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Targeted prodrug for treating castration-resistant prostate cancer as well as nano preparation and preparation method of targeted prodrug

A technology for castration resistance and prostate cancer, which is applied in the direction of antineoplastic drugs, pharmaceutical formulas, medical preparations of non-active ingredients, etc., can solve the problems of poor water solubility of CPT, and achieve the advantages of simple preparation method and excellent specific recognition effect Effect

Inactive Publication Date: 2015-12-23
SHANGHAI PUTUO DISTRICT CENT HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In order to solve the above-mentioned problems in the prior art, the inventor intends to covalently link CPT to polymers through esterase-sensitive β-thioester bonds, which can effectively overcome the problem of poor water solubility of CPT

Method used

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  • Targeted prodrug for treating castration-resistant prostate cancer as well as nano preparation and preparation method of targeted prodrug
  • Targeted prodrug for treating castration-resistant prostate cancer as well as nano preparation and preparation method of targeted prodrug
  • Targeted prodrug for treating castration-resistant prostate cancer as well as nano preparation and preparation method of targeted prodrug

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preparation example Construction

[0045] In a second aspect, the present invention provides a method for preparing the above-mentioned targeted prodrug for treating castration-resistant prostate cancer, the synthetic route of the method is as follows: figure 1 As shown, it specifically includes the following steps:

[0046] (1) Preparation of intermediate product P(OEGMA-co-BSMA):

[0047] Add a certain amount of reversible addition-fragmentation chain transfer initiator trithioester BPTPA, oligoethylene glycol methacrylate OEGMA, monomer BSMA containing β-thiocarboxyl group, solvent and free radical initiator into the glass tube, Freeze and thaw three times in vacuum and seal the tube; then, react at 20-80°C for 0.5-40 hours to obtain the crude product P(OEGMA-co-BSMA); finally purify the crude product P(OEGMA-co-BSMA) Obtain the P(OEGMA-co-BSMA);

[0048] (2) Preparation of target product P(OEGMA-co-CPT-co-AR16):

[0049] Dissolve a certain amount of P(OEGMA-co-BSMA), N-hydroxysuccinimide, CPT, condensing...

Embodiment 1

[0071] AR16 peptide-modified poly(oligoethylene glycol methacrylate-co-camptothecin-co-AR16) macromolecular prodrug specifically targeting castration-resistant prostate cancer, namely P(OEGMA-co- CPT-co-AR16) preparation of targeted prodrug:

[0072] (1) Preparation of P(OEGMA-co-BSMA): A certain amount of BPTPA (33mg, 0.1mmol), OEGMA (2.70g, 9.0mmol), BSMA (218mg, 1.0mmol) and AIBN (1.6mg, 0.01mmol) Add to glass tube. Add 10 mL of dioxane, vacuum freeze-thaw three times, and then seal the tube. Thereafter, the reaction was carried out at 70° C. for 5 hours. The obtained reaction crude product was dialyzed in water for 24 hours to remove impurities, and freeze-dried. through 1 According to HNMR analysis, the degree of polymerization of P(OEGMA-co-BSMA) was 74, and the molar percentages of OEGMA and BSMA were 88% and 12%, respectively. Determined by GPC, P(OEGMA-co-BSMA) molecular weight M n =22,000, molecular weight distribution M w / M n = 1.02.

[0073] (2) Preparati...

Embodiment 2

[0075] Preparation of P(OEGMA-co-CPT-co-AR16) nano drug solution:

[0076] Dissolve 10 mg of P (OEGMA-co-CPT-co-AR16) in 1 mL of DMSO, drop the solution into 9 mL of stirred water, then put the solution into a dialysis bag (molecular weight cut-off of 7,000 Da) and dialyze for 24 hours to remove the organic solvent. That is, the nano drug solution is obtained. Its particle size is about 85.8nm (±1.56) (see Figure 4 ), potential -4.5mV (±0.18).

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Abstract

The invention provides a targeted prodrug for treating targeted prodrug for treating castration-resistant prostate cancer; the targeted prodrug is P (OEGMA-co-CPT-co-AR16), wherein POEGMA is a water-soluble polymer having a long circulation function, CPT is chemotherapeutic camptothecin having an antineoplastic activity and AR16 is polypeptide showing specific targeting to castration-resistant prostate cancer; the invention also provides a method for preparing the P (OEGMA-co-CPT-co-AR16), wherein the method, on the basis of a polymer P (OEGMA-co-BSMA) containing -thiocarboxyl, carries out esterification and ammonolysis reactions so as to modify CPT and AR16 on the polymer in a covalent mode, so that the targeted CPT macromolecular prodrug P (OEGMA-co-CPT-co-AR16) is obtained. In addition, the invention also provides a nano preparation and a preparation method of the targeted prodrug. The nano preparation of the targeted prodrug P (OEGMA-co-CPT-co-AR16) prepared by the method disclosed by the invention can be used for effectively killing cancer cells with a relatively low dosage, and can show an excellent specific recognition effect on castration-resistant prostate cancer.

Description

technical field [0001] The present invention relates to the technical field of tumor targeted delivery and sustained-release drug delivery system, in particular to a targeted prodrug for treating castration-resistant prostate cancer, a preparation method of the prodrug, and a nano-preparation of the prodrug and The preparation method of this nano preparation. Background technique [0002] Prostate cancer is the first and most common cancer in men worldwide, with 1.1 million newly diagnosed prostate cancer patients in 2012, accounting for about 15% of the total number of new cancer cases. In the past ten years, the incidence of prostate cancer in my country has shown a high incidence trend, and large cities have become the "hardest hit areas" for the incidence of prostate cancer. Prostate cancer is a hormone-dependent malignant tumor. Androgen plays an important role in the occurrence and development of prostate cancer. Castration (surgery or drugs) or combined androgen dep...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K31/4745A61K9/19A61P35/00
Inventor 殷佩浩刘涛袁易彭文袁夏贾婷婷邱艳艳邹瑜石晓静于卉
Owner SHANGHAI PUTUO DISTRICT CENT HOSPITAL
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