PLK1 inhibitor-loaded polymer vesicle drug and preparation method and application thereof

A technology of polymers and inhibitors, applied in the field of medicine, can solve the problem of limited tumor accumulation

Pending Publication Date: 2021-06-25
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, like other small molecule drugs, Vol is usually cleared rapidly by the body and has limited

Method used

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  • PLK1 inhibitor-loaded polymer vesicle drug and preparation method and application thereof
  • PLK1 inhibitor-loaded polymer vesicle drug and preparation method and application thereof
  • PLK1 inhibitor-loaded polymer vesicle drug and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] PEG-P(TMC-DTC)-PAsp (Mn = 5.0-(15.0-2.0)-1.29 kg / mol) was synthesized according to existing reports, such as CN2019104726138 (reduction-sensitive reversible cross-linked polymer capsule with asymmetric membrane structure Bubbles and their application in the preparation of drugs for the treatment of liver cancer) Example 1 PEG-P (TMC-DTC)-KD10; N-hydroxysuccinimide functionalized block polymer NHS-PEG-P (TMC-DTC ) (Mn=7.5-(15.0-2.0) kg / mol, Mw / Mn=1.1) was synthesized according to existing reports, such as the preparation example of CN2020105763476 (carbonate polymer vesicles loaded with small molecule drugs and its preparation method and application) NHS-PEG-P (TMC-DTC).

[0031] A3-PEG-P (TMC-DTC) was obtained by the amidation reaction of A3 polypeptide (cDGWGPNc) and the above-mentioned NHS-PEG-P (TMC-DTC). Briefly, NHS-PEG-(TMC-DTC) (200 mg, 6.2 μmol) was dissolved in 2 mL DMF, and it was added dropwise to A3 polypeptide (13.6 mg, 12.4 μmol) and triethylamine under n...

Embodiment 2

[0034] The preparation of embodiment two Ps-Vol and A3-Ps-Vol

[0035] The DMSO solution of PEG-P(TMC-DTC)-PAsp and A3-PEG-P(TMC-DTC) with a concentration of 10 mg / mL was mixed with a mass ratio of 80:20, and 100 mL of DMSO solution with Vol ( 20 mg / mL, 5 mL), then add 0.9 mL of HEPES (5 mM, pH 6.8) buffer solution, stir at 200 rpm for 5 minutes, turn to a shaker (100 rpm, 35°C) and incubate for 6 h, then in Dialyzed in HEPES (5 mM, pH 7.4) (dialysis bag molecular weight cut-off is 7000 Da) to obtain Vol-loaded vesicles 20A3-Ps-Vol with a surface density of 20% of A3. Unless otherwise noted, the A3-Ps-Vol mentioned in subsequent experiments are Vol-loaded vesicles with a surface density of 20%. The particle size, Zeta potential, Vol drug loading (DLC) and encapsulation efficiency (DLE) of the vesicles were determined by DLS, electrophoresis and ultraviolet absorption, respectively.

[0036] By further adjusting the mass ratio of PEG-P(TMC-DTC)-PAsp and A3-PEG-P(TMC-DTC), suc...

Embodiment 3

[0046] Example 3 Anti-tumor activity and endocytosis research at the cell level

[0047] The targeting of A3-Ps-Vol to SKOV3 cells was studied by flow cytometry and confocal laser microscopy (CLSM), using FITC-labeled Vol (Vol-FITC) as a fluorescent probe. Briefly, SKOV3 cells were plated into 6-well plates, 300,000 per well, and after overnight attachment, A3-Ps-Vol, Ps-Vol and free Vol-FITC loaded with Vol-FITC at different A3 densities were added and incubated for 4 hours (Vol-FITC at a concentration of 200 nM). Afterwards, they were washed with PBS, trypsinized, centrifuged (1000 rpm, 3 min), and redispersed in PBS for flow cytometry measurements. To demonstrate the specificity of A3-Ps-Vol targeting, DU145 cells were used as a negative control.

[0048] In CLSM experiments, SKOV3 cells were plated into 12-well plates (including small discs), 50,000 per well, and after overnight attachment, Ps-Vol-FITC or A3-Ps-Vol-FITC (Vol concentration was 200 nM ) for 4 h. Then sta...

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Abstract

The invention discloses a PLK1 inhibitor-loaded polymer vesicle drug and a preparation method and application thereof. The polymer vesicle A3-Ps based on PEG-P (TMC-DTC) has a compact disulfide bond cross-linked membrane, excellent stability and rapid intracellular drug release are brought, short-chain polyaspartic acid in an inner shell of the vesicle membrane can enhance the capacity of the vesicle for loading a molecular targeting drug Volasertib (Vol), and the A3-Ps is high in drug loading capacity and drug loading rate and small in particle size. The Vol-loaded vesicles A3-Ps-Vol have the advantages that the anti-tumor activity of the Vol is improved, the systematic toxicity of the Vol-loaded vesicles A3-Ps-Vol is reduced, the A3-Ps-Vol, the non-targeted Ps-Vol and the free drug Vol have the best activity of inhibiting SKOV-3 cells compared with the A3-Ps-Vol, the non-targeted Ps-Vol and the free drug Vol, the IC50 is 49 nM and is 3.5 times lower than that of the free drug Vol, and the double-targeted nano preparation is a high-efficiency and low-toxicity therapy for treating ovarian cancer.

Description

technical field [0001] The invention belongs to medical technology, and in particular relates to a polymer vesicle drug loaded with PLK1 inhibitor, a preparation method and application thereof. Background technique [0002] As a fatal malignant tumor among female diseases, the five-year survival rate of ovarian cancer is only 30%-40%. The high mortality rate is due to relapse and drug resistance after frequent chemotherapy (such as platinum and taxane) in patients with advanced ovarian cancer. Therefore, there is an urgent need for the development of drugs for the treatment of ovarian cancer clinically. In the treatment of various malignant tumors, targeted molecular drugs with clear specificity and low toxicity have gradually become better alternatives to traditional chemotherapy drugs. The polyadenosine diphosphate-ribose polymerase (PARP) inhibitor olaparib has shown good therapeutic effects in BRCA-mutated ovarian cancer cases, which account for about 10%-15% of all ov...

Claims

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Application Information

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IPC IPC(8): A61K9/127A61K31/525A61K47/34A61K47/42A61P35/00
CPCA61K9/1273A61K31/525A61K47/34A61K47/42A61P35/00
Inventor 钟志远王哲夏一枫赵松松孟凤华
Owner SUZHOU UNIV
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