KR20190094931A - Method for delivering drug efficiently in brain using additional focused ultrasound stimulation - Google Patents
Method for delivering drug efficiently in brain using additional focused ultrasound stimulation Download PDFInfo
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Abstract
Description
본 발명은 뇌에서의 약물전달 방법에 관한 것으로, 더욱 상세하게는 추가적 집속초음파 자극을 이용한 뇌에서의 효율적인 약물전달 방법에 관한 것이다.The present invention relates to a method for drug delivery in the brain, and more particularly to an efficient drug delivery method in the brain using additional focused ultrasound stimulation.
뇌혈관 장벽(Blood Brain Barrier, BBB)은 뇌혈관의 내피세포 간의 밀착연접(tight junction) 및 이를 더욱 강화하는 성상세포(astrocyte)로 이루어진 구조물로서, 혈관 내부의 물질이 혈관벽을 통과하여 뇌 실질 내로 쉽게 이동하지 못하게 하는 기능을 한다.Blood Brain Barrier (BBB) is a structure made up of tight junctions between endothelial cells of the cerebrovascular vessels and astrocytes that further strengthen them, and substances inside the blood vessels pass through the blood vessel walls and into the brain parenchyma. This function prevents you from moving easily.
이렇듯, 뇌혈관 장벽은 뇌조직에 있는 모세혈관이 다른 조직의 모세혈관에 비해 낮은 혈관 투과성을 유지함으로써 불필요한 물질들의 이동을 최소한으로 유지하므로, 뇌혈관 장벽을 이루는 주된 구조는 모세혈관 내피세포(capillary endothelial cell)에 있는 밀착연접(tight junction)을 의미한다고 볼 수 있다.As such, the cerebrovascular barrier maintains minimal vascular transport by capillary vessels in the brain tissue compared to the capillaries of other tissues, thereby minimizing the movement of unnecessary substances. Thus, the main structure of the cerebrovascular barrier is capillary endothelial cells (capillary). Tight junction in the endothelial cells can be seen as meaning.
뇌혈관 장벽은 이온이나 단백질, 기타 물질이 중추신경계 환경으로 불특정 유입되는 것을 차단하므로, 이러한 장벽으로서의 역할은 혈액으로부터 공급되는 해로운 성분들로부터 신경원을 보호하며 필수적인 물질들은 투과되도록 하고 신경조직에 필요한 작은 분자량의 물질은 세포막에 있는 운반물질(carrier)과 결합되어 내피를 통해 뇌실질로 들어간다.The cerebrovascular barrier blocks the unspecified entry of ions, proteins and other substances into the central nervous system environment, thus acting as a barrier to protect neurons from harmful components supplied from the blood, allowing essential substances to permeate and Molecular weight material is combined with a carrier in the cell membrane and enters the brain parenchyma through the endothelium.
그러나, 뇌경색, 외상 및 뇌종양과 같은 뇌 손상의 대부분은 뇌혈관 장벽의 붕괴와 연관되며 이는 신경원의 이차적인 손상을 초래한다. 따라서, 뇌혈관 장벽의 발생 기전과 조절에 대한 연구는 중추신경계 질환을 이해하고 치료하는데 매우 중요하다.However, most of the brain damages such as cerebral infarction, trauma and brain tumors are associated with the breakdown of the cerebrovascular barrier, which leads to secondary damage of neurons. Therefore, the study of the mechanism and regulation of cerebrovascular barrier is very important for understanding and treating central nervous system diseases.
또한, 많은 종류의 약물과 대사물질이 뇌혈관 장벽을 투과하지 못하므로, 뇌혈관 장벽의 적절한 조절은, 치매를 포함한 여러가지 뇌질환을 치료함에 있어서 약물을 적재적소에 투여할 수 있는 아주 중요한 부분이 된다고 할 수 있다. 뇌혈관 장벽은 염증성질환(inflammatory disease), 종양(tumor) 등 여러 질환에서 손상되며, 외상(injury) 후에도 2 내지 3 주일 정도 기능을 못하는 경우가 있다. 이러한 성질을 이용하여 혈액 내로 추적물질(tracer substance)을 준 후 이 물질이 뇌의 어느 부분으로 투과해 들어가는지를 관찰하면 병변이 있는 장소를 추측하는 등의 연구가 이루어지고 있다.In addition, since many types of drugs and metabolites do not penetrate the cerebrovascular barrier, proper control of the cerebrovascular barrier is a very important part of the right place for the administration of drugs in the treatment of various brain diseases including dementia. It can be said. Cerebrovascular barrier is damaged in various diseases such as inflammatory disease (tumor), tumor (tumor), and may not function for about 2 to 3 weeks after the injury (injury). Using this property, a tracer substance is given into the blood, and then, where the substance penetrates into the brain, the place where the lesion is located is estimated.
그러나, 뇌혈관 장벽으로 인해 대부분의 약물은 뇌에 전달되지 못하는 것이 현 상황이며, 현재 시판되고 있는 뇌질환 관련 약물은 뇌조직으로의 전달과 관련하여 어느 정도의 부작용을 나타내지만 치료 효과를 고려하여 사용되고 있는 것이 현실이다. 이에 따라, 뇌혈관 장벽를 통과하여 약물을 효과적으로 뇌조직으로 전달하는 방법에 대하여 꾸준한 연구가 진행되고 있다.However, due to the cerebrovascular barrier, most of the drugs cannot be delivered to the brain. Current marketed drugs for brain disease show some side effects related to delivery to brain tissue, but considering the therapeutic effect The reality is that it is being used. Accordingly, steady research is being conducted on how to effectively deliver drugs to brain tissue through the cerebrovascular barrier.
본 발명의 발명자들은 초음파(집속초음파)를 이용한 뇌혈관 장벽 통과 약물 전달이 비침습적, 국소적으로 개통하므로 비외과적 방법으로서 관심받고 있으나, 전달되는 약물 대비 부작용이 여전히 존재하므로 이를 최소화하기 위한 약물의 효율적 전달 방법에 대하여 연구하던 중, 기존의 집속초음파 처리 단계에 앞서 추가적인 1차 처리 단계(마이크로버블의 처리 없이 집속초음파 처리)를 수행하는 집속초음파 처리 방법을 수행하면 기존 방법에 의한 경우보다 약 2.6배 높은 약물전달 효과가 있다는 것을 발견하였다.The inventors of the present invention are receiving attention as a non-surgical method because the drug delivery through the cerebrovascular barrier using ultrasound (focused ultrasound) is non-invasive and locally open, but side effects compared to the delivered drug still exist, so drugs to minimize this While researching the efficient delivery method of, the focused ultrasound processing method that performs the additional first processing step (focused ultrasound processing without the microbubble processing) prior to the existing focused ultrasound processing step is weaker than the conventional method. The drug delivery effect was found to be 2.6 times higher.
따라서, 본 발명은 기존의 집속초음파 처리 단계에 앞서 마이크로버블의 처리 없이 집속초음파 처리를 수행하는 약물전달 방법을 제공하는 것을 목적으로 한다.Accordingly, an object of the present invention is to provide a drug delivery method for performing focused ultrasound processing without the processing of microbubbles prior to the existing focused ultrasound processing step.
본 발명의 일 측면에 따라, (a) 개체에 마이크로버블의 처리 없이 집속초음파를 파워 0.1 - 10 Mpa로 10 - 500초 동안 처리하는 1차 처리 단계; (b) 마이크로버블의 처리와 함께 집속초음파를 파워 0.1 - 10 Mpa로 10 - 500초 동안 처리하는 2차 처리 단계; 및 (c) 개체에 약물을 투여하는 단계를 포함하는, 뇌혈관 장벽(BBB)을 통한 약물전달 방법이 제공된다.According to one aspect of the invention, (a) the first processing step of treating the focused ultrasound for 10-500 seconds power 0.1 ~ 10 Mpa without the microbubble treatment on the subject; (b) a secondary processing step of treating the focused ultrasound with a power of 0.1-10 Mpa for 10-500 seconds together with the processing of the microbubbles; And (c) administering a drug to the subject, a method for drug delivery via the cerebrovascular barrier (BBB) is provided.
일 구현예에서, 단계(a)에서 상기 집속초음파를 파워 1 Mpa로 처리하거나, 120초 동안 처리할 수 있다.In one embodiment, the focused ultrasound may be treated with a power of 1 Mpa or may be processed for 120 seconds in step (a).
일 구현예에서, 단계(b)에서 상기 집속초음파를 파워 0.47 Mpa 내지 0.6 Mpa로 처리하거나, 120초 동안 처리할 수 있다.In one embodiment, in step (b) the focused ultrasound can be treated with a power of 0.47 Mpa to 0.6 Mpa, or for 120 seconds.
일 구현예에서, 단계(c)에서 상기 약물을 정맥으로 투여할 수 있다.In one embodiment, the drug may be administered intravenously in step (c).
일 구현예에서, 상기 개체는 랫트, 개 및 고양이로 이루어진 군에서 선택된 1종이거나, 인간일 수 있다.In one embodiment, the subject may be one or a human selected from the group consisting of rats, dogs, and cats.
본 발명의 다른 측면에 따라, 상기 약물전달 방법을 이용한 뇌로의 약물전달 기기가 제공된다.According to another aspect of the present invention, there is provided a drug delivery device to the brain using the drug delivery method.
본 발명에 의해, 기존의 집속초음파 처리 단계에 앞서 추가적인 1차 처리 단계(마이크로버블의 처리 없이 집속초음파 처리)를 수행하는 집속초음파 처리 방법을 수행함으로써, 독소루비신을 이용하여 뇌조직으로의 약물전달을 확인한 결과, 기존 방법에 의한 경우보다 약 2.6배 높은 약물전달 효과가 있는 것으로 확인되어, 더 적은 양의 약물로도 효과적인 치료가 가능하여 부작용을 최소화할 수 있다는 것이 밝혀졌다.According to the present invention, prior to the existing focused ultrasound processing step by performing a focused ultrasound processing method that performs an additional primary processing step (focused ultrasound processing without the microbubble processing), drug delivery to brain tissues using doxorubicin As a result, it was confirmed that the drug delivery effect was about 2.6 times higher than the conventional method, and it was found that the effective treatment can be minimized with a smaller amount of the drug, thereby minimizing side effects.
따라서, 본 발명의 기존의 집속초음파 처리 단계에 앞서 마이크로버블의 처리 없이 집속초음파 처리를 수행하는 약물전달 방법은 뇌혈관 장벽으로 인해 치료가 어려운 퇴행성 뇌질환, 뇌암 등 장벽이 높은 뇌질환 치료 분야의 약물전달 방법 또는 의료기기 기술로서 유용하게 사용될 수 있다.Therefore, the drug delivery method for performing focused ultrasound treatment without the treatment of microbubbles prior to the focused ultrasound treatment step of the present invention is difficult to treat due to the cerebrovascular barrier, such as brain disease treatment of high barriers such as degenerative brain disease, brain cancer It can be usefully used as a drug delivery method or a medical device technology.
도 1은 MRgFUS 기기를 이용한 초음파 처리에 사용된 FUS 기기(RK-100) 구성의 개략도이다.
도 2는 동물에 집속초음파 처리 과정을 나타낸 개략도이다[(A) BBBD 처리군; (B) FUS 처리군; (C) FUS 및 BBBD 처리군].
도 3은 에반스 블루(Evans blue)의 투과성(permeability)을 나타낸 사진이다[(A): 대조군; (B) 에반스 블루 투여군].
도 4는 독소루비신(Doxorubicin, DOX)을 이용한 약물 전달을 확인한 결과이다.
도 5는 동물에 집속초음파 조사한 후, 뇌의 MRI 사진이다[(A) FUS+BBBD protocol과 BBBD protocol의 결과를 비교한 데이터; (B) FUS protocol과 비처리 결과를 비교한 데이터]. 1 is a schematic diagram of a configuration of an FUS device (RK-100) used for ultrasonic processing using an MRgFUS device.
2 is a schematic view showing a focused ultrasound treatment process in an animal [(A) BBBD treatment group; (B) FUS treatment group; (C) FUS and BBBD treatment groups].
3 is a photograph showing the permeability of Evans blue ((A): control; (B) Evans blue administration group].
Figure 4 is a result confirming drug delivery using doxorubicin (DOX).
5 is an MRI photograph of the brain after focused ultrasound irradiation on animals [(A) data comparing the results of the FUS + BBBD protocol and the BBBD protocol; (B) data comparing FUS protocol with untreated results].
본 발명은 (a) 개체에 마이크로버블의 처리 없이 집속초음파를 파워 0.1 - 10 Mpa로 10 - 500초 동안 처리하는 1차 처리 단계; (b) 마이크로버블의 처리와 함께 집속초음파를 파워 0.1 - 10 Mpa로 10 - 500초 동안 처리하는 2차 처리 단계; 및 (c) 개체에 약물을 투여하는 단계를 포함하는, 뇌혈관 장벽(BBB)을 통한 약물전달 방법을 제공한다.The present invention (a) the first processing step of processing the focused ultrasound for 10-500 seconds power 0.1 ~ 10 Mpa without the microbubble treatment of the subject; (b) a secondary processing step of treating the focused ultrasound with a power of 0.1-10 Mpa for 10-500 seconds together with the processing of the microbubbles; And (c) administering a drug to the subject, the method provides drug delivery through the cerebrovascular barrier (BBB).
본 발명에서는 뇌혈관 장벽 붕괴를 유도할 수 있는 기술인 MRI 유도성 집속초음파(MRI-guided Focused Ultrasound, MRgFUS)를 이용하여 다양한 처리 조건에서의 뇌혈관 장벽의 붕괴 정도를 측정하여 뇌질환 관련 약물을 뇌조직으로 효율적으로 전달하기 위한 특정 조건을 도출하였다.In the present invention, MRI-guided Focused Ultrasound (MRI-guided Focused Ultrasound, MRgFUS), a technology capable of inducing cerebrovascular barrier by measuring the degree of disruption of the cerebrovascular barrier under various treatment conditions, the brain disease-related drugs Specific conditions have been derived for efficient delivery to the organization.
상기 단계(a)는 기존의 집속초음파 처리 단계에 앞서 마이크로버블의 처리 없이 집속초음파 처리를 수행하는 단계이다.Step (a) is a step of performing focused ultrasound processing without the processing of microbubbles prior to the existing focused ultrasound processing step.
일 구현예에서, 단계(a)에서의 상기 집속초음파는 파워 1 Mpa로 처리하거나, 120초 동안 처리할 수 있다.In one embodiment, the focused ultrasound in step (a) may be treated with a power of 1 Mpa, or 120 seconds.
상기 단계(b)는 마이크로버블의 처리 없이 집속초음파 처리를 수행한 이후에 마이크로버블의 처리와 함께 집속초음파를 처리하는 단계이다.Step (b) is a step of processing the focused ultrasound together with the processing of the microbubbles after performing the focused ultrasound processing without the processing of the microbubbles.
일 구현예에서, 단계(b)에서의 상기 집속초음파는 파워 0.47 Mpa 내지 0.6 Mpa로 처리하거나, 120초 동안 처리할 수 있다.In one embodiment, the focused ultrasound in step (b) may be treated with a power of 0.47 Mpa to 0.6 Mpa, or 120 seconds.
일 구현예에서, 단계(c)에서 상기 약물을 정맥으로 투여할 수 있다. 상기 약물은 뇌질환 분야에서 사용되는 뇌질환 관련 약물이다.In one embodiment, the drug may be administered intravenously in step (c). The drug is a brain disease related drug used in the field of brain disease.
일 구현예에서, 상기 개체는 MRgFUS 기술이 사용가능한 개체라면 제한되지 않으며, 바람직하게는 랫트, 개 및 고양이로 이루어진 군에서 선택된 1종이거나, 인간일 수 있다.In one embodiment, the subject is not limited as long as the MRgFUS technology is available, preferably one selected from the group consisting of rats, dogs, and cats, or may be human.
또한, 본 발명은 상기 약물전달 방법을 이용한 뇌로의 약물전달 기기를 제공한다.The present invention also provides a drug delivery device to the brain using the drug delivery method.
이하, 본 발명을 실시예를 통하여 더욱 상세히 설명한다. 그러나, 하기 실시예는 본 발명을 예시하기 위한 것으로, 본 발명의 범위가 이에 제한되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following examples are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.
<실시예><Example>
1. 초음파 처리1. Ultrasonic Treatment
MRgFUS 기기를 이용한 초음파 처리는 FUS 기기(RK-100)를 사용하였으며, 도 1에 기기 구성의 개략도가 나타나 있다.Ultrasonic treatment using the MRgFUS device was used a FUS device (RK-100), a schematic diagram of the device configuration is shown in FIG.
초음파 처리 과정은 하기와 같다. MRI를 통한 이미지 가이드로서 T1 및 T2-강조(weight) MR 이미지를 촬영하였다. 초음파 처리 영역은 랫트 뇌의 T2-강조 이미지를 대상으로 하였다. 마이크로버블 처리 단계가 포함되지 않는 과정에서는, 적합한 파워의 네가티브 음압(peak negative acoustic pressure)을 사용하였다(1 Mpa). 마이크로버블 처리 단계가 포함되는 과정에서는, 초음파 처리 전에, 활성화된 마이크로버블(microbubble)을 생리식염수로 1:50으로 희석하고, 자동화 시린지 펌프(Pump 11, Harvard Apparatus, Holliston, MA, USA)를 사용하여 개시로 10 초 동안 꼬리 정맥 카테터를 통해 주입하였다. 그 다음, 각 처리 단계에 적합한 파워의 네가티브 음압(peak negative acoustic pressure)을 사용하여(0.47 Mpa 또는 0.6 Mpa) 초점 영역에 미세 주입하여 뇌혈관 장벽을 붕괴시켰다. 초음파 처리 후, 약물(독소루비신, 5.67 mg/kg)을 투여(IV)하고, 뇌혈관 장벽 붕괴 확인을 위해 에반스 블수 염료를 투여(IV)하여 T1-강조 MR 이미지를 찍었고, 독소루비신 처리한 후 24시간 지난 후에 랫트를 치사시켜 뇌조직을 적출하였다.The sonication process is as follows. T1 and T2-weighted MR images were taken as image guides via MRI. The sonication area was targeted to T2-weighted images of the rat brain. In the course of not including the microbubble processing step, a peak negative acoustic pressure of a suitable power was used (1 Mpa). In the process involving the microbubble treatment step, prior to sonication, the activated microbubble is diluted 1:50 with physiological saline and an automated syringe pump (Pump 11, Harvard Apparatus, Holliston, MA, USA) is used. By infusion via tail vein catheter for 10 seconds. The cerebrovascular barrier was then disrupted by microinjection into the focal region using peak negative acoustic pressures (0.47 Mpa or 0.6 Mpa) of power appropriate for each treatment step. After sonication, the drug (doxorubicin, 5.67 mg / kg) was administered (IV), and Evans bleed dye was administered (IV) to confirm cerebrovascular disruption, followed by T1-weighted MR images, and 24 hours after doxorubicin treatment. After that, rats were killed to extract brain tissue.
초음파 처리는 도 2 및 하기 표 1에 나타난 프로토콜(protocol)로 수행하였으며, (A) 마이크로버블의 처리와 함께 집속초음파를 처리한 군[BBBD], (B) 마이크로버블의 처리 없이 집속초음파를 처리한 군[FUS], (C) 마이크로버블의 처리 없이 집속초음파 처리를 수행한 후에 마이크로버블의 처리와 함께 집속초음파를 처리한 군[FUS+BBBD]으로 나누어 수행하였다. 초음파 처리 파라미터(parameter)는 하기 표 1과 같다.Ultrasonic treatment was carried out by the protocol shown in Figure 2 and Table 1, (A) the group treated with focused ultrasound with the treatment of microbubbles [BBBD], (B) treated with focused ultrasound without the treatment of microbubbles One group [FUS], (C) after performing focused ultrasound treatment without the microbubble treatment was performed by dividing into the group [FUS + BBBD] treated with the focused ultrasound together with the microbubble treatment. The ultrasonic treatment parameters are shown in Table 1 below.
** PRF : Pulse Repetition Frequency* 0.47 Mpa: Anterior (Caudate putamen), Posterior (Thalamus)
** PRF: Pulse Repetition Frequency
2. 염료 및 약물의 뇌조직으로의 전달 결과2. Results of delivery of dyes and drugs to brain tissue
에반스 블루(Evans blue)의 투과성(permeability)을 측정한 결과를 도 3에 나타내었다[(A): 대조군; (B) 에반스 블루 투여군]. 도 3에 나타난 바와 같이, 본 발명의 방법을 이용한 랫트의 뇌조직 왼쪽 부위가 기존 방법에 의한 뇌조직 오른쪽 부위보다 진한 색을 나타내는 것을 알 수 있다.The results of measuring the permeability of Evans blue are shown in FIG. 3 ((A): control; (B) Evans blue administration group]. As shown in Figure 3, it can be seen that the left portion of the brain tissue of the rat using the method of the present invention shows a darker color than the right portion of the brain tissue by the conventional method.
또한, 도 4에 독소루비신(Doxorubicin, DOX)을 이용한 약물전달 결과가 나타나 있다. 도 4에 나타난 바와 같이, 본 발명의 방법을 이용한 뇌조직 부위가 기존 방법에 의한 뇌조직 부위보다 약 2.6배 높은 약물 농도를 나타내는 것을 알 수 있다.In addition, Figure 4 shows the drug delivery using doxorubicin (DOX). As shown in Figure 4, it can be seen that the brain tissue region using the method of the present invention shows a drug concentration about 2.6 times higher than the brain tissue region by the conventional method.
3. MRI 측정 결과3. MRI measurement results
FUS+BBBD 프로토콜, BBBD 프로토콜, FUS 프로토콜 및 비처리 결과를 도 5에 나타내었다. 도 5에 나타난 바와 같이, FUS+BBBD 프로토콜 영역이 BBBD 프로토콜 영역보다 MR 강도(intensity)가 증가한 것을 알 수 있고, FUS 프로토콜만 처리한 영역은 비처리한 영역과 유사하게 MR 강도의 변화가 없는 것을 알 수 있다.The FUS + BBBD protocol, BBBD protocol, FUS protocol and untreated results are shown in FIG. 5. As shown in FIG. 5, it can be seen that the MR intensity (intensity) of the FUS + BBBD protocol region is increased than that of the BBBD protocol region, and that the region treated only with the FUS protocol has no change in MR intensity similarly to the untreated region. Able to know.
Claims (9)
(b) 마이크로버블의 처리와 함께 집속초음파를 파워 0.1 - 10 Mpa로 10 - 500초 동안 처리하는 2차 처리 단계; 및
(c) 개체에 약물을 투여하는 단계
를 포함하는, 뇌혈관 장벽(BBB)을 통한 약물전달 방법.
(a) a primary processing step of treating the focused ultrasound for 10-500 seconds at a power of 0.1-10 Mpa without treatment of microbubbles to the subject;
(b) a secondary processing step of treating the focused ultrasound with a power of 0.1-10 Mpa for 10-500 seconds together with the processing of the microbubbles; And
(c) administering the drug to the individual
Including, the drug delivery method through the cerebrovascular barrier (BBB).
The method of claim 1, wherein in step (a), the focused ultrasound is treated with a power of 1 Mpa.
The drug delivery method according to claim 1, wherein the focused ultrasound is treated for 120 seconds in step (a).
The method of claim 1, wherein in step (b), the focused ultrasound is treated with a power of 0.47 Mpa to 0.6 Mpa.
The method of claim 1, wherein in step (b), the focused ultrasound is treated for 120 seconds.
The method of claim 1, wherein in step (c), the drug is administered intravenously.
The method of claim 1, wherein the subject is a drug delivery method, characterized in that the one selected from the group consisting of rats, dogs and cats.
The method of claim 1, wherein the subject is a human.
A drug delivery device to the brain using the drug delivery method of any one of claims 1 to 8.
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