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Small molecule drug-loaded polymer vesicles and their preparation method and application

A drug-loaded polymer and polymer technology, applied in drug combination, drug delivery, pharmaceutical formulation, etc., can solve the problems of low hydrophilic drug loading efficiency, limited overall improvement, and low available dose, and achieve good drug entrapment Effect, good polymer biocompatibility, fast release effect

Active Publication Date: 2022-07-19
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Vincristine sulfate (VCR) is a water-soluble, potent drug that primarily acts on tubulin and arrests mitosis in metaphase, but the available doses are low due to its severe neurotoxicity
Although the liposomal vincristine sulfate (Marqibo®) nanomedicine approved for marketing in 2012 can prolong the circulation time of VCR and reduce toxic and side effects, the overall improvement is relatively limited
The existing liposome-like polymer vesicles have a hydrophilic inner cavity, which can be used to load hydrophilic small molecule drugs. However, the loading efficiency of hydrophilic drugs such as VCR is low, and there is still a lack of collective internal circulation stability. Multifunctional properties such as anti-tumor, tumor-specific targeting, rapid intracellular drug release, and excellent biocompatibility

Method used

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  • Small molecule drug-loaded polymer vesicles and their preparation method and application
  • Small molecule drug-loaded polymer vesicles and their preparation method and application
  • Small molecule drug-loaded polymer vesicles and their preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1 Synthesis of polymer N 3 -PEG-P(TMC-DTC)

[0054] Polymer N 3 -PEG-P(TMC-DTC) is based on DPP as catalyst, N 3 -PEG-OH is a macromolecular initiator, and it is obtained by initiating ring-opening copolymerization of TMC and DTC. First, weigh N under nitrogen in the glove box 3 -PEG-OH ( M n = 7.9 kg / mol, 0.79 g, 0.1 mmol), TMC (1.50 g, 14.8 mmol) and DTC (0.20 g, 1.0 mmol) in a closed reactor, add 5.0 mL of anhydrous DCM to dissolve, then add DPP (0.25 g , 1.2 mmol), and sealed the reactor, transferred it out of the glove box, and placed it at 30ºC for four days. After the reaction, it was precipitated twice with glacial ether and dried in vacuo to obtain a white flocculent polymer N. 3 -PEG-P(TMC-DTC), yield: 85.4%. attached figure 1 N at δ 3.38 and 3.63 ppm can be seen in 3 - Characteristic peaks for PEG, characteristic peaks for TMC at δ 2.03 and 4.18 ppm, and characteristic peaks for DTC at δ 2.99 and 4.22 ppm. N can be calculated from the ratio...

Embodiment 2

[0056] Example 2 Synthesis of polymer PEG-P(TMC-DTC)-KD z

[0057] Polymer PEG-P(TMC-DTC)-KD z The synthesis is divided into two steps, that is, using p-NPC to activate the terminal hydroxyl group of PEG-P(TMC-DTC) (5.0-(15.0-2.0) kg / mol), and then react with KD z Polypeptide molecules are reacted. PEG-P(TMC-DTC)-KD 5The synthesis of PEG-P(TMC-DTC) (1.0 g, 45.5 μmol) was dissolved in 10 mL of anhydrous DCM under nitrogen atmosphere, and then transferred to an ice-water bath and added with pyridine (18.0 mg, 45.5 μmol). 227.5 μmol), and after stirring for 10 minutes, a solution of p-NPC (48.4 mg, 240.3 μmol) in DCM (1.0 mL) was added dropwise. After the completion of the dropwise addition in 30 minutes, the reaction was continued for 24 hours at room temperature, and then the pyridinium salt was removed by suction filtration, and the polymer solution was collected by rotary evaporation and concentrated to ~100 mg / mL, precipitated with glacial ether, and dried in vacuo to ob...

Embodiment 3

[0058] Example 3 Preparation of VCR-loaded reversibly cross-linked biodegradable vesicles (Ps-VCR)

[0059] Ps-VCR was prepared by a solvent displacement method, in which VCR was synthesized with KD z The electrostatic interaction between them is encapsulated. PEG-P(TMC-DTC)-KD z Dissolve in DMSO (40 mg / mL), dispense 100 µL into standing 900 µL HEPES (pH 6.8, 10 mM) containing VCR, stir at 300 rpm for 3 minutes, and add HEPES (pH 7.4, 10 mM) ) Ps-VCR was obtained by dialysis for 8 hours. The theoretical drug loading of VCR was set at 4.8-11.1 wt.%, and it was found that the particle size of the obtained Ps-VCR was between 26-40 nm and the particle size distribution was 0.05-0.20 (Table 1). The encapsulation efficiency of Ps-VCR was calculated as high as 97.2% by measuring its absorbance at 298 nm by UV-Vis spectroscopy. Based on the same method, under the theoretical drug loading of 4.8%, PEG-P(LA-DTC)-KD 5 , PEG-P(CL-DTC)-KD 5 The encapsulation efficiencies of the prepa...

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Abstract

The invention discloses a small-molecule drug-carrying polymer vesicle, a preparation method and application thereof. The small-molecule drug-carrying polymer vesicle is prepared by assembling an amphiphilic block polymer and a small molecule drug; The polymer is assembled and cross-linked with the functionalized amphiphilic block polymer, loaded with small molecule drugs, and then reacted with the targeted monoclonal antibody. The vesicle system of the present invention has many unique advantages, including small size, simple and controllable preparation, excellent biocompatibility, high in vivo circulation stability, strong tumor cell specific selectivity, rapid intracellular drug release, and tumor growth inhibition. The effect is remarkable, etc. Therefore, this vesicle system is expected to be a simple and all-in-one nanoplatform for efficient and specific targeted delivery of vincristine sulfate to multiple myeloma cells.

Description

technical field [0001] The invention belongs to the technical field of polymer nano-drugs, and in particular relates to a reversibly cross-linked degradable polymer vesicle loaded with vincristine sulfate, a preparation method thereof, and an application in tumor targeted therapy. Background technique [0002] Vincristine sulfate (VCR) is a water-soluble, potent drug that acts primarily on tubulin to arrest mitosis in metaphase, but its severe neurotoxicity results in lower doses available. Although the liposomal vincristine sulfate (Marqibo®) nanomedicine approved for marketing in 2012 can prolong the circulation time of VCR and reduce toxic and side effects, the overall improvement is limited. Therefore, how to achieve efficient and stable encapsulation and tumor-targeted delivery of VCR is crucial. The prior art discloses a vincristine sulfate liposome and a preparation method thereof. The vincristine sulfate liposome is composed of vincristine sulfate and nanoliposomes ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/127A61K31/475A61K47/10A61K47/34A61K47/68A61K47/69A61P35/00B82Y5/00B82Y30/00B82Y40/00
CPCA61K9/1273A61K47/34A61K31/475A61K47/10A61K47/6849A61K47/6915A61P35/00B82Y5/00B82Y30/00B82Y40/00
Inventor 孙欢利余娜张翼帆钟志远
Owner SUZHOU UNIV
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