5): (1-1.5); the molar concentration range of the 4-bromine-1, 8-naphthalic anhydride dissolved in the absolute ethyl alcohol solution is 0.2-0.5 mol.L-1(ii) a (b) The molar ratio of the compound 1 to the p-phenylenediamine is 1: (9-10); the molar concentration range of the compound 1 dissolved in ethylene glycol monomethyl ether is 0.1-0.15 mol.L-1(ii) a The volume ratio of the dichloromethane to the ethanol in the column purification is (20-10): 1.
3. the method for preparing the two-photon prodrug of medical treatment targeting golgi pH response according to claim 1, wherein the two-photon prodrug of medical treatment targeting golgi pH response comprises the following steps: the molar ratio of the compound 2 to the 4- (2-N-Boc-hydrazino) benzoic acid in the step (2) (c) is 1: (1-1.5); EDC & HCl and NHS molar ratio range 1: (0.4-0.6); (d) the molar concentration range of the medium compound 3 dissolved in dichloromethane is 0.0075-0.01 mol.L-1(ii) a (e) The molar ratio of DOX hydrochloride to the compound 4 is 1: (3-3.2); the molar concentration range of the compound 4 dissolved in methanol is 0.015-0.02 mol.L-1(ii) a The volume of the trifluoroacetic acid is 0.5-1 mL; the volume ratio of the methanol to the acetonitrile is 1: (8-12).
4. The method for preparing the two-photon prodrug of medical treatment targeting golgi pH response according to claim 1, wherein the two-photon prodrug of medical treatment targeting golgi pH response comprises the following steps: in the step (3) (f), the molar concentration range of the compound 5 dissolved in the mixed solution of TFA and DCM is 0.1-0.15 mol.L-1(ii) a The ratio of TFA to DCM was 1: (1-1.5); (g) the mol ratio of the compound 6 to the L-cysteine is 1: (1-1.5); the molar concentration range of the compound 6 dissolved in the dimethylformamide is 0.05-0.08 mol.L-1(ii) a The volume of triethylamine is 1-1.5 mL; the volume ratio of ethyl acetate to ethanol in column purification is (10-5): 1.
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Cited By (1)

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CN115177739A (en) * 2022-02-22 2022-10-14 中南大学湘雅医院 Bionic preparation with tissue-cell-organelle three-level targeting function and preparation method and application thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115177739A (en) * 2022-02-22 2022-10-14 中南大学湘雅医院 Bionic preparation with tissue-cell-organelle three-level targeting function and preparation method and application thereof
CN115177739B (en) * 2022-02-22 2024-04-30 中南大学湘雅医院 Tissue-cell-organelle three-level targeting bionic preparation, and preparation method and application thereof

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