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Combined use of tetravalent cisplatin predrug and biological reducing drug

A cisplatin and prodrug technology, applied in the field of combined use of tetravalent cisplatin prodrugs and bioreductive drugs, can solve problems such as poor effect, and achieve the effects of single and stable size, low systemic toxicity and simple reaction conditions

Active Publication Date: 2018-12-11
SHANGHAI JIAO TONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the use of bioreductive drugs alone against tumors is often ineffective against cells with sufficient oxygen

Method used

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  • Combined use of tetravalent cisplatin predrug and biological reducing drug
  • Combined use of tetravalent cisplatin predrug and biological reducing drug
  • Combined use of tetravalent cisplatin predrug and biological reducing drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Synthesis of hyperbranched platinum prodrugs. Take 168 mg of cis-dichlorodiamine dimethyl bisacetamido methyl methacrylate platinum (IV) and 283.2 mg of 2-methacryloxyethyl phosphoric acid choline into a 50 mL eggplant-shaped reaction flask, then Add 9.1 mg of RAFT chain transfer agent 2-(dodecyl trithiocarbonate)-2-isobutyric acid and 1 mg of initiator azobisisobutyronitrile in turn, and then add 10 mL of anhydrous dimethyl methylene The mixed solvent of sulfone / anhydrous methanol is protected by nitrogen, and the stirring is turned on, followed by three freeze-pump-thaw processes, the reaction time is 20 hours, and the reaction temperature is 60-70°C. After the completion of the reaction, the reaction product was cooled to room temperature, and the reaction product was dropped into 200 mL of cold ether. The precipitate appeared and was allowed to stand for 2 hours. The precipitate was collected by centrifugation and dried to obtain a light yellow solid.

Embodiment 2

[0056] Synthesis of hydrogel type tetravalent platinum prodrugs. Take 26.88mg of cis-dichlorodiamine dimethylbisacetamido methyl methacrylate platinum (IV) and 283.2mg of 2-methacryloxyethyl phosphorylcholine into a 50mL eggplant-shaped reaction flask, Then 9.1 mg of RAFT chain transfer agent 2-(dodecyl trithiocarbonate)-2-isobutyric acid and 1 mg of initiator azobisisobutyronitrile were added in sequence, followed by 10 mL of anhydrous dimethyl The mixed solvent of sulfoxide / anhydrous methanol is protected by nitrogen, and the stirring is turned on, followed by three freeze-pump-thaw processes, the reaction time is 20 hours in the dark, and the reaction temperature is 60-70°C. After the completion of the reaction, the reaction product was cooled to room temperature, and the reaction product was dropped into 200 mL of cold ether. The precipitate appeared and was allowed to stand for 2 hours. The precipitate was collected by centrifugation and dried to obtain a light yellow soli...

Embodiment 3

[0061] This embodiment relates to a preparation method of a platinum prodrug loaded with a hypoxic drug tirapazamine, which includes the following specific steps:

[0062] Dissolve 1~10mg of Tirapazamine in 1~10mL of platinum prodrug with a concentration of 1~10mg / mL, stir for 1-24 hours in the dark, and then dialyzate. The content of Tirapazamine is loaded by UV / visible spectroscopy. It is obtained by measuring the absorption at 500nm by the luminance meter.

[0063] Figure 4 This is the in vitro release curve of the cisplatin long-circulating nanogel prepared in Example 3. In vitro release measurement method: accurately pipet 2 mL of freshly prepared purified cisplatin liposomes into a dialysis bag (30KD). Put into 20mL release medium, sample 1mL at 0, 1, 2, 4, 8, 10, 18, 30, 42, 50h, and supplement 1mL of fresh medium at the same time. ICP-AES test is used to test Pt content, using ultraviolet / Visible spectrophotometer test wavelength at 500nm is used to test TPZ content, ca...

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Abstract

The invention discloses combined use of a tetravalent cisplatin predrug and a biological reducing drug. The structural f formula of the tetravalent cisplatin predrug is represented by a formula (I) (shown in description), wherein m represents 0-1000, n represents 1-1000, and I represents 1-1000. The tetravalent cisplatin predrug is loaded with a biological reducing drug, namely tirapazamine, a cisplatin anti-cancer drug is released through degradation in a tumor microelement,and the high expression of enzyme families of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) in cancer cells can be induced, so that the oxygen consumption rate of the cancer cells is increased, the pesticide effect of the biological reducing drug, namely tirapazamine is further improved, and the treatment effect of the whole cancer treatment process can be improved through synergistic treatment.

Description

Technical field [0001] The present invention relates to the field of tumor treatment, in particular to the application field of platinum-based polymer synergistic therapy, and specifically relates to the combined use of a tetravalent cisplatin-based prodrug and a bioreductive drug. Background technique [0002] Clinically, platinum drugs, including cisplatin, carboplatin, oxaliplatin, etc., are a class of metal complexes with anti-cancer activity. They were first discovered by B. Rosenborg and others in 1965 that they can inhibit the growth of tumor cells. , It is widely used in cancer chemotherapy and occupies an important position in chemotherapy drugs. Platinum drugs have the characteristics of broad anti-cancer spectrum, strong action, and synergistic effects with a variety of anti-tumor drugs. They are used as first-line drugs in the treatment of lung cancer, esophageal cancer, ovarian cancer, testicular cancer, bladder cancer, head and neck cancer, and gastric cancer. In p...

Claims

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Application Information

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IPC IPC(8): C08F230/02C08F230/04A61K33/24A61K47/58A61P35/00A61K31/53
CPCA61K31/53A61K33/24A61K47/58A61P35/00C08F230/02C08F2438/03C08F230/04A61K2300/00
Inventor 朱新远郭东波吾麦尔·亚森徐舒婷张川金鑫童刚生
Owner SHANGHAI JIAO TONG UNIV
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