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Sonodynamic therapy

A chemotherapeutic agent and sound sensitizer technology, applied in the field of improvement of sonodynamic therapy, can solve problems such as side effects

Inactive Publication Date: 2020-07-03
UNIVERSITY OF ULSTER
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this combination, known as FOLFIRINOX, causes significant side effects and should only be used in otherwise fit and able-bodied patients

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0206] Example 1 - Synthesis of Biotin-Gemcitabine (Biotin-Gem) and Biotin-Gemcitabine-Rose Bengal (Biotin-Gem-RB) Conjugates

[0207] 1.1 Synthesis of biotinylated gemcitabine (biotin-GEM):

[0208] Biotinylated gemcitabine was synthesized according to Protocol 1. The program is provided below.

[0209]

[0210] Scheme 1: Synthetic scheme for preparing biotin-Gem

[0211] (2R,3R,5R)-5-(4-Amino-2-oxopyrimidin-1(2H)-yl)-4,4-difluoro-3hydroxytetrahydrofuran-2-yl)methyl(2-( Synthesis of 5-(2-oxohexahydro-1H-thieno[3,4-d)imidazol-4-yl)pentanamido)ethyl)carbonate (4):

[0212]Compound 2 was prepared following literature procedures (see McEwan et al. Biomaterials. 2016:80, 20-32). To a solution of 2 (0.28 g, 0.9 mmol) in DCM (10 mL) was added 4-nitrophenylchloroformate (0.59 g, 2.9 mmol), DIPEA (0.50 g, 3.9 mmol) and a catalytic amount of pyridine and stirred at room temperature for 24 hours. The reaction mixture was then concentrated to dryness in vacuo. The crude resid...

Embodiment 2

[0232] Example 2- Preparation, Stability and Loading Efficiency of Avidin Functionalized Paclitaxel (PTX) Loaded Microbubbles (MB)

[0233] 2.1 Preparation of lipid-stabilized MB (PTX-MB) doped with PTX in the shell:

[0234] By first adding the lipids 1,2-dibehenyl-sn-glycero-3-phosphocholine (DBPC) (4.0mg, 4.43umol), 1,2-distearoyl-sn-glycero-3-phosphate Ethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG(2000)) (1.35mg, 0.481μmol) and DSPE-PEG(2000)-biotin (1.45mg, 0.481μmol) dissolved Avidin-functionalized lipid-stabilized microbubbles with hydrophobically incorporated PTX in the shell were prepared in chloroform to achieve a molar ratio of 82:9:9. To this solution was added paclitaxel (5 mg, 5.86 μmol) dissolved in chloroform. The solution was heated at 40°C for 30 minutes until the chloroform evaporated. The dried lipid film was reconstituted in 3 mL of Ringer's solution (PBS, glycerol, propylene glycol (8:1:1 by volume)) and heated on a 75 °C water bath for ...

Embodiment 3

[0243] Example 3 - Biological testing of PTX-MB-RB, PTX-MB-Gem and PTX-MB-Gem-RB

[0244] 3.1 Efficacy of Biotin-Gem and Biotin-Gem-RB in BxPC-3 cells:

[0245] To ensure that the antimetabolite efficacy of biotin-Gem and biotin-Gem-RB was not affected by chemical modification, the cytotoxicity of the conjugates was determined in the human pancreatic cancer cell line BxPc-3. at 37°C in humidified 5% CO 2 Cells were maintained in RPMI-1640 supplemented with 10% (v / v) fetal calf serum in atmosphere. These cells were seeded into 96-well plates at a density of 5000 cells per well. Plates were then incubated for 24 hours before adding 100 uL of media spiked with Gem, Biotin-Gem or Biotin-Gem-RB. The concentrations used for Biotin-Gem were 0, 0.1, 5, 10, 25, 50, 100 and 100 μM, while for Biotin-Gem-RB, 0.01 μM, 0.05 μM, 0.1 μM, 0.5 μM, 1 μM, Concentrations of 5 μM and 10 μM. In each case the corresponding concentration of Gem was used. Cells were then incubated for a further...

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Abstract

The invention relates to microbubble complexes for use in methods of sonodynamic therapy which comprise a microbubble attached to or otherwise associated with one or more linking groups, each linkinggroup being bound to at least one sonosensitising agent and at least one chemotherapeutic agent. It further relates to the microbubble complexes themselves and to pharmaceutical compositions which contain them. The invention is particularly suitable for the treatment of deep-sited tumors, in particular pancreatic cancer.

Description

technical field [0001] The present invention relates generally to and relates to improvements in sonodynamic therapy, and more particularly to such methods for the treatment of diseases characterized by hyperproliferative and / or abnormal cells. [0002] More specifically, the present invention relates to the targeted treatment of deep tumors, such as pancreatic cancer, using combined sonodynamic and anticancer therapies. Background technique [0003] Conventional treatment for deep tumors often includes major surgery, chemotherapy, radiation, or a combination of all of these. All three interventions can lead to various complications, including sepsis. Therefore, there is an urgent need to develop more targeted and less invasive therapies with higher efficacy to treat such patients. Pancreatic cancer is an example of a deep tumor. It remains one of the deadliest types of cancer known, with fewer than 20 percent of those diagnosed eligible for surgery. It accounts for appr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K41/00A61K47/69A61P35/00C07H19/16C07D495/04
CPCA61K41/0033C07D495/04A61K47/6925A61P35/00C07H15/24C07H15/244C07H19/06A61K31/337A61K47/55A61K47/551A61K45/06A61K2300/00A61K47/558A61K47/557A61K47/542A61K47/549A61K31/7048A61K31/7068A61K41/0042A61K47/24
Inventor 约翰·卡兰安东尼·麦克海尔苏坎塔·卡米拉凯兰·洛根
Owner UNIVERSITY OF ULSTER
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