Application of micromolecule drug-loaded polymer vesicle in preparation of drug for treating acute lymphocytic leukemia

A technology of polymers and small molecules, applied in drug combinations, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc., can solve the problem of low loading efficiency of hydrophilic drugs, limited overall improvement, expression differences, etc. problem, to achieve good drug loading effect, small size and fast release speed

Active Publication Date: 2021-12-24
SUZHOU UNIV
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Problems solved by technology

[0002] The prior art adopts the method of ELISA to detect the expression of sB7-H3 in the cerebrospinal fluid of 176 leukemia patients, and according to the internationally recognized FAB (French-Amer-ican-British) classification system, the acute leukemia patients are classified; The expression of sB7-H3 is significantly different between lymphoid leukemia and acute myeloid leukemia. In the subtypes of acute myeloid leukemia, the expression of sB7-H3 is not significantly different. In the subtypes of acute myeloid leukemia, the expression of sB7-H3 is in There are significant differences between M3 and M5 and between M4 and M5
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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  • Application of micromolecule drug-loaded polymer vesicle in preparation of drug for treating acute lymphocytic leukemia
  • Application of micromolecule drug-loaded polymer vesicle in preparation of drug for treating acute lymphocytic leukemia
  • Application of micromolecule drug-loaded polymer vesicle in preparation of drug for treating acute lymphocytic leukemia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Embodiment one synthetic polymer N 3 -PEG-P(TMC-DTC)

[0056] 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, 0.79g, 0.1 mmol), TMC (1.50 g, 14.8 mmol) and DTC (0.20 g, 1.0 mmol) in a closed reactor, add 5.0mL 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 the...

Embodiment 2

[0058] Example 2 Synthetic Polymer PEG-P(TMC-DTC)-KD z

[0059] 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 5 As 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 after stirring for 10 minutes, a DCM solution (1.0 mL) of p-NPC (48.4 mg, 240.3 μmol) was added dropwise thereto. 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 ...

Embodiment 3

[0060] Example 3 Preparation of reversibly cross-linked biodegradable vesicles loaded with VCR (Ps-VCR)

[0061] 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 application of a micromolecule drug-loaded polymer vesicle in preparation of a drug for treating acute lymphocytic leukemia; the micromolecule drug-loaded polymer vesicle is prepared from a micromolecule drug and an amphiphilic block polymer; or the micromolecule drug-loaded polymer vesicle is prepared from the micromolecule drug, the amphiphilic block polymer, a functionalized amphiphilic block polymer and a targeted monoclonal antibody molecule. A vesicle system in the invention has a plurality of unique advantages including small size, simplicity and controllability in preparation, excellent biocompatibility, high in-vivo circulation stability, high tumour cell specific selectivity, high intracellular drug release speed, remarkable tumour growth inhibition effect and the like.

Description

technical field [0001] The invention belongs to the technical field of polymer nano-medicines, in particular to a reversible cross-linked degradable polymer vesicle loaded with vincristine sulfate, its preparation method and its application in tumor targeted therapy, especially in the preparation of anti-acute gonorrhea Applications in leukemia nanomedicine. Background technique [0002] The prior art adopts the ELISA method to detect the expression of sB7-H3 in the cerebrospinal fluid of 176 leukemia patients, and the acute leukemia patients are classified according to the internationally recognized FAB (French-Amer-ican-British) classification system; The expression of sB7-H3 is significantly different between lymphoid leukemia and acute myeloid leukemia. In the subtype of acute myeloid leukemia, the expression of sB7-H3 is not significantly different. In the subtype of acute myeloid leukemia, the expression of sB7-H3 is in Significant differences exist between M3 and M5 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/127A61K47/34A61K47/68A61K45/00A61P35/02
CPCA61K9/1273A61K47/34A61K47/68A61K45/00A61P35/02Y02A50/30
Inventor 孙欢利张翼帆余娜钟志远
Owner SUZHOU UNIV
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