WO2023005401A1 - 一种多模态微泡造影剂及其制备方法和应用 - Google Patents

一种多模态微泡造影剂及其制备方法和应用 Download PDF

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WO2023005401A1
WO2023005401A1 PCT/CN2022/096138 CN2022096138W WO2023005401A1 WO 2023005401 A1 WO2023005401 A1 WO 2023005401A1 CN 2022096138 W CN2022096138 W CN 2022096138W WO 2023005401 A1 WO2023005401 A1 WO 2023005401A1
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solution
contrast agent
microbubble contrast
phospholipid
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郑海荣
盛宗海
胡德红
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深圳先进技术研究院
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
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    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0032—Methine dyes, e.g. cyanine dyes
    • A61K49/0034—Indocyanine green, i.e. ICG, cardiogreen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
    • A61K49/0052—Small organic molecules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
    • A61K49/0089—Particulate, powder, adsorbate, bead, sphere
    • A61K49/0091—Microparticle, microcapsule, microbubble, microsphere, microbead, i.e. having a size or diameter higher or equal to 1 micrometer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres

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  • the invention belongs to the technical field of biomedical materials, and in particular relates to a multimodal microbubble contrast agent and its preparation method and application.
  • Fluorescence imaging is an extremely important tool in molecular biology and medical research.
  • the near-infrared band 600-900nm
  • the autofluorescence of biomolecules in this range is weak, which can avoid background interference and obtain high analytical sensitivity, and the penetration of near-infrared fluorescent dyes
  • the permeability is also significantly stronger than fluorescent dyes in the visible light band.
  • Indocyanine green ICG is a near-infrared fluorescent dye, often used as a fluorescent tracer in imaging diagnosis, widely used in cancer diagnosis, surgical resection treatment, prostate puncture, gastrectomy, etc.
  • Ultrasound imaging has the characteristics of non-invasive, convenient, and real-time imaging, and is the most widely used imaging technology in clinical practice.
  • Ultrasound contrast agents can significantly enhance ultrasound imaging signals, provide doctors with clearer tissue and blood pool images, and have good application prospects in medical imaging diagnosis.
  • An ideal ultrasound contrast agent can be distributed to all parts of the body along with the blood flow, reflecting the blood perfusion of organs, and has a long stable time and good contrast effect, which significantly improves the accuracy of diagnosis.
  • Photoacoustic imaging is a new non-invasive and non-ionizing biomedical imaging method developed in recent years.
  • Photoacoustic imaging combines the advantages of high selectivity in pure optical tissue imaging and deep penetration in pure ultrasonic tissue imaging to obtain high-resolution and high-contrast tissue images, avoiding the influence of light scattering in principle, and breaking through High-resolution optical imaging depth "soft limit" ( ⁇ 1mm), can achieve 50mm deep in vivo tissue imaging.
  • the object of the present invention is to provide a multimodal microbubble contrast agent and its preparation method and application.
  • the present invention provides a multimodal microbubble contrast agent, which is prepared from the following raw materials: phospholipids and indocyanine green;
  • the mass ratio of the phospholipid to indocyanine green is (20-1000):1.
  • the mass ratio of the phospholipid to indocyanine green is 200:1.
  • the structure of the phospholipid comprises a carbon chain of 12-24 carbons and at least one of phosphatidylcholine, phosphatidylethanolamine, phosphatidic acid and phosphatidylglycerol.
  • the phospholipids include 1,2-distearoyl-sn-glyceryl-3-phosphocholine (DSPC), 1,2-dipalmitoyl-sn-glyceryl-3-phosphatidylcholine ( DPPC), 1,2-dipalmitoyl-sn-glyceryl-3-phosphatidic acid (DPPA), distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG2000), distearoylphosphatidylethanolamine - at least one of polyethylene glycol 2000 (DSPE-PEG5000); preferably 1,2-distearoyl-sn-glyceryl-3-phosphocholine (DSPC), distearoylphosphatidylethanolamine - Combination of polyethylene glycol 2000 (DSPE-PEG2000).
  • DSPC 1,2-distearoyl-sn-glyceryl-3-phosphocholine
  • DPPC 1,2-dipalmitoyl-sn-glyceryl-3-phosphatidic
  • the present invention provides a method for preparing any one of the above multimodal microbubble contrast agents, comprising the following steps:
  • step (3) Vacuumize the solution obtained in step (3) until no bubbles are found when flicking the bottle body of the container, and then fill it with an inert substance several times continuously to prepare the multimodal microbubble contrast agent.
  • the concentration of the phospholipid solution described in step (1) is 1-50 mg/ml
  • the concentration of the indocyanine green solution in step (1) is 0.1-10 mg/ml.
  • volume ratio of the phospholipid solution and the indocyanine green solution described in step (2) is (0.1-100): 1;
  • the main purpose of the heating is to accelerate the volatilization of the solution, and the temperature may be 20-100°C.
  • step (3) is 20-100°C
  • the Tris buffer has a concentration of 0.01-0.2 mol/L and a pH of 7.4.
  • the inert substance described in step (4) includes air, nitrogen, carbon dioxide, fluorocarbon gas, C5-C12 fluorocarbon liquid;
  • the number of times of filling inert substances in step (4) is 1-20 times.
  • the prepared multimodal microbubble contrast agent is composed of liposome in the form of microbubble as carrier and nanostructure formed by self-assembly of ICG.
  • the present invention provides an application of any one of the multimodal microbubble contrast agents described above as a fluorescence imaging agent, an ultrasound imaging contrast agent, or a photoacoustic imaging agent.
  • the present invention provides a method for using any one of the multimodal microbubble contrast agents described above, including shaking in a silver pump blender for a certain period of time, resuspending in PBS and storing on ice for use.
  • the present invention provides a multimodal microbubble contrast agent, which is composed of liposomes in the form of microbubbles as a carrier and a nanostructure formed by self-assembly of ICG, which can integrate fluorescence, photoacoustic and Ultrasonic multiple imaging modes; and before the microbubbles are shaken, the fluorescence signal of the solution is weaker, the photoacoustic signal is stronger, and there is no ultrasonic signal.
  • the photoacoustic signal of the solution After shaking the bubble, the photoacoustic signal of the solution is weakened, the fluorescence signal is enhanced, and the ultrasonic signal is enhanced; Under the action of ultrasound, the targeted explosion of microbubbles is realized, the fluorescence signal of the solution is weakened and the photoacoustic signal is enhanced.
  • This ratiometric imaging of fluorescence and photoacoustics can precisely locate tumors and metastatic lymph nodes, providing more clinical diagnostic information. All the materials selected in the present invention are FDA-approved materials, which are expected to be used clinically.
  • the multimodal microbubble contrast agent prepared by the preparation method of the present invention is shaken into microbubbles. , the fluorescence is enhanced, which can greatly reduce the clinical dosage. Mainly by adjusting the ratio of raw materials, the fluorescence intensity of the ICG near-infrared first and second regions is enhanced, which can greatly reduce the clinical dosage.
  • Figure 1 is a confocal image of microbubbles
  • Figure 2 is a multi-modal imaging diagram of microbubbles under different conditions.
  • microbubbles shaking bubbles: After shaking in a silver pump blender for 45 seconds, resuspend in PBS and store on ice for use.
  • microbubbles Drop the microbubbles onto the glass slide and place them under a confocal microscope to observe the shape and size of the microbubbles. The results are shown in Figure 1. It can be seen from Figure 1 that the microbubbles have a uniform particle size and a size of about 20 ⁇ m.

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Abstract

本发明公开了一种多模态微泡造影剂及其制备方法和应用，多模态微泡造影剂由以下原料制备而成：磷脂、吲哚菁绿；所述磷脂和吲哚菁绿的质量比为(20-1000)：1。本发明提供的多模态微泡造影剂，其由作为载体的微泡形式的脂质体和ICG自组装形成的纳米结构组成，能够综合荧光、光声和超声多种成像模式；并且该微泡在没有摇泡之前，溶液的荧光信号较弱光声信号较强没有超声信号，在摇泡后溶液的光声信号减弱，荧光信号增强，超声信号增强；在超声作用下实现微泡靶向爆破，溶液的荧光信号得以减弱而光声信号得以增强。这种荧光和光声的比率成像可以精准定位肿瘤和转移淋巴结位置，为临床提供了更多的诊断信息。

Description

一种多模态微泡造影剂及其制备方法和应用 技术领域
本发明属于生物医用材料技术领域，具体涉及一种多模态微泡造影剂及其制备方法和应用。
背景技术
荧光成像是分子生物学和医学研究中极为重要的手段。其中，近红外波段(600-900nm)是光学成像的“诊断窗”，其范围内的生物分子的自身荧光较弱，可避免背景干扰而获得较高的分析灵敏度，而且近红外荧光染料的穿透能力也明显强于可见光波段的荧光染料。吲哚菁绿ICG是一种近红外荧光染料，常作为荧光示踪剂用于影像学诊断中，广泛用于癌症诊断、手术切除治疗、前列腺穿刺、胃切除手术等。超声成像具有无创、便捷、实时成像等特点，是临床上使用最广泛的一类成像技术。超声造影剂能够显著增强超声成像信号，为医生提供更加清晰的组织和血池图像，在医学影像诊断方面具有很好的应用前景。理想的超声造影剂能够随血流分布到全身各处，反映器官的血流灌注情况，而且稳定时间长，造影效果好，显著提高了诊断的准确率。光声成像是近年来发展起来的一种非入侵式和非电离式的新型生物医学成像方法。光声成像结合了纯光学组织成像中高选择特性和纯超声组织成像中深穿透特性的优点，可得到高分辨率和高对比度的组织图像，从原理上避开了光散射的影响，突破了高分辨率光学成像深度“软极限”(～1mm)，可实现50mm的深层活体内组织成像。
淋巴结的无创性检查一直备受临床关注。经皮下注射近红外荧光染料行活体荧光成像寻找前哨淋巴结在国内外已有应用，具有很高的灵敏度，但是受限于成像深度，影响了在深部淋巴结检测中的应用。而超声成像定位淋巴结具有较高的分辨率，但是灵敏度不够高，逐一寻找较为麻烦且容易遗漏。综上所述，单一成像模式的造影剂已经不能满足临床诊断的需要。
发明内容
为了解决上述背景技术中所提出的问题，本发明的目的在于提供一种多模态微泡造影剂及其制备方法和应用。
为了达到上述目的，本发明所采用的技术方案为：一方面，本发明提供了一种多模态微泡造影剂，由以下原料制备而成：磷脂、吲哚菁绿；
所述磷脂和吲哚菁绿的质量比为(20-1000)：1。通过调节原料的配比为该范围下，可以增强ICG近红外一区和二区的荧光强度。
进一步地，所述磷脂和吲哚菁绿的质量比为200：1。
进一步地，所述磷脂的结构包含12～24个碳的碳链以及磷脂酰胆碱、磷脂酰基乙醇胺、磷脂酸和磷脂酰基甘油中的至少一种。
进一步地，所述磷脂包括1，2-二硬脂酰基-sn-甘油基-3-磷酸胆碱(DSPC)、1，2-二棕榈酰基-sn-甘油基-3-磷脂酰胆碱(DPPC)、1，2-二棕榈酰基-sn-甘油基-3-磷脂酸(DPPA)、二硬脂酰磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG2000)、二硬脂酰磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG5000)中的至少一种；优选为1，2-二硬脂酰基-sn-甘油基-3-磷酸胆碱(DSPC)、二硬脂酰磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG2000)的组合。
另一方面，本发明提供了一种上述任一所述的多模态微泡造影剂的制备方法，包括以下步骤：
(1)分别配制一定浓度的磷脂溶液和吲哚菁绿溶液；
(2)将磷脂溶液和吲哚菁绿溶液加入容器中，在一定温度下加热并充分混匀，涡旋，同时向容器中充入氮气，直至溶液挥发完全；将容器封口同时保证容器内气体可与外界连通，将容器进行抽真空使容器中的溶剂挥发完全；
(3)在一定温度下加入Tris缓冲液对薄膜进行水化，待容器壁上的脂质膜完全脱落后，对其进行超声直至形成透明澄清溶液，然后除去未装载的吲哚菁绿；
(4)将步骤(3)中得到的溶液抽真空至轻弹容器瓶身未见气泡产生，然后连续多次充惰性物质制备得到所述多模态微泡造影剂。
进一步地，步骤(1)中所述磷脂溶液的浓度为1-50mg/ml；
步骤(1)中所述吲哚菁绿溶液的浓度为0.1-10mg/ml。
进一步地，步骤(2)中所述磷脂溶液和吲哚菁绿溶液的体积比为(0.1-100)：1；
优选地，所述加热的主要目的是加速溶液的挥发，温度可选为20-100℃。
进一步地，步骤(3)中所述温度为20-100℃；
优选地，所述Tris缓冲液的浓度为0.01-0.2mol/L，pH＝7.4。
进一步地，步骤(4)中所述惰性物质包括空气、氮气、二氧化碳、氟碳烃气体、C5-C12氟碳烃液体；
优选地，步骤(4)中所述充惰性物质的次数为1-20次。
进一步地，制备得到的多模态微泡造影剂由作为载体的微泡形式的脂质体和ICG自组装形成的纳米结构组成。
再一方面，本发明提供了一种上述任一所述的多模态微泡造影剂作为荧光成像剂、超声 成像造影剂、光声成像剂的应用。
再一方面，本发明提供了一种上述任一所述的多模态微泡造影剂的使用方法，包括银泵调和机中振荡一定时间，PBS重悬置于冰上保存使用。
本发明的有益效果为：本发明提供了一种多模态微泡造影剂，其由作为载体的微泡形式的脂质体和ICG自组装形成的纳米结构组成，能够综合荧光、光声和超声多种成像模式；并且该微泡在没有摇泡之前，溶液的荧光信号较弱光声信号较强没有超声信号，在摇泡后溶液的光声信号减弱，荧光信号增强，超声信号增强；在超声作用下实现微泡靶向爆破，溶液的荧光信号得以减弱而光声信号得以增强。这种荧光和光声的比率成像可以精准定位肿瘤和转移淋巴结位置，为临床提供了更多的诊断信息。本发明所选的材料全部是FDA批准的材料，有望用于临床。
现有技术制备荧光微泡的方法很多，其荧光性质大多是由于装载的荧光染料所表现的单纯的发光性质，而本发明制备方法制备得到的多模态微泡造影剂当摇成微泡后，荧光得以增强，这样可以大大减少临床的使用剂量。主要是通过调节原料的配比，增强了ICG近红外一区和二区的荧光强度，这样可以大大减少临床的使用剂量。
附图说明
图1为微泡的共聚焦图；
图2为不同条件下微泡的多模态成像图。
具体实施方式
为了更好地理解本发明的内容，下面结合具体实施方法对本发明内容作进一步说明，但本发明的保护内容不局限以下实施例。
实施例1：
1.称取DSPC、DSPE-PEG2000分别溶于CHCl 3中，ICG分别溶于甲醇溶液中，使其母液浓度分别为20mg/ml、18mg/ml、2mg/ml。
2.分别取DSPC、DSPE-PEG2000母液538μl、236μl加入试管中，并加入100μlICG，将混合溶液于65℃水浴加热并充分混匀，在涡旋器上涡旋，同时向试管中充入速率适中且流速稳定的氮气，直至CHCl 3溶液挥发完全，试管内无液体残留。用封口膜将试管口封口，并用利器在封口膜上戳孔，保证试管内气体可与外界连通，将试管置于真空器皿中抽真空3h，使试管中的CHCl 3有机溶剂挥发完全。
3.在65℃水浴条件下加入5ml Tris缓冲液(pH＝7.4)对薄膜进行水化，待试管壁上的脂质膜完全脱落后，将试管置于超声清洗机中(水温65℃)水浴超声3-5min，直至形成透明澄清溶液。配制Tris缓冲液2L，通过透析(MWCO 3500DA)除去未装载的ICG。
4.使用西林瓶分装，加盖抽真空1h至清弹瓶身未见气泡产生，连续3次充全氟丙烷，造影剂MB-ICG制备完成，4℃避光保存。
5.微泡的使用(摇泡)：银泵调和机中振荡45s后，PBS重悬置于冰上保存使用。
6.将微泡滴加到载玻片上，并置于共聚焦显微镜下观察微泡的形态和大小，结果如图1所示，从图1可以看出，微泡粒径均匀，大小约为20μm。
7.将微泡前体溶液(未摇泡前)和微泡溶液(摇泡后)进行光声成像、超声成像和近红外二区荧光成像，结果如图2所示，从图2中可以发现微泡前体溶液的光声信号比较强，近红外二区信号比较弱，没有超声成像信号；微泡溶液光声信号比较弱，近红外二区信号比较强，出现了很强的超声成像信号。接着我们采用超声波将微泡击破，发现击破后的溶液光声信号变强，近红外二区信号变弱，超声成像信号变弱；继续将该溶液摇泡处理，发现重新摇泡后光声信号变弱，近红外二区信号变强，超声成像信号变强。
以上所述仅为本发明的具体实施方式，不是全部的实施方式，本领域普通技术人员通过阅读本发明说明书而对本发明技术方案采取的任何等效的变换，均为本发明的权利要求所涵盖。

Claims (10)

  1. 一种多模态微泡造影剂，其特征在于，由以下原料制备而成：磷脂、吲哚菁绿；
    所述磷脂和吲哚菁绿的质量比为(20-1000)：1。
  2. 根据权利要求1所述的多模态微泡造影剂，其特征在于，所述磷脂和吲哚菁绿的质量比为200：1。
  3. 根据权利要求1或2所述的多模态微泡造影剂，其特征在于，所述磷脂的结构包含12～24个碳的碳链以及磷脂酰胆碱、磷脂酰基乙醇胺、磷脂酸和磷脂酰基甘油中的至少一种。
  4. 根据权利要求3所述的多模态微泡造影剂，其特征在于，所述磷脂包括1，2-二硬脂酰基-sn-甘油基-3-磷酸胆碱(DSPC)、1，2-二棕榈酰基-sn-甘油基-3-磷脂酰胆碱(DPPC)、1，2-二棕榈酰基-sn-甘油基-3-磷脂酸(DPPA)、二硬脂酰磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG2000)、二硬脂酰磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG5000)中的至少一种；优选为1，2-二硬脂酰基-sn-甘油基-3-磷酸胆碱(DSPC)、二硬脂酰磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG2000)的组合。
  5. 权利要求1-4任一项所述的多模态微泡造影剂的制备方法，其特征在于，包括以下步骤：
    (1)分别配制一定浓度的磷脂溶液和吲哚菁绿溶液；
    (2)将磷脂溶液和吲哚菁绿溶液加入容器中，在一定温度下加热并充分混匀，涡旋，同时向容器中充入氮气，直至溶液挥发完全；将容器封口同时保证容器内气体可与外界连通，将容器进行抽真空使容器中的溶剂挥发完全；
    (3)在一定温度下加入Tris缓冲液对薄膜进行水化，待容器壁上的脂质膜完全脱落后，对其进行超声直至形成透明澄清溶液，然后除去未装载的吲哚菁绿；
    (4)将步骤(3)中得到的溶液抽真空至轻弹容器瓶身未见气泡产生，然后连续多次充惰性物质制备得到所述多模态微泡造影剂。
  6. 根据权利要求5所述的制备方法，其特征在于，步骤(1)中所述磷脂溶液的浓度为1-20mg/ml；
    步骤(1)中所述吲哚菁绿溶液的浓度为0.1-10mg/ml。
  7. 根据权利要求5所述的制备方法，其特征在于，步骤(2)中所述磷脂溶液和吲哚菁绿溶液的体积比为(0.1-100)：1。
  8. 根据权利要求5所述的制备方法，其特征在于，步骤(3)中所述温度为20-100℃；
    优选地，所述Tris缓冲液的浓度为0.01-0.2mol/L，pH＝7.4。
  9. 根据权利要求5所述的制备方法，其特征在于，步骤(4)中所述惰性物质包括空气、 氮气、二氧化碳、氟碳烃气体、C5-C12氟碳烃液体；
    优选地，步骤(4)中所述充惰性物质的次数为1-20次。
  10. 权利要求1-4任一项所述的多模态微泡造影剂作为荧光成像剂、超声成像造影剂、光声成像剂的应用。
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