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WO2023211207A1 - Appareil de traitement par ultrasons focalisés fonctionnant conjointement avec un véhicule de nanomédicament, procédé de commande d'ultrasons et véhicule de nanomédicament associé - Google Patents

Appareil de traitement par ultrasons focalisés fonctionnant conjointement avec un véhicule de nanomédicament, procédé de commande d'ultrasons et véhicule de nanomédicament associé Download PDF

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Publication number
WO2023211207A1
WO2023211207A1 PCT/KR2023/005790 KR2023005790W WO2023211207A1 WO 2023211207 A1 WO2023211207 A1 WO 2023211207A1 KR 2023005790 W KR2023005790 W KR 2023005790W WO 2023211207 A1 WO2023211207 A1 WO 2023211207A1
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WIPO (PCT)
Prior art keywords
focused ultrasound
nano
nanodrug
carrier
ultrasound
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Ceased
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PCT/KR2023/005790
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English (en)
Korean (ko)
Inventor
유영복
김대승
손건호
정은아
문형원
구자운
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IMGT Co Ltd
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IMGT Co Ltd
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Publication date
Priority claimed from KR1020230054041A external-priority patent/KR20230153940A/ko
Application filed by IMGT Co Ltd filed Critical IMGT Co Ltd
Publication of WO2023211207A1 publication Critical patent/WO2023211207A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a nano-drug carrier that delivers a nano-drug to a lesion site, and a focused ultrasound treatment device that operates in conjunction with a nano-drug carrier that allows the nano-drug carrier to cavitate and release the nano-drug by irradiation of ultrasound; and its ultrasonic control method.
  • the present invention was derived from research conducted as part of the pan-ministerial medical device research and development project of the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, the Ministry of Health and Welfare, and the Ministry of Food and Drug Safety [Project identification number: 9991006682, KMDF_PR_20200901_0009, research project Name: Commercialization and development of market-leading pancreatic cancer fusion treatment ultrasound image-guided high-intensity focused ultrasound treatment device, Research management agency: Pan-Ministerial Life Cycle Medical Device Research and Development Project Group, Contribution rate: 100%, Host research institute: IM Co., Ltd. GT, research period: 2022.3.1 ⁇ 2022.12.31].
  • Surgical incisions, radiation therapy, and chemotherapy are used to treat cancer.
  • chemotherapy is one of the most used methods than other treatments.
  • Conventional chemotherapy causes toxic effects on lesion sites such as tumor cells and inhibits their growth.
  • chemotherapy distributes drugs randomly or widely, causing side effects in healthy tissues and biological systems.
  • Drug carriers have great potential as targeted therapies that can increase treatment efficacy by increasing the accumulation of nano-sized drugs at the lesion site.
  • liposomes are leading the market due to their unique properties and wide range of biomedical applications.
  • liposomes can stabilize drugs, increase tissue absorption, and improve bioavailability.
  • the shape of liposomes is a spherical endoplasmic reticulum with a lipid bilayer surrounding a separate aqueous core. Because liposomes have an aqueous core and a hydrophobic lipid bilayer, they can encapsulate a wide range of drugs.
  • Liposomes are basically composed of a combination of various biocompatible phospholipids. And the physiological and biological properties of liposomes are fully dependent on the type of lipid that makes up the liposome. Shell properties such as surface charge, rigidity and stiffness in relation to lipid composition critically influence pharmacokinetics, biodistribution and excretion. And the properties of the shell are controlled by changing the species and ratio of lipids.
  • existing liposomes are still limited in effective cancer treatment despite the progression of tumor delivery by the EPR effect, long circulation, and protection of drugs. The low therapeutic efficiency is due to the liposome's inability to release the drug in lesional tissues such as tumors.
  • Site-specific drug release requires release in response to internal or external stimuli such as pH, temperature, enzymes, radiation, and ultrasound.
  • internal or external stimuli such as pH, temperature, enzymes, radiation, and ultrasound.
  • the combination of nanomedicine and ultrasound is expected to overcome the limitations of nanoparticle drug delivery systems by controlling the release of drugs to desired areas in the human body.
  • NIR near infrared
  • ultrasound can be means of physical stimulation to release drugs.
  • NIR rays can easily release drugs into the affected area, but their application is limited because they can only penetrate a short distance from the irradiated area.
  • radiation can compensate for the shortcomings of near-infrared irradiation, continuous exposure can cause genotoxicity.
  • ultrasound can achieve physical drug release that overcomes the disadvantages of near-infrared irradiation, and is the optimal method for drug release because it is safe and can reach the amount of lesions located in the body non-invasively.
  • Ultrasounds can induce the cavitation effect, a phenomenon in which bubbles expand to several times their resonance size and then explode during a single compression, creating high gas pressures and temperatures. These energies can cause particle destruction and are suitable for drug release from nano-sized particles.
  • Ultrasound-induced release of liposomes can be induced using plane wave ultrasound and high-intensity focused ultrasound (HIFU). However, in order to release ultrasound-responsive drug-loaded liposomes within the desired tissue, the ultrasound release characteristics must be appropriately adjusted.
  • a focused ultrasound treatment device that operates in conjunction with a nano drug delivery vehicle, an ultrasonic control method thereof, and a nano drug delivery vehicle are proposed.
  • a focused ultrasound control method operating in conjunction with a nano drug delivery system includes the steps of acquiring an image of a lesion site; And aligning a focused ultrasound transducer with the acquired image to irradiate focused ultrasound to generate cavitation of the nano-drug carrier at the lesion site.
  • the pulse repetition frequency of the focused ultrasound may be 10 to 300 Hz
  • the frequency of the focused ultrasound may be 20 kHz to 5 MHz
  • the intensity may be 50 W/cm 2 or more.
  • the duty cycle of focused ultrasound may be 10% or less.
  • cavitation occurs due to irradiation of focused ultrasound as described above, and the nano drug therein is released.
  • a focused ultrasound treatment device operating in conjunction with a nano drug delivery system includes an imaging transducer that acquires an image of a lesion area; And a focused ultrasound transducer aligned with the imaging transducer, wherein the focused ultrasound transducer irradiates focused ultrasound to generate cavitation of the nano-drug carrier at the lesion site visualized by the imaging transducer to deliver the nano-drug. Let it release.
  • the pulse repetition frequency of the focused ultrasound may be 10 to 300 Hz
  • the frequency of the focused ultrasound may be 20 kHz to 5 MHz
  • the intensity may be 50 W/cm 2 or more.
  • the nanodrug release characteristics of the nanodrug delivery system can be effectively controlled.
  • DOX In vitro doxorubicin
  • FUS Focused Ultra-Sound
  • PRF pulse repetition frequency
  • exposure time the release of DOX was proportional to the total ultrasound energy in relation to intensity and exposure time.
  • the release of DOX was critically related to intensity and PRF.
  • intensity is more important than duty cycle, and PRF for cavitation is essential to generate strong acoustic wave pressure.
  • DOX is released from liposomes accumulated in lesion tissues such as tumor tissue, killing cancer cells and having an inhibitory effect on lesions such as tumors.
  • the focused ultrasound treatment device can facilitate drug delivery to a specific part of the body using ultrasound images. Because various drugs can be encapsulated in liposomes, they can be applied to a variety of indications. Additionally, the use of ultrasound-responsive liposomes for targeted drug delivery can be utilized in various fields.
  • FIGS. 1A and 1B are diagrams showing the in vitro nanodrug release characteristics of a nanodrug delivery vehicle and commercial liposome DOX (DOXIL) according to an embodiment of the present invention
  • FIGS. 2A to 2D are diagrams showing the in vitro doxorubicin (DOX) release pattern of the nanodrug delivery system according to various focused ultrasound parameters according to an embodiment of the present invention
  • Figure 3 is a diagram showing a focused ultrasound treatment device according to an embodiment of the present invention, and the treatment procedure and results thereof;
  • Figure 4 is a diagram comparing the in vivo doxorubicin release results of a nano-drug carrier according to an embodiment of the present invention and a commercial liposome (DOXIL) under focused ultrasound irradiation using a focused ultrasound treatment device according to an embodiment of the present invention.
  • DOXIL commercial liposome
  • the lipid composition of the nano drug delivery vehicle is DSPC/DSPE-PEG/cholesterol/DOPE/MSPC.
  • Nanodrug carriers are prepared by ethanol injection followed by extrusion. Briefly, 1.50 g DSPC, 2.66 g DSPE-PEG, 2.20 g cholesterol, 9.16 g DOPE, and 0.50 g MSPC were dissolved in 62.5 mL of ethanol. The organic phase was gently heated to 60°C to dissolve the lipid components. Next, lipid-containing ethanol was injected into 437.5 mL of 250 mM ammonium sulfate solution at 250 rpm.
  • Multilamellar vesicles were assembled and dispersed during ethanol injection with polycarbonate filter pore sizes ranging from 200 to 80 nm using a LIPEX® 800 mL Thermobarrel extruder (Evonik, Canada) and scaled down by successive extrusion cycles. The temperature of the vesicles was maintained at 50 °C during extrusion. The dispersion of extruded liposomes was exchanged in pH 6.5, 10% sucrose, and 10mM histidine buffer using a 12-14-kDa dialysis membrane. Ammonium sulfate was exchanged into buffer to create an ammonium gradient across the liposomal membrane.
  • DOX was encapsulated into the aqueous phase within liposomes using a remote loading method. DOX was added to the liposome dispersion at a ratio of 1:8 to liposomes and stirred for 2 h at 37°C. DOX-loaded liposomes were diluted with buffer to a DOX concentration of 2 mg/mL and stored at 2-8 °C.
  • FIGS. 1A and 1B are diagrams showing the in vitro nanodrug release characteristics of a nanodrug delivery vehicle and commercial liposome DOX (DOXIL) according to an embodiment of the present invention.
  • DOXIL commercial liposome DOX
  • plane wave ultrasound was irradiated with a pin-type ultrasound generator at a frequency of 24 kHz and a continuous ultrasound intensity of 92 kW/cm 2 for 1 minute.
  • a r and A o represent the sonicated liposome suspension and original absorbance intensity, respectively.
  • a focused ultrasound (FUS) device was used with a water bath equipped with a temperature controller and deaerator to analyze the effect of focused ultrasound on DOX release.
  • the center frequency of the FUS transducer was 1 MHz, and the beam resolution of the focal area was 6 dB, showing a circle with a diameter of 1 mm and a circle with a length of 1 cm.
  • nanodrug carriers were exposed to ultrasound with various FUS parameters of intensity, duty cycle, pulse repetition frequency (PRF), and exposure time/spot. Before focused ultrasound irradiation, the nanodrug carrier was embedded in a dialysis membrane and maintained at 37°C with water degassing for 1 h.
  • DOX release Quantification of DOX release was analyzed by measuring optical absorbance at 475 nm.
  • the DOX released after intensive ultrasonic irradiation was purified using a desalting column, and the amount was calculated using the method described above.
  • Commercial liposome DOX (DOXIL) was used as an ultrasound-insensitive liposome.
  • the two liposome solutions were exposed to low frequency continuous waves.
  • the nanodrug delivery system according to an embodiment of the present invention shows a DOX release rate of 58.8%.
  • DOXIL only accounted for 10.2%. Therefore, it can be seen that the nano drug delivery system according to an embodiment of the present invention releases more than 5 times more DOX than DOXIL.
  • the properties of liposomes are related to the composition and ratio of phospholipid types.
  • Phospholipid structure determines the thermodynamic and physicochemical properties of liposomes.
  • the double membrane rearrangement into an inverted cone shape was achieved under ultrasound stimulation.
  • DOPE consists of a hydrophilic head with a small hydrodynamic volume and a large hydrophobic tail, which defines a high packing parameter (PP > 1) and transforms the lamellae into an inverted hexagonal phase under sonic pressure, leading to destabilization.
  • DOXIL is mainly composed of HSPC and has a cylindrical structure with equal volumes of hydrophobic chains and hydrophilic heads. This structure aligns the linear bilayer of the liposome shell and increases the stability of the liposome. Therefore, the nanodrug carrier according to one embodiment of the present invention significantly increases DOX release under ultrasonic pressure compared to DOXIL.
  • the DOX release rate was similar to the release characteristics of continuous ultrasound.
  • the DOX release ratios of the nano drug delivery system and DOXIL according to an embodiment of the present invention are 48.1% and 23.3%, respectively.
  • Ultrasound-induced destabilization of liposomes was confirmed using cryo-TEM images. The morphology of liposomes changed after ultrasound irradiation.
  • Figure 1b it can be seen that the frequency and thickness of DOX rods in liposomes decreased after ultrasound exposure, and the wide size distribution range also shows ultrasound-induced destabilization of liposomes.
  • FIGS. 2A to 2D are diagrams illustrating the in vitro doxorubicin (DOX) release pattern of a nanodrug delivery system according to various focused ultrasound parameters according to an embodiment of the present invention.
  • DOX in vitro doxorubicin
  • DOX release into the tumor-like lesion site was evaluated under focused ultrasound irradiation using a subcutaneous MDA-MB-231 human breast cancer xenograft model (female, balb/c nude mice, 12-14 weeks old). Nanodrug delivery vehicle and DOXIL (20 mg/kg) were injected intravenously. Focused ultrasound at an intensity of 2.0 kW/cm 2 , 2.0% duty cycle, 250 Hz PRF, and 10 s/spot was irradiated after administration of each agent.
  • PRF has a significant impact on the release operation of the nano drug delivery system according to an embodiment of the present invention.
  • the drug release rate tended to increase up to 250 Hz of PRF, but decreased above 250 Hz of PRF.
  • PRF is an important factor related to cavitation generation. Since the frequency is related to the wave pressure of the medium, an increase in PRF causes a strong shock wave and enhances the release of DOX from the nanodrug delivery system according to one embodiment of the present invention.
  • exposure time also affects the release of DOX from the nano drug delivery system according to an embodiment of the present invention.
  • the emission rate increases with irradiation time.
  • ultrasound was irradiated at various duty cycles and intensities to investigate important factors causing the release of DOX from the nano-drug delivery system according to an embodiment of the present invention.
  • the nano drug delivery system according to one embodiment of the present invention was equally exposed to the total energy of ultrasound with a spatial peak time average (ISPTA) of 56 W/cm 2 (FIG. 2d). Duty cycle and intensity are related to heat and pressure, respectively. Drug release occurred at intensities above 2.8 kW/cm 2 .
  • ISPTA spatial peak time average
  • Figure 3 is a diagram showing a focused ultrasound treatment device according to an embodiment of the present invention, and the treatment procedure and results thereof.
  • the ultrasound-induced release of nanodrug carrier and DOX according to one embodiment of the present invention was compared using live fluorescence imaging analysis.
  • the lesion area such as a tumor
  • the lesion area is visualized three-dimensionally using ultrasound images.
  • the region of interest in the lesion US image for FUS exposure was determined by the number of exposure points.
  • the FUS was precisely exposed to the target area by mechanically aligning it between the FUS and the US imaging transducer.
  • the DOX fluorescence emission from the nanodrug carrier and DOXIL according to one embodiment of the present invention was quenched in the core of the two liposomes, the fluorescence intensity of DOX was significantly enhanced by the emission. Therefore, the nano drug delivery system and DOXIL according to an embodiment of the present invention were injected intravenously into MDA-MB-231 xenograft mice, and the lesion site was immediately irradiated with FUS.
  • the focused ultrasound treatment device that operates in conjunction with the nano drug delivery system includes an imaging transducer 310 that acquires an image of the lesion area and a focused ultrasound transducer 320 aligned with the imaging transducer 310, , the focused ultrasound transducer 320 emits focused ultrasound to generate cavitation of the nano-drug carrier at the lesion site visualized by the imaging transducer 310 to release the nano-drug.
  • Figure 4 is a diagram comparing the in vivo doxorubicin release results of a nano-drug carrier according to an embodiment of the present invention and a commercial liposome (DOXIL) under focused ultrasound irradiation using a focused ultrasound treatment device according to an embodiment of the present invention.
  • DOXIL commercial liposome
  • Figure 4 shows DOX release after FUS exposure in an in vivo experiment.
  • the nanodrug carrier according to one embodiment of the present invention was slightly released from the lesion area, such as a tumor, without FUS exposure. Therefore, after 1 hour of FUS irradiation, DOX was strongly released from the nano drug delivery system according to an embodiment of the present invention, and the fluorescence intensity increased in a time-dependent manner due to the release of DOX. Meanwhile, DOXIL was hardly observed at the tumor (lesion) site in both the FUS-exposed and non-exposed groups. The fluorescence intensity of DOXIL continued to quench for 6 hours. These results showed that DOXIL was fairly stable regardless of FUS exposure.
  • the nano drug delivery vehicle according to an embodiment of the present invention effectively released DOX under FUS irradiation, and the combination of FUS and the nano drug delivery vehicle according to an embodiment of the present invention improved the anticancer effect of DOX.
  • the description is focused on experiments on tumors and the results thereof, but the same can be applied not only to tumors but also to various lesions.

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Abstract

Sont divulgués un véhicule de nanomédicament qui administre un nanomédicament au niveau d'un site de lésion, un appareil de traitement par ultrasons focalisés qui fonctionne conjointement avec le véhicule de nanomédicament et qui permet au véhicule de nanomédicament de libérer un nanomédicament en subissant une cavitation due à une exposition à des ultrasons, et un procédé de commande ultrasonore. Un procédé de commande d'ultrasons focalisés fonctionnant conjointement avec un véhicule de nanomédicament selon un mode de réalisation de la présente invention comprend les étapes consistant : à obtenir une image d'un site de lésion ; et à aligner un transducteur d'ultrasons focalisés sur l'image obtenue et à exposer à des ultrasons focalisés pour faire subir une cavitation au véhicule de nanomédicament au niveau du site de lésion. Par l'intermédiaire d'un procédé de commande d'ultrasons selon un mode de réalisation, des caractéristiques de libération de nanomédicament du véhicule de nanomédicament peuvent être efficacement commandées.
PCT/KR2023/005790 2022-04-28 2023-04-27 Appareil de traitement par ultrasons focalisés fonctionnant conjointement avec un véhicule de nanomédicament, procédé de commande d'ultrasons et véhicule de nanomédicament associé Ceased WO2023211207A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2022-0052637 2022-04-28
KR20220052637 2022-04-28
KR10-2023-0054041 2023-04-25
KR1020230054041A KR20230153940A (ko) 2022-04-28 2023-04-25 나노약물 전달체와 연동하여 동작하는 집중 초음파 치료장치, 초음파 제어방법 및 그 나노약물 전달체

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011256172A (ja) * 2003-06-13 2011-12-22 Cerevast Therapeutics Inc 改変超音波技術を使用する非侵襲性血管内血栓溶解
KR20120002943A (ko) * 2010-07-01 2012-01-09 포항공과대학교 산학협력단 세균유래 마이크로베시클을 이용한 암치료 및 암진단 방법
JP5340728B2 (ja) * 2005-06-07 2013-11-13 コーニンクレッカ フィリップス エヌ ヴェ 超音波ドラッグデリバリーのための方法及び装置、並びに相可変流体による熱治療
KR20190138369A (ko) * 2018-06-05 2019-12-13 한국과학기술연구원 고강도-저강도 집속초음파 치료장치
KR20210110578A (ko) * 2018-11-30 2021-09-08 얼테라, 인크 초음파 치료의 효능 향상을 위한 시스템 및 방법

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011256172A (ja) * 2003-06-13 2011-12-22 Cerevast Therapeutics Inc 改変超音波技術を使用する非侵襲性血管内血栓溶解
JP5340728B2 (ja) * 2005-06-07 2013-11-13 コーニンクレッカ フィリップス エヌ ヴェ 超音波ドラッグデリバリーのための方法及び装置、並びに相可変流体による熱治療
KR20120002943A (ko) * 2010-07-01 2012-01-09 포항공과대학교 산학협력단 세균유래 마이크로베시클을 이용한 암치료 및 암진단 방법
KR20190138369A (ko) * 2018-06-05 2019-12-13 한국과학기술연구원 고강도-저강도 집속초음파 치료장치
KR20210110578A (ko) * 2018-11-30 2021-09-08 얼테라, 인크 초음파 치료의 효능 향상을 위한 시스템 및 방법

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