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In-vivo phase transition tumor targeted nanobubble, its preparation method and application

A tumor-targeting and nanobubble technology, applied in the field of biomedicine, can solve the problems of loss of biological activity of targeting factors, poor reproducibility of preparation process, and poor uniformity of particle size, achieving highly uniform particle size, easy large-scale preparation, The effect of mild preparation conditions

Active Publication Date: 2012-12-26
HUAZHONG UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, these methods have many problems in practical application, such as: it is difficult to obtain nanoscale microbubbles, the obtained microbubbles have large particle size and poor particle size uniformity, poor reproducibility of the preparation process, severe mechanical action and / or Or high temperature may cause targeting factors such as peptides, proteins, antibodies to lose biological activity, etc.

Method used

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  • In-vivo phase transition tumor targeted nanobubble, its preparation method and application
  • In-vivo phase transition tumor targeted nanobubble, its preparation method and application
  • In-vivo phase transition tumor targeted nanobubble, its preparation method and application

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Embodiment 1

[0065] (1) Preparation of copolymer

[0066] Referring to literature methods (S.Penczek, et al. Poly J. Chem., 2001, 75: 117-181; K. W. Leong, et al. J. Control. Rel., 2003, 92: 39-48.), synthesize poly Phosphate-polyester amphiphilic block copolymer.

[0067] Use 2-chloro-oxygen-1,3,2-dioxopentacycline phosphate and ethanol to synthesize ethyl phosphate ethyl ester, dissolve 0.29mol 2-chloro-oxygen-1,3,2-dioxopentacycline phosphate in In 250mL of dry treated benzene, cool down to -5°C, slowly drop the mixture of 0.29mol ethanol and 0.29mol triethylamine into the benzene solution under stirring, keep the temperature at -5°C during the dropwise addition. After the dropwise addition was completed, the reaction was carried out at room temperature for 1.5h. By-products were removed by filtration, and ethyl ethyl phosphate was obtained by distillation. The copolymerization reaction of ethyl ethyl phosphate and D,L-lactide was carried out with triisobutylaluminum as the initiator...

Embodiment 2

[0074] (1) Preparation of copolymer

[0075] Adopt 2-chloro-oxygen-1,3,2-dioxopentacycline phosphate and isopropanol to synthesize ethyl phosphate isopropyl ester with the method of embodiment 1, take ethyl phosphate isopropyl ester and L-lactide as The polymerized monomer is subjected to a copolymerization reaction to obtain a polyethyl phosphate isopropyl ester-poly L-lactide copolymer. The number average molecular weight of the synthesized product measured by GPC was 26000, and the block ratio of phosphate ester and polyester segment was 1:2.

[0076] (2) Preparation of lactoferrin-coupled copolymers

[0077] References (M. Elfinger, et al. Biomaterials, 2007, 28(23): 3448-3455; K. Hu, et al. J. Control. Rel., 2009, 134(1): 55-61.) Methods Lactoferrin was chemically coupled to polyphosphate-polylactide copolymer. First, polyethylphosphoric acid isopropyl ester-poly L-lactide copolymer is subjected to aminolysis reaction to obtain polyethylphosphoramide-poly L-lactide cop...

Embodiment 3

[0081] (1) Preparation of copolymer

[0082] Adopt 2-chloro-oxygen-1,3,2-dioxopentacycline phosphate and ethanol to synthesize ethyl phosphate ethyl ester with the method of embodiment 1, use ethyl phosphate ethyl ester and glycolide-lactide oligomer Carry out copolymerization reaction for polymerizing monomers, and synthesize polyethyl phosphate-polyglycolide-lactide copolymer. The number average molecular weight of the synthesized product measured by GPC was 17500, and the block ratio of phosphate ester and polyester segment was 1:4.

[0083] (2) Preparation of RGD peptide-coupled copolymers

[0084] The same method as in Example 2 was used to prepare the RGD peptide-coupled polyethylene ethyl phosphate-polyglycolide-lactide copolymer.

[0085] (3) Preparation of nanobubbles

[0086] RGD peptide-coupled polyethylene ethyl phosphate-polyglycolide-lactide copolymer nanobubbles were prepared by pre-double emulsion-hollow membrane tube emulsification method. The hollow membr...

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Abstract

Belonging to the technical field of biomedicine, the invention specifically relates to an in-vivo phase transition tumor targeted nanobubble, its preparation method and application. The nanobubble takes a polyphosphate-polyester copolymer of a coupling tumor targeting factor as a coating material, adopts perfluoropentane able to undergo liquid-gas phase transition in vivo as a bubble core filling material, and is prepared by a pre-multiple emulsion-hollow membrane tube emulsification method. When the nanobubble enters the body, the liquid perfluoropentane undergoes liquid-gas phase transition at body temperature to form a gas-containing nanobubble. By means of the specific combination of a targeting factor and a tumor cell, the nanobubble can concentrate a tumor focus part, thus improving the tumor focus ultrasonic imaging effect. The nanobubble can be loaded with an MRI contrast agent to improve the tumor focus MRI imaging effect. The nanobubble can also be loaded with an antitumor drug and used for targeted treatment of tumors, thus being a novel diagnosis-treatment integrated multifunctional imageological nano-contrast agent.

Description

field of invention [0001] The content of the present invention belongs to the technical field of biomedicine. It relates to an in vivo phase transition tumor-targeting nanobubble and its membrane preparation method and application. The nanobubble is prepared by the method of pre-emulsion-hollow membrane tube emulsification, and can be used for ultrasound imaging of tumor lesions, MRI imaging diagnosis and targeted therapy of tumors , is a new type of multifunctional imaging nano-contrast agent integrating diagnosis and treatment. Background technique [0002] Microbubbles are a class of ultrasound imaging contrast agents that can significantly enhance medical ultrasound detection signals. The high acoustic impedance difference between the gas in the microbubbles and the surrounding living tissue makes the microbubbles produce strong reflections, resulting in enhanced backscattering in the blood (in color and spectral Doppler mode can be as high as 27dB), so as to achieve th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K49/18A61K49/22A61K9/10A61K45/00A61K47/34A61P35/00
Inventor 刘卫徐海波陈云超杨祥良程欣李欢罗斌华万江陵周小顺
Owner HUAZHONG UNIV OF SCI & TECH
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