Tumor-targeted polypeptide drug conjugate and preparation method and application thereof
A drug conjugate, tumor targeting technology, applied in antitumor drugs, drug combinations, pharmaceutical formulations, etc., can solve the problems of insufficient targeting polypeptide penetration ability, poor selectivity of antitumor drugs, poor water solubility, etc. In vivo circulation time, increased drug efficacy, high yield and high product purity effects
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Embodiment 1
[0044] A tumor-targeted polypeptide drug conjugate has the following structural formula:
[0045]
[0046] The preparation method of the above-mentioned polypeptide drug conjugate is as follows:
[0047] (1) Preparation of 4-(2-pyridyldithio)benzyl alcohol:
[0048] Lithium aluminum hydride (1.5 g, 38.8 mmol) was suspended in 30 mL of tetrahydrofuran, and kept at 0°C under nitrogen protection. A tetrahydrofuran solution (20 mL) of 4-mercaptobenzoic acid (2.0 g, 12.96 mmol) was slowly added dropwise into the lithium aluminum hydride tetrahydrofuran system and kept overnight. The reaction was quenched with 1.0 mL of water, the pH was adjusted to about 2 with 2M hydrochloric acid, and extracted with ethyl acetate. The organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography gave 4-mercaptobenzyl alcohol (880 mg, 54%).
[0049] Dipyridine d...
Embodiment 2
[0060] A nanomicelle containing the polypeptide-drug conjugate of Example 1 was prepared by the following method: 20 mg of the polypeptide-drug conjugate and 10 μL of medium-chain fatty acid triglycerides were placed in water, then ultrasonicated for 1 min, filtered through the membrane, and poured into the The mannitol is added to freeze-dry to obtain the reduction-responsive polypeptide drug nano-micelle freeze-dried powder. The particle size and distribution of the nanomicelles were determined by dynamic light scattering (Dynamic Light Scattering, DLS) ( image 3 ).
Embodiment 3
[0062] A tumor-targeted polypeptide drug conjugate has the following structural formula:
[0063]
[0064] The preparation method of the above polypeptide drug conjugate precursor is as follows:
[0065] 1) Preparation of 4-nitrophenyl-SN38 active ester:
[0066] SN38 (1.0g, 2.55mmol) and 4-dimethylaminopyridine DMAP (140mg, 1.3mmol) were dissolved in 50mL of dichloromethane, and p-nitrophenyl chloroformate (510mg, 2.55mmol) was added dropwise at 0°C After DCM solution (20 mL), the reaction was incubated at 0° C. for 8 hours. The organic phase was washed with 0.1M HCl solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 0.9 g of white solid with a yield of 64%. product 1 H NMR and MS tests show that the 4-nitrophenyl SN38 active ester of structure shown in formula d is obtained.
[0067] (2) Preparation of 4-(2-pyridyldithio)benzyl-SN38 carbonate:
[0068] 4-Nitrophenyl SN38 activ...
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