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Use of tetravalent cisplatin prodrugs in combination with bioreductive drugs

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, high yield, and improved curative effect

Active Publication Date: 2020-02-18
SHANGHAI JIAOTONG 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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  • Use of tetravalent cisplatin prodrugs in combination with bioreductive drugs
  • Use of tetravalent cisplatin prodrugs in combination with bioreductive drugs
  • Use of tetravalent cisplatin prodrugs in combination with bioreductive drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Synthesis of hyperbranched platinum prodrugs. Get 168mg of cis-dichlorodiamine dimethyl diacetamido methyl methacrylate platinum (IV) and 283.2mg and add 2-methacryloyloxyethyl phosphorylcholine to a 50mL eggplant type reaction flask, then 9.1 mg of RAFT chain transfer agent 2-(dodecyltrithiocarbonate)-2-isobutyric acid and 1 mg of initiator azobisisobutyronitrile were sequentially added, followed by 10 mL of anhydrous dimethylmethylene The mixed solvent of sulfone / anhydrous methanol was protected by nitrogen gas, and the stirring was started, followed by three freezing-pumping-thawing processes, the reaction time was 20 hours in the dark, and the reaction temperature was 60-70°C. After the reaction was completed, cool down to room temperature, absorb the reaction product and drop it into 200mL of cold ether, a precipitate appeared and allowed to stand for 2 hours, then the precipitate was collected by centrifugation, and a light yellow solid was obtained after drying. ...

Embodiment 2

[0054] Synthesis of hydrogel-type tetravalent platinum prodrugs. Take 26.88 mg of cis-dichlorodiamine dimethyl diacetamidomethyl methacrylate platinum (IV) and 283.2 mg of 2-methacryloyloxyethyl phosphorylcholine into a 50 mL eggplant-shaped reaction bottle, Then 9.1 mg of RAFT chain transfer agent 2-(dodecyltrithiocarbonate)-2-isobutyric acid and 1 mg of initiator azobisisobutyronitrile were sequentially added, followed by 10 mL of anhydrous dimethyl The mixed solvent of sulfoxide / anhydrous methanol was protected by nitrogen, and the stirring was started, followed by three freezing-pumping-thawing processes, the reaction time was 20 hours in the dark, and the reaction temperature was 60-70°C. After the reaction was completed, cool down to room temperature, absorb the reaction product and drop it into 200mL of cold ether, a precipitate appeared and allowed to stand for 2 hours, then the precipitate was collected by centrifugation, and a light yellow solid was obtained after dr...

Embodiment 3

[0059] This embodiment relates to a preparation method of platinum-based prodrug-loaded hypoxic drug tirapazamine, which includes the following specific steps:

[0060] Dissolve 1-10 mg of tirapazamine in 1-10 mL of platinum prodrug with a concentration of 1-10 mg / mL, stir in the dark for 1-24 hours, dialyze, and the loaded tirapazamine content is determined by using UV / Vis spectroscopy It is obtained by measuring the absorption at 500nm with a luminance meter.

[0061] Figure 4 is the in vitro release curve of the cisplatin long-circulation nanogel prepared in Example 3. In vitro release assay method: Precisely pipette 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, and 50 hours respectively, and supplement 1mL of fresh medium at the same time, the test of ICP-AES is used to test the Pt content, using ultraviolet / Visible spectrophotometer test wavelength at 500nm...

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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 invention relates to the field of tumor treatment, in particular to the application field of platinum-based polymer synergistic therapy, in particular to the use of a tetravalent cisplatin-based prodrug combined with a bioreductive drug. Background technique [0002] In clinical practice, platinum drugs, including cisplatin, carboplatin, oxaliplatin, etc., are a class of metal complexes with anticancer activity, which were first discovered by B. Rosenborg et al. in 1965 to inhibit the growth of tumor cells. , 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 effect, and synergistic effect with various anti-tumor drugs. In particular, the early cure rate of testicular cancer is 100%, and the early cure rate of ovarian cancer is over 80%. However, cisplatin and other anticancer drugs are traditional small molecule drugs, and ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08F230/02C08F230/04A61K33/243A61K47/58A61P35/00A61K31/53
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 JIAOTONG UNIV
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