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Micromolecule drug-loaded polymer vesicle as well as preparation method and application thereof

A drug-loaded polymer and polymer technology, applied in drug combination, drug delivery, pharmaceutical formulation, etc., can solve the problems of low loading efficiency of hydrophilic drugs, limited overall improvement, and low available dose, so as to avoid loss and toxicity Side effects, efficient and stable entrapment, and good biocompatibility

Active Publication Date: 2020-11-24
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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  • Micromolecule drug-loaded polymer vesicle as well as preparation method and application thereof
  • Micromolecule drug-loaded polymer vesicle as well as preparation method and application thereof
  • Micromolecule drug-loaded polymer vesicle as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Embodiment one synthetic polymer N 3 -PEG-P(TMC-DTC)

[0054] Polymer N 3 -PEG-P(TMC-DTC) uses DPP as catalyst, N 3 -PEG-OH is a macromolecular initiator, which is obtained by initiating ring-opening copolymerization of TMC and DTC. First, weigh N in the glove box nitrogen environment 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 the sealed reactor was transferred out of the glove box and placed at 30ºC for four days. After the reaction, precipitated twice with glacial ether, and dried in vacuum to obtain 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 - The characteristic peaks of PEG, the characteristic peaks of TMC at δ 2.03 and 4.18 ppm, and the characteristic peaks of DTC at δ 2.99 and 4.22 ppm. N can be calculated by the ratio of t...

Embodiment 2

[0056] Example 2 Synthetic Polymer PEG-P(TMC-DTC)-KD z

[0057] Polymer PEG-P(TMC-DTC)-KD z The synthesis of PEG-P(TMC-DTC) (5.0-(15.0-2.0) kg / mol) is divided into two steps. z Polypeptide molecules are reacted. PEG-P(TMC-DTC)-KD 5As an example, the specific operation is as follows: PEG-P(TMC-DTC) (1.0 g, 45.5 μmol) was dissolved in 10 mL of anhydrous DCM under a nitrogen atmosphere, then transferred to an ice-water bath and pyridine (18.0 mg , 227.5 μmol), and p-NPC (48.4 mg, 240.3 μmol) in DCM (1.0 mL) was added dropwise after stirring for 10 minutes. After the dropwise addition was completed in 30 minutes, the reaction was continued at room temperature for 24 hours, and then the pyridinium salt was removed by suction filtration, and the collected polymer solution was concentrated by rotary evaporation to ~100 mg / mL, precipitated with glacial ether, and dried in vacuo to obtain the product PEG-P ( TMC-DTC)-NPC, yield: 90.0%. Subsequently, under the protection of nitrog...

Embodiment 3

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

[0059] Ps-VCR was prepared by a solvent replacement method, in which VCR was prepared with KD z The electrostatic interaction between them is wrapped. PEG-P(TMC-DTC)-KD z Dissolve in DMSO (40 mg / mL), inject 100 µL into 900 µL HEPES (pH 6.8, 10 mM) containing VCR, and stir at 300 rpm for 3 minutes, then use HEPES (pH 7.4, 10 mM ) dialyzed for 8 hours to obtain Ps-VCR. The theoretical drug loading of VCR was set at 4.8-11.1 wt.%, and the study 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 as high as 97.2% calculated by measuring its absorbance at 298 nm wavelength by ultraviolet-visible spectroscopy. Based on the same method, at a theoretical drug loading of 4.8%, PEG-P(LA-DTC)-KD 5 、PEG-P(CL-DTC)-KD 5 The encapsulation efficiencies of the ...

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Abstract

The invention discloses a micromolecule drug-loaded polymer vesicle as well as a preparation method and application thereof. The micromolecule drug-loaded polymer vesicle is prepared by assembling anamphiphilic block polymer and a micromolecule drug, or assembling and crosslinking the amphiphilic block polymer and a functionalized amphiphilic block polymer, loading the micromolecule drug, and reacting with the targeting monoclonal antibody. The vesicle system provided by the invention has many unique advantages, including small size, simple and controllable preparation, excellent biocompatibility, high in-vivo cycling stability, strong tumor cell specific selectivity, high intracellular drug release speed, remarkable tumor growth inhibition effect and the like. Therefore, the vesicle system is expected to become a simple nano platform integrating multiple functions, and is used for efficiently and specifically delivering vincristine sulfate to multiple myeloma cells in a targeted manner.

Description

technical field [0001] The invention belongs to the technical field of polymer nano-medicines, and in particular relates to a reversibly cross-linked degradable polymer vesicle loaded with vincristine sulfate, a preparation method thereof, and an application in targeted tumor therapy. Background technique [0002] Vincristine sulfate (VCR) is a water-soluble potent drug that mainly acts on tubulin to arrest mitosis in metaphase, but due to its severe neurotoxicity, the available dose is low. 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. Therefore, how to achieve efficient and stable packaging of VCR and tumor-targeted delivery is very important. The prior art discloses a vincristine sulfate liposome and a preparation method thereof, the vincristine sulfate liposome is composed of vincristine sulfate and...

Claims

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Application Information

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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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