Organelle targeting photosensitizer capable of activating pyroptosis of tumor cells and preparation method and application thereof

Abstract

The invention discloses an organelle targeting photosensitizer capable of activating pyroptosis of tumor cells and a preparation method and application thereof. The Mito-ZS photosensitizer is a mitochondrial targeting photosensitizer; the Lyso-ZS photosensitizer is a lysosome targeting photosensitizer; the ER-ZS photosensitizer is an endoplasmic reticulum targeting photosensitizer. The photosensitizer activates a pyroptosis pathway by performing precise targeting therapy on organelles in tumor cells so that photodynamic therapy and immunotherapy strategies are perfectly combined, and the photosensitizer has a wide application prospect in the field of cancer therapy.

Description

technical field

[0001] The invention belongs to the technical field of biomaterials and biomedicine, and specifically relates to an organelle-targeting photosensitizer capable of activating tumor cell pyroptosis and a preparation method thereof, and the application of the photosensitizer to photodynamic therapy of tumors and enhanced tumor immunotherapy. Background technique

[0002] Due to its characteristics such as easy recurrence, easy invasion and distant migration, cancer still has great challenges in clinical treatment, and it is one of the diseases that cause the largest number of human deaths [1] . In traditional treatment methods, in addition to surgical treatment, chemotherapy occupies an important position as the first-line clinical program to suppress cancer. However, most of the chemotherapeutic drugs commonly used at present achieve the purpose of treating tumors by promoting apoptosis. However, the inherent anti-apoptotic ability of cancer cells and multi-d...

Examples

Embodiment 1

[0066] Preparation of mitochondria-targeted photosensitizer Mito-ZS:

[0067] (1) Synthesis of Compound 1

[0068]

[0069] 2,3,3-Trimethyl-3H-benzo[g]indole (3.57g, 17mmol) and ethyl iodide (3.21g, 20.6mmol) were dissolved in 15mL of acetonitrile and refluxed at 90°C overnight. The reaction was detected with a TCL plate. After the reaction was complete, the precipitate was cooled to room temperature and filtered, washed with ether for 3 times, and dried to obtain compound 1 with a yield of 81.18%.

[0070] (2) Synthesis of compound Mito-ZS

[0071]

[0072] Compound 1 (300 mg, 0.82 mmol) and 3,5-diiodo-4-hydroxybenzaldehyde (368 mg, 0.98 mmol) were dissolved in 16 mL of absolute ethanol, and 3 drops of piperidine (150 μL) were added dropwise. The reaction was carried out overnight at room temperature. After the reaction, the precipitate was filtered, washed with ice-absolute ethanol for 3 times, and dried to obtain the compound Mito-ZS with a yield of 50%.

Embodiment 2

[0074] Preparation of lysosome-targeted photosensitizer Lyso-ZS:

[0075] (1) Synthesis of Compound 2

[0076]

[0077] 2,3,3-Trimethyl-3H-benzo[g]indole (1.06g, 5.08mmol) and p-bromomethylbenzoic acid (1.21g, 5.59mmol) were dissolved in 24mL of acetonitrile, at 85°C Reflux overnight. The reaction was detected with a TCL plate. After the reaction was complete, the precipitate was filtered after cooling to room temperature, washed with cold acetone for 3 times, and dried to obtain compound 2 with a yield of 40%.

[0078] (2) Synthesis of Compound S-1

[0079]

[0080] Compound 2 (200 mg, 0.47 mmol) and 3,5-diiodo-4-hydroxybenzaldehyde (211 mg, 0.56 mmol) were dissolved in 10 mL of absolute ethanol, and 3 drops of piperidine (150 μl) were added dropwise. The reaction was carried out overnight at room temperature. After the reaction, the precipitate was filtered, washed with ice-absolute ethanol three times, and dried to obtain compound S-1 with a yield of 51%.

[0081]...

Embodiment 3

[0085] Preparation of endoplasmic reticulum targeting photosensitizer ER-ZS:

[0086] (1) Synthesis of compound 3

[0087]

[0088] Dissolve ethylenediamine (1.5g, 25mmol) in 100mL of dichloromethane, then dissolve p-toluenesulfonyl chloride (0.953g, 5mmol) in 20mL of dichloromethane and drop it into the reaction system within 2 hours using a constant velocity funnel , overnight reaction at room temperature. After the reaction, dichloromethane was removed by rotary evaporation under reduced pressure, and purified by silica gel column to obtain the final product Compound 3 with a yield of 79%.

[0089] (2) Synthesis of compound ER-ZS

[0090]

[0091] Compound S-1 (100mg, 0.13mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (99mg, 0.26mmol) Dissolve in 5mL N,N-dimethylformamide, then add N,N-diisopropylethylamine (48μL, 0.26mM), stir at room temperature for 1 hour, then add compound 3 (21μL, 0.14mmol) and React at room temperature for ...

technical field

[0001] The invention belongs to the technical field of biomaterials and biomedicine, and specifically relates to an organelle-targeting photosensitizer capable of activating tumor cell pyroptosis and a preparation method thereof, and the application of the photosensitizer to photodynamic therapy of tumors and enhanced tumor immunotherapy. Background technique

[0002] Due to its characteristics such as easy recurrence, easy invasion and distant migration, cancer still has great challenges in clinical treatment, and it is one of the diseases that cause the largest number of human deaths [1] . In traditional treatment methods, in addition to surgical treatment, chemotherapy occupies an important position as the first-line clinical program to suppress cancer. However, most of the chemotherapeutic drugs commonly used at present achieve the purpose of treating tumors by promoting apoptosis. However, the inherent anti-apoptotic ability of cancer cells and multi-d...

Examples

Embodiment 1

[0066] Preparation of mitochondria-targeted photosensitizer Mito-ZS:

[0067] (1) Synthesis of Compound 1

[0068]

[0069] 2,3,3-Trimethyl-3H-benzo[g]indole (3.57g, 17mmol) and ethyl iodide (3.21g, 20.6mmol) were dissolved in 15mL of acetonitrile and refluxed at 90°C overnight. The reaction was detected with a TCL plate. After the reaction was complete, the precipitate was cooled to room temperature and filtered, washed with ether for 3 times, and dried to obtain compound 1 with a yield of 81.18%.

[0070] (2) Synthesis of compound Mito-ZS

[0071]

[0072] Compound 1 (300 mg, 0.82 mmol) and 3,5-diiodo-4-hydroxybenzaldehyde (368 mg, 0.98 mmol) were dissolved in 16 mL of absolute ethanol, and 3 drops of piperidine (150 μL) were added dropwise. The reaction was carried out overnight at room temperature. After the reaction, the precipitate was filtered, washed with ice-absolute ethanol for 3 times, and dried to obtain the compound Mito-ZS with a yield of 50%.

Embodiment 2

[0074] Preparation of lysosome-targeted photosensitizer Lyso-ZS:

[0075] (1) Synthesis of Compound 2

[0076]

[0077] 2,3,3-Trimethyl-3H-benzo[g]indole (1.06g, 5.08mmol) and p-bromomethylbenzoic acid (1.21g, 5.59mmol) were dissolved in 24mL of acetonitrile, at 85°C Reflux overnight. The reaction was detected with a TCL plate. After the reaction was complete, the precipitate was filtered after cooling to room temperature, washed with cold acetone for 3 times, and dried to obtain compound 2 with a yield of 40%.

[0078] (2) Synthesis of Compound S-1

[0079]

[0080] Compound 2 (200 mg, 0.47 mmol) and 3,5-diiodo-4-hydroxybenzaldehyde (211 mg, 0.56 mmol) were dissolved in 10 mL of absolute ethanol, and 3 drops of piperidine (150 μl) were added dropwise. The reaction was carried out overnight at room temperature. After the reaction, the precipitate was filtered, washed with ice-absolute ethanol three times, and dried to obtain compound S-1 with a yield of 51%.

[0081]...

Embodiment 3

[0085] Preparation of endoplasmic reticulum targeting photosensitizer ER-ZS:

[0086] (1) Synthesis of compound 3

[0087]

[0088] Dissolve ethylenediamine (1.5g, 25mmol) in 100mL of dichloromethane, then dissolve p-toluenesulfonyl chloride (0.953g, 5mmol) in 20mL of dichloromethane and drop it into the reaction system within 2 hours using a constant velocity funnel , overnight reaction at room temperature. After the reaction, dichloromethane was removed by rotary evaporation under reduced pressure, and purified by silica gel column to obtain the final product Compound 3 with a yield of 79%.

[0089] (2) Synthesis of compound ER-ZS

[0090]

[0091] Compound S-1 (100mg, 0.13mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (99mg, 0.26mmol) Dissolve in 5mL N,N-dimethylformamide, then add N,N-diisopropylethylamine (48μL, 0.26mM), stir at room temperature for 1 hour, then add compound 3 (21μL, 0.14mmol) and React at room temperature for ...

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