This research is funded by an operating grant from the Canadian Institutes of Health Research (CIHR) to C.A. and D.A.J. The authors acknowledge the Canadian Foundation for Innovation and Princess Margaret Cancer Foundation for funding the STTARR research facility that enables the imaging and therapy research components of this work.

1.脂质体制备<ol><li>溶解脂质1,2- Dipalmitoyl- SN -glycero -3-磷酸胆碱（DPPC），1-硬脂酰-2-羟基- SN -glycero -3-磷脂酰胆碱（MSPC或S-溶血PC）和N - （羰基甲氧基聚乙二醇2000）-1,2- distearoyl- SN -glycero -3-磷酸（MPEG 2000 -DSPE）的氯仿。例如，对于准备以10ml HTLC的，称出314.4毫克DPPC，39.4毫克MSPC，和83.9毫克的mPEG 2000 -DSPE成琥珀色玻璃小瓶中。然后，溶解脂质在2毫升氯仿和加热小瓶30秒在60℃的水浴中。 </li><li>除去使用旋转蒸发器将氯仿。放置在真空高压O / N所产生的脂质薄膜。 </li><li> 10 ml的HTLC的，水合用5ml 0.1N Tris缓冲液（pH7.4）中1小时的脂质膜。与此同时，称量出162.4毫克1,2- dipalmitoyl- SN -glycero -3-磷酸甘油（DPPG）类脂和100mg顺铂粉末和水合物瓦特第i 5 ml的0.1N含30％乙醇（pH7.4）中1小时的Tris缓冲液中。 </li><li>对于钆HTLC制剂，称出DPPG脂质和10mg CDDP粉末的相同的量，然后用2.5毫升的Gd-HP-DO3A溶液（279.3毫克/毫升）加2.5含30％乙醇毫升0.1N Tris缓冲液水合（ pH7.4）中1小时。期间水合，该混合物必须保持在琥珀色小瓶中，并放置在热板上在70℃下在恒定搅拌下和涡旋每10分钟。 </li><li>结合脂质混合物和脂质药物混合物中，并再水合1小时。涡每次15-20分钟。 </li><li>组装10毫升挤出机的两个堆栈为200nm的聚碳酸酯过滤器。挤出机的thermobarrel连接到循环水浴在70℃，挤出机连接到一个压缩氮气罐。 </li><li>立即水合后，将混合物转移到挤出机腔室。打开氮气流（设定压力至200psi）通过膜挤出脂质体。收集liposomES在50ml管。保持管中的热水浴（70℃）在任何时候都在挤出过程。重复此过程5次。 </li><li>拆卸挤出机改为两叠100 nm的聚碳酸酯过滤器。重新组装挤出机压力设为400磅。重复步骤5，除了挤出脂质体10次。从最终挤出的样品收集到15毫升管。 </li><li>降温的脂质体至RT，并离心机在1000×g离心3分钟以沉淀不溶CDDP。 </li><li>透析脂质体O / N对0.9％的盐水中透析管与15000分子量截留（MWCO）在无菌条件下。 </li><li>稀释10微升在990微升蒸馏水中的脂质体。使用动态光散射来测量HTLC和钆HTLC的尺寸分布。进行3次测量各10次。 </li><li>稀释40微升3,960微升蒸馏水脂质体。使铂和钆5-6标准溶液在0.1至20微克/毫升的浓度范围。使用电感耦合等离子体原子发射光谱仪（ICP-AES）在3个不同的波长测定铂和钆的浓度。进行3次测量在每个波长平均结果。 </li><li>确定凝胶来使用差示扫描热量计（DSC）的HTLC脂质体制剂的液晶相转变温度（T M）。负载5-10毫克HTLC成DSC盘中，并使用空盘作为参比。使用5℃/分钟的扫描速率斜坡上升的温度从0℃至60℃。 </li><li>包裹脂质体中铝箔防止光曝光，并储存于4℃。 </li></ol> 2.从脂质体体外释放 <ol><li>准备离心柱。 <ol><li>孵育在400ml 0.9％的盐水50个克凝胶过滤珠在RT 3-4小时。卷起一块玻璃棉，湿用0.9％的盐水，将其放入1毫升注射器的尖端。按玻璃棉以填充约注射器的0.05-0.1毫升。使用玻璃吸管逐渐添加约1ml的凝胶过滤介质进入注射器。 </li><li>将注射器入15ml试管并离心在1000×g离心3分钟。取出旋转柱，并放入15毫升管。 </li></ol></li><li>样品400微升HTLC或Gd-HTLC成8 1英钱玻璃小瓶中并在任一37℃或42℃孵育在恒温水浴中。取出一个小瓶在每个时间点（即，5，15，30和60分钟），并立即将其置于冰上。 </li><li>加入100微升的0.9％盐水到准备好的离心柱，然后孵育（对照）前添加100μl的HTLC或Gd-HTLC的或孵化的水浴到离心柱后。离心在1000×g离心3分钟。从管中取出注射器和稀释在管对于ICP-AES分析的溶液。 </li></ol> 3.颈椎植入皮下异种瘤<ol><li>所有的动物研究，根据批准的大学健康网络的动物保健委员会（UHN）动物使用的协议进行的。 </li><li>请在生物安全柜（BSC）的所有动物研究。高压灭菌所有手术工具的任何手术前。每个手术后，擦拭用70％乙醇的外科手术工具和消毒用热珠灭菌一次。 </li><li>对于安乐死，将动物放在一个绝缘的CO 2室中，然后执行颈椎脱位。 </li><li>对于使用100％的氧气全身麻醉，用5％异氟烷诱导和维持2％。为了确保麻醉深度，施加压力钳的足垫掌面，观察动物反应。敷眼润滑剂，以防止干燥，而在麻醉下。 </li><li>对于已经经历手术的动物，放置在一个干净笼子的动物没有其他动物的公司。监视直到有足够的意识正在苏醒。 </li><li>文化在ME-180细胞中的α-极小必需培养基（α-MEM），补充有10％胎牛血清（FBS）和抗生素。 </li><li>收获细胞，并保持细胞的完全培养基接种前。计数使用血球细胞。 </li><li>每个接种供体小鼠承担肌肉注射（IM）ME-180（人宫颈癌细胞）肿瘤。 注:生长在即时通讯站点，以便确保良好的血管瘤的发展被选择。购买雌性SCID小鼠（6〜8周龄，约20克）从内部养殖基地。 <ol><li>麻醉雌性SCID小鼠和注射1×10 6个ME-180细胞进入后肢的腓肠肌用27G的针。 </li><li>使用卡尺，直到肿瘤达到9-12毫米，其最大尺寸测量肿瘤的大小。终止研究如果肿瘤已经超过12mm时，或者如果肿瘤块损害正常行为，行走，食物和水的摄入。 </li></ol></li><li>植入肿瘤块从供体小鼠到受体小鼠。 <ol><li>麻醉用5％异氟烷供体小鼠。使用麻醉下颈椎脱臼安乐死鼠标。取下供体小鼠供体肿瘤。切肿瘤为2-3毫米的3立方米的碎片。 </li><li>麻醉，用5％异氟烷接受者小鼠。注入0.5毫克100微升/毫升昔康皮下手术前。适用的碘手术擦洗溶液，然后70％的乙醇，最后碘溶液的剃光皮肤上。剃须的受体小鼠的左后肢。做一个切口处的皮肤的水平。将一个供体肿瘤块皮下通过切口。关闭使用1-2伤口剪辑（S）的切口。 </li><li>植入后取下夹子3-5天。皮下肿瘤需要使用基于激光的加热设置。 </li><li>允许肿瘤的加热处理之前生长2-3周。 </li></ol></li></ol> 4.设计，设备与供应一个形激光传输照明的体内暖气布莱和校准<ol><li>使用763纳米二极管激光器耦合到使用光纤的共形照明器实现组织加热。 <ol><li>照明提供了异种移植瘤的均匀表面的激光照射。它由含有三个零距离接触光积分腔室球与一个腔室中的中间（直径16mm）和图2的小室在任一侧（16毫米长和5毫米高反射材料30×20×17毫米的块的在直径）（ 图1）。 </li><li>为了让光从一个腔室传递到另一个，两个小直径5毫米的孔，​​小的外室和较大的中间室之间切割。光从激光输送到使用400微米的切断端光纤连接到通过一个600微米的直径的孔传递到腔室中的激光的外腔室。 </li><li>由于光的int性质eraction与腔室壁，光递送到的小室中的一个在空间上均匀化之后，通过内部端口进入较大的腔室，其中它是进一步空间上均匀化。光然后退出上中间室的直径10毫米的端口。 </li></ol></li><li>校准照明光传输相对于采用NIST的激光功率设置校准50毫米积分球测量的输出功率。 <ol><li>计算使用基于肿瘤的简化几何Monte Carlo模拟的光分布的肿瘤。产生在写入用市售的计算软件包和基座上的光传输蒙特卡洛模拟在Jacques等14的多层组织的标准代码的自定义算法的蒙特卡洛代码。 </li><li>模拟肿瘤为半球躺在平皮肤线的直径在皮肤表面和一个匹配的7毫米的平均肿瘤尺寸，他飞行的5毫米。表面通过随机发射的光子在整个暴露的半球和直接在球的中心模型均匀照明。 </li><li>使用的光学性能，包括吸收，μ 一个 = 0.025毫米-1，散射，μS = 10个毫米-1，各向异性因子克= 0.9和折射率，n = 1.4。在计算中使用百万光子。 </li><li>执行前，任何在体内的加热实验初始校准后没有进一步的修改，这些测量。 </li></ol></li></ol>使用自定义设计的激光室设置肿瘤的5形加热<ol><li>连接一个激光光纤到激光装置上，另一端向所述照射器的一端。 </li><li>麻醉，用5％异氟烷的动物。将一个27G的注射导管插入侧尾静脉鼠标。插入一个22克导管进入肿瘤的中心。将光纤温度公关OBE入空心导管监测温度的变化。 </li><li>覆盖与照明器（ 图2）整个肿瘤。首先将电源为0.8-1 W.打开激光，等待温度上升。通过手动调节0.1-0.8 W之间的激光功率维持肿瘤的在42℃的温度</li></ol> 6.温度分布的评估通过磁共振温度（MRT） <ol><li>测量通过质子谐振频率偏移（PRF移）MRT 7特斯拉临床前MR成象系统 15上结合的光纤温度探针测量使用基于激光的加热设置加热肿瘤的温度分布。 </li><li>以10秒的间隔用2D-FLASH脉冲序列（回波时间4.5毫秒;重复时间156.25毫秒）取得测温图像312 x 312μm的平面分辨率和光纤的水平2毫米层厚在一个片温度亲是。 </li></ol>代理发行的七，监测<ol><li>执行Ť1 -加权成像之前和钆HTLC给药后20分钟。 </li><li>植入物2的肿瘤使用在第3上述用于植入的方法的雌性SCID小鼠的，各有一个后肢，。预热的左后肢5分钟的肿瘤在42℃在注射前的Gd-HTLC的66.3毫克/公斤的Gd-HP-DO3A和1.4毫克/千克CDDP的剂量，然后加热该肿瘤为额外的20分钟后注射。期间加热处理进行注射。使用上的右后肢肿瘤作为未加热的控制。 </li><li>获取动态磁共振图像（36×20毫米的视场的，200×200微米的面内分辨率，2毫米切片厚度; MR序列协议）来监视的Gd-HP-DO3A释放在12秒的间隔在整个20分钟后期管理钆类水滑石的，刚开始30秒前注射。 </li><li>轮廓肿瘤（加热和不加热）和肌肉体积。每个轮廓体积内计算所有体素的平均MR信号。 </li></ol>

<ol>
	<li>Maeda, H., Wu, J., Sawa, T., Matsumura, Y., Hori, K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Tumor+vascular+permeability+and+the+EPR+effect+in+macromolecular+therapeutics:+a+review.">Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review.</a> J Control Releas. 65 (1-2), 271-284 (2000).</li><li>Simard, P., Leroux, J. C., Allen, C., Meyer, O. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Liposomes+for+Drug+Delivery.">Liposomes for Drug Delivery.</a> Nanoparticles for Pharmaceutical Application. , (2007).</li><li>O'Brien, M. E. R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Reduced+cardiotoxicity+and+comparable+efficacy+in+a+phase+III+trial+of+pegylated+liposomal+doxorubicin+HCl+(CAELYX+(TM)/Doxil+(R))+versus+conventional+doxorubicin+for+first-line+treatment+of+metastatic+breast+cancer.">Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX (TM)/Doxil (R)) versus conventional doxorubicin for first-line treatment of metastatic breast cancer.</a> Ann Onco. 15 (3), 440-449 (2004).</li><li>White, S. C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Phase+II+study+of+SPI-77+(sterically+stabilised+liposomal+cisplatin)+in+advanced+non-small-cell+lung+cancer.">Phase II study of SPI-77 (sterically stabilised liposomal cisplatin) in advanced non-small-cell lung cancer.</a> Br J Cancer. 95 (7), 822-828 (2006).</li><li>Laginha, K. M., Verwoert, S., Charrois, G. J. R., Allen, T. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Determination+of+doxorubicin+levels+in+whole+tumor+and+tumor+nuclei+in+murine+breast+cancer+tumors.">Determination of doxorubicin levels in whole tumor and tumor nuclei in murine breast cancer tumors.</a> Clin Cancer Res. 11 (19), 6944-6949 (2005).</li><li>Baronzio, G. F., Hager, E. D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Hyperthermia in cancer treatment: a primer. , (2006).</li><li>Landon, C. D., Park, J. Y., Needham, D., Dewhirst, M. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Nanoscale+Drug+Delivery+and+Hyperthermia:+The+Materials+Design+and+Preclinical+and+Clinical+Testing+of+Low+Temperature-Sensitive+Liposomes+Used+in+Combination+with+Mild+Hyperthermia+in+the+Treatment+of+Local+Cancer.">Nanoscale Drug Delivery and Hyperthermia: The Materials Design and Preclinical and Clinical Testing of Low Temperature-Sensitive Liposomes Used in Combination with Mild Hyperthermia in the Treatment of Local Cancer.</a> Open Nanomed. 3, 38-64 (2011).</li><li>Koning, G. A., Eggermont, A. M., Lindner, L. H., ten Hagen, T. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Hyperthermia+and+thermosensitive+liposomes+for+improved+delivery+of+chemotherapeutic+drugs+to+solid+tumors.">Hyperthermia and thermosensitive liposomes for improved delivery of chemotherapeutic drugs to solid tumors.</a> Pharm Res. 27 (8), 1750-1754 (2010).</li><li>Viglianti, B. L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=In+vivo+monitoring+of+tissue+pharmacokinetics+of+liposome/drug+using+MRI:+illustration+of+targeted+delivery.">In vivo monitoring of tissue pharmacokinetics of liposome/drug using MRI: illustration of targeted delivery.</a> Magn Reson Me. 51 (6), 1153-1162 (2004).</li><li>Ponce, A. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Magnetic+resonance+imaging+of+temperature-sensitive+liposome+release:+drug+dose+painting+and+antitumor+effects.">Magnetic resonance imaging of temperature-sensitive liposome release: drug dose painting and antitumor effects.</a> J Natl Cancer Ins. 99 (1), 53-63 (2007).</li><li>Kong, G., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Efficacy+of+liposomes+and+hyperthermia+in+a+human+tumor+xenograft+model:+importance+of+triggered+drug+release.">Efficacy of liposomes and hyperthermia in a human tumor xenograft model: importance of triggered drug release.</a> Cancer Res. 60 (24), 6950-6957 (2000).</li><li>Yarmolenko, P. S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Comparative+effects+of+thermosensitive+doxorubicin-containing+liposomes+and+hyperthermia+in+human+and+murine+tumours.">Comparative effects of thermosensitive doxorubicin-containing liposomes and hyperthermia in human and murine tumours.</a> Int J Hyperthermia. 26 (5), 485-498 (2010).</li><li>Wang, L. H., Jacques, S. L., Zheng, L. Q. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=MCML-Monte+Carlo+modeling+of+photon+transport+in+multi-layered+tissues.">MCML-Monte Carlo modeling of photon transport in multi-layered tissues.</a> Comput Meth Prog Bio. 47, 131-146 (1995).</li><li>Rieke, V., Butts Pauly, K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=MR+thermometry.">MR thermometry.</a> J Magn Reson Imaging. 27 (2), 376-390 (2008).</li><li>Dou, Y. N., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Heat-activated+thermosensitive+liposomal+cisplatin+(HTLC)+results+in+effective+growth+delay+of+cervical+carcinoma+in+mice.">Heat-activated thermosensitive liposomal cisplatin (HTLC) results in effective growth delay of cervical carcinoma in mice.</a> J Control Release. 178, 69-78 (2014).</li><li>Lammers, T., Kiessling, F., Hennink, W. E., Storm, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Nanotheranostics+and+image-guided+drug+delivery:+current+concepts+and+future+directions.">Nanotheranostics and image-guided drug delivery: current concepts and future directions.</a> Mol Pharm. 7 (6), 1899-1912 (2010).</li><li>Lee, H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+novel+64Cu-liposomal+PET+agent+(MM-DX-929)+predicts+response+to+liposomal+chemotherapeutics+in+preclinical+breast+cancer+models.">A novel 64Cu-liposomal PET agent (MM-DX-929) predicts response to liposomal chemotherapeutics in preclinical breast cancer models.</a> Thirty-Fifth Annual CTRC-AACR San Antonio Breast Cancer Symposium. , (2012).</li></ol>

There are no disclosures.

脂质体首先在20世纪60年代作为药物递送载体携带亲水性药物在其内部的水的体积和疏水性药物内的脂质双分子层2开发。除了 ​​在治疗性应用中使用，当标记的放射性核素或装入成像造影剂的脂质体17已探索用于诊断应用。在最近几年，治疗诊断学和治疗诊断对已被进行，以提供用于图像引导的患者分层和药物输送17,18的机会。目前的研究基础上图像引导的药物递送的概念，以评估来自使用MR引导下定制设计的基于激光的加热设置热敏脂质体触发药物释放。 如上所述，水浴或加热导管有常见的是用于加热皮下肿瘤。水浴方法需要整个肢体在热瓦特浸渍亚特，导致非特异性药物释放，在整个除了肢体以释放在肿瘤部位。使用一个加热导管的需要18G的导管在肿瘤的中心放置，并已显示出以达到热稳定状态11必要加热在相对 ​​长的时间（15分钟）期间。 在本研究中，新设计的基于激光的加热装置提供了递送热量至肿瘤体积就证明了的温度分布图（图5）的MRI基于评估的共形方式。异质性在未加热的右后肢和右肢肿瘤在图5的PRF-换档图谱可能反映低信号对噪声的敏感性工件和轻微生理或加热引起的运动的附近的组合，其可以直接折衷加热和基线图像配准，而且各地的诱导领域引进的微小变化偏移磁化率的区域。此外，人们发现，热稳定状态可在提出的加热1-2分钟来实现。此外，基于点的光纤温度传感器，以保持在42℃的温度，并尽量减少温度波动允许实时调整激光功率。然而，关键是要放置光纤温度传感器中的肿瘤内的相对中心的位置。磁共振成像可以使用，以验证切口点传感器。在加热过程中，激光功率应仔细调节，以保持在42℃的温度与0.8 W的初始功率加热协议通过的Gd-HP-DO3A释放的实时监测来替代药物顺铂进行了优化。从HTLC脂质体有效释放包封的药物的翻译成改善的功效，与被加热的HTLC组产生了显著治疗ADVAN踏歌比其他治疗组和对照组16。 所述加热装置的照明器被设计成加热5-7毫米的肿瘤中的最大尺寸。照明器的设计进行修改以加热较大的肿瘤和多个光纤温度传感器在整个肿瘤体积监测温度相比于当前的单点基础的测量可以插入。此外，由于便携式装置从MR-相容材料，制成的3维磁共振温度测量可以进行，以评估在整个肿瘤体积的温度分布。 最后，基于激光的加热装置提供的热敏脂质体配制剂的临床前开发的宝贵工具。图像引导的药物递送的方法，如在本研究中所使用的，有显著潜力临床翻译和执行个性化药物的包括真实添E监测治疗的。

的实体瘤导致纳米级系统的增强的渗透性和保留（EPR）的病理生理。这导致了许多药物递送系统利用这一效果优点为目标的肿瘤组织，同时最小化的全身副作用1的开发。脂质体递送的技术已被广泛研究用于药物或成像探针2。虽然脂质体已显著降低全身毒性相比常规化疗，已经出现了在临床疗效3,4-一些改进。研究表明，该有限的功效是由于从载体4,5-缺乏药物的释放。其结果是，被激活以释放包封药物响应于外部刺激脂质体的发展已经引起相当大的关注。热疗已经采用了几十年作为一个相对安全的治疗方式对癌症病人6。因此，开发热敏脂质体与热彪作为外部触发已与显著的潜在临床翻译的逻辑组合。事实上，含lysolipid-热敏脂质体多柔比星制剂的，被称为LTSL-DOX，现在已经达到了临床评价7。 与LTSL-Dox最近的临床数据表明，协议热量传输是可以严重影响患者的预后8的关键因素。在人类中，射频，微波，激光和超声换能器被用于局部应用热疗在肿瘤部位9。在临床前研究中，需要皮下肿瘤加热，加热导管10,11和水浴12,13最经常使用的。在该手稿，介绍用于加热使用定制设计的基于激光的加热设置，这使得肿瘤体积的更适形加热皮下肿瘤的新方法。使用MR兼容马terials，设置足够小以适合小动物的MR成像器的孔内，从而允许改变组织温度的实时监测在激光加热过程中。 的MR造影剂，钆特醇（钆-HP-DO3A），被共同封装了CDDP成CDDP（HTLC），称为钆HTLC的热敏脂质体配制剂，用于实时MR图像引导下监测的热和评估活化的药物释放和加热协议的验证。我们的结果表明，基于激光的加热装置中有效地激活包封剂的释放从钆HTLC制剂而经由MR成像监测。

<table><tbody><tr><td>Rotary evaporator</td><td>Heidolph Instruments GmbH &amp;amp; Co.KG</td><td>Laborota 4000</td><td></td></tr><tr><td>High pressure extruder</td><td>Northern Lipids Inc.</td><td>T.001</td><td>10 ml thermobarrel</td></tr><tr><td>Heating circulator</td><td>VWR International LLC.</td><td>11305</td><td>Connected to extruder</td></tr><tr><td>Polycarbonate membrane filter</td><td>Whatman</td><td>110605;110606</td><td></td></tr><tr><td>Differential scanning calorimeter (DSC)</td><td>TA Instruments</td><td>Q100</td><td></td></tr><tr><td>Inductively coupled plasma-atomic emission spectrometer (ICP-AES)</td><td>PerkinElmer</td><td>Optima 7300DV</td><td></td></tr><tr><td>Zetasizer</td><td>Malvern Instruments Ltd.</td><td>Nano-ZS</td><td></td></tr><tr><td>Cell incubator</td><td>NuAire Inc.</td><td>NU-5800</td><td></td></tr><tr><td>Autoclip wound clip applier</td><td>Becton Dickinson</td><td>427630</td><td></td></tr><tr><td>Autoclip wound clip remover</td><td>Becton Dickinson</td><td>427637</td><td></td></tr><tr><td>Wound clips</td><td>Becton Dickinson</td><td>427631</td><td>9 mm</td></tr><tr><td>763 nm Laser device</td><td>Biolitec</td><td>Ceralas CD 403 laser</td><td></td></tr><tr><td>Laser probe</td><td>Thorlabs Inc.</td><td>FT400EMT</td><td>With SMA and flat cleave connectors</td></tr><tr><td>Spectralon (illuminator)</td><td>Labsphere Inc.</td><td>FAST-SL-5CMX5CM</td><td></td></tr><tr><td></td><td></td><td>CSTM-SL-5CMX5CM</td><td></td></tr><tr><td>7 Tesla prelinical magnetic resonance (MR) imaging system</td><td>Bruker Corporation</td><td>Biospec 70/30</td><td></td></tr><tr><td>Fiber optic temperature sensor</td><td>LumaSense Technologies Inc.</td><td>Luxtron FOT Lab Kit</td><td></td></tr><tr><td>Integrating sphere</td><td>Newport Corporation</td><td>819C</td><td></td></tr><tr><td>Optical power meter</td><td>Newport Corporation</td><td>1830-R</td><td></td></tr></tbody></table>

custom-designed laser-based heating apparatus for triggered release of cisplatin from thermosensitive liposomes with magnetic resonance image guidance

脂质体已被用作药物递送系统通过开发增强的渗透性和造成显著减少全身毒性保留（EPR）效果的靶向实体瘤。尽管如此，从脂质体释放包封的药物的不足限制了它们的临床疗效。温度敏感脂质体已被工程化以提供药物的位点特异性释放为了克服有限肿瘤药物生物利用度的问题。我们的实验室已经设计和开发的顺铂的热活化热敏脂质体剂型（顺铂），被称为HTLC，提供顺铂触发释放的实体肿瘤。 体内热活化递送是使用定制的基于激光的加热装置，它提供了保形加热图案在肿瘤部位证实了磁共振温度（MRT）来实现在鼠模型。一种光纤温度监视装置是用来测量在实时的温度在整个采暖期热传递的在线调整交替的激光功率。药物递送被磁共振（MR）图像引导下优化通过共封装的MR造影剂（例如，钆特醇）与顺铂入热敏脂质体作为验证加热协议，并评估肿瘤积累的装置。加热协议包括了5分钟之前HTLC施用和20分钟的加热后喷射的预热期。该加热方案导致有效释放在温水肿瘤观察到相比于未加热的肿瘤和肌肉的最高的MR信号变化的包封剂。这项研究表明基于激光的加热装置，用于临床前热敏脂质体的发展和加热协议用于药物递送的优化的MR引导验证的重要性的成功应用。

的HTLC脂质体使用的是普通的方法，包括脂质膜的形成，水化，挤出和透析制造。在涉及顺铂的步骤，应谨慎采取不暴露CDDP任何铝材，如顺铂将通过一个黑色沉积物的形成被停用。 HTLC的图示示于图3。HTLC所述的物理化学性质总结在最近发表在杂志控释 16的手稿。的钆HTLC制剂的钆和铂浓度为1.87±0.28毫克/ ml和0.10±0.02毫克/毫升。 基于激光的加热设置的照明器使用三个小，连接腔室，提供了一个均匀的光分布（±15％）的直径为10mm出口。根据激光的功率设置，功率为0.5的范围内输送到1.7瓦/厘米2，如测量d。使用校准的积分球。结果示在图4中的横截面通过肿瘤。假设1瓦的总功率，最大注量率在肿瘤的任何点为70毫瓦/厘米2。激光功率由因子2在皮肤水平相比只是肿瘤表面低于峰值注量减小。 使用基于激光的加热设置加热产生相对均匀的温度分布图，证实了该PRF移MRT（图5）。 PRF-转移轨道捷运从点源（ 即光纤温度传感器）加热前获得的绝对基线测量相对温度变化。 从MR信号分析（图6C），加热的肿瘤显示在比较最高相对信号提高到未加热的肿瘤和肌肉的Gd-HTLC，它一直保持到结束的给药后采暖期。 <img alt="图1" src="/files/ftp_upload/53055/53055fig1.jpg" /> 图发光器1的设计。 （A）外形尺寸照明的。（B）的内室尺寸。 <a href="https://www-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/53055/53055fig1large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图2" src="/files/ftp_upload/53055/53055fig2.jpg" /> 图2图示了基于激光的加热设置连同一个温度监视装置。激光纤维（蓝线）开光的照明器。一种光纤温度探头（黄线）置于肿瘤的中心通过一个22克导管监测温度变化。实时脾气ATURE读数显示在计算机屏幕上。从杂志受控 2014 版，178，69-78。16修改<a href="https://www-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/53055/53055fig2large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图3" src="/files/ftp_upload/53055/53055fig3.jpg" /> 的HTLC制剂（不按比例）的图3示意图。脂质组合物中，HTLC脂质体顺铂的浓度和尺寸示出。从杂志受控 2014 版，178，69-78。16修改<a href="https://www-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/53055/53055fig3large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图4" src="/files/ftp_upload/53055/53055fig4.jpg" /> 图4. Modelin克光线传递到肿瘤用小积分球。（A）模型显示肿瘤的正常皮下组织上面提出的原理图。红色箭头表示覆盖率和在计算初始光子的方向。照明覆盖凸起肿瘤的整个表面积。（B）的计算结果示出在肿瘤光注量分布。（C）的光注量相对于深度的横断面图，沿虚线白在（B）中所示的线。注量率在肿瘤处皮肤的深度是最大通量率的50％。 <a href="https://www-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/53055/53055fig4large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图5" src="/files/ftp_upload/53055/53055fig5.jpg" /> 通过磁共振温度图5.温度分布进行评估。＆＃160;从加热左侧肿瘤至42℃，用基于激光的加热设置产生（A）的 T2加权图像，其显示两个双侧植入肿瘤的解剖位置（B）的温度分布图，而右肿瘤仍然不加热。数据从控制 2014 版 ，178 杂志 ，69-78重新分析。16 <a href="https://www-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/53055/53055fig5large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图6" src="/files/ftp_upload/53055/53055fig6.jpg" /> 从在热活化的钆HTLC脂质体钆特醇释放的图6的MR监测:T 1 -加权的小鼠带有两个皮下ME-180的肿瘤，与一个在每个后肢MR图像（同一窗口级别应用）（ A）预注入钆类水滑石和（B）的 20分钟后注射钆HTLC的（即，在整个加热周期后）。（C）相对的MR信号变化归一动态磁共振采集鼠标中所示（A）和在第一时间点（ B）。数据表示平均值±SD表示。数据从控制 2014 版 ，178 杂志 ，69-78重新分析。16 <a href="https://www-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/53055/53055fig6large.jpg" target="_blank">请点击此处查看该图的放大版本。</a>

Watch this Scientific Journal Video about Custom-designed Laser-based Heating Apparatus for Triggered Release of Cisplatin from Thermosensitive Liposomes with Magnetic Resonance Image Guidance at JoVE

Custom-designed Laser-based Heating Apparatus for Triggered Release of Cisplatin from Thermosensitive Liposomes with Magnetic Resonance Image Guidance

的MRI兼容的定制设计的基于激光的加热装置已经开发出来，提供以激活从热敏脂质体释放剂特别在肿瘤区域皮下肿瘤的局部加热。

定制设计的基于激光的加热装置顺铂触发释放的热敏脂质体与磁共振成像制导

Liposomes have been employed as drug delivery systems to target solid tumors through exploitation of the enhanced permeability and retention (EPR) effect ...

custom-designed-laser-based-heating-apparatus-for-triggered-release

Universidad San Sebastian

Research

JoVE Journal

Bioengineering

9.0K 次观看.  University of Toronto. 的MRI兼容的定制设计的基于激光的加热装置已经开发出来，提供以激活从热敏脂质体释放剂特别在肿瘤区域皮下肿瘤的局部加热。 

视频: Custom-designed Laser-based Heating Apparatus for Triggered Release of Cisplatin from Thermosensitive Liposomes with Magnetic Resonance Image Guidance

One Minute, Sub-One-Watt Photothermal Tumor Ablation Using Porphysomes, Intrinsic Multifunctional Nanovesicles

We recently developed porphysomes as intrinsically multifunctional nanovesicles. A photosensitizer, pyropheophorbide &alpha;, was conjugated to a phospholipid and then self-assembled to liposome-like spherical vesicles. Due to the extremely high density of porphyrin in the porphyrin-lipid bilayer, porphysomes generated large extinction coefficients, structure-dependent fluorescence self-quenching, and excellent photothermal efficacy. In our formulation, porphysomes were synthesized using high pressure extrusion, and displayed a mean particle size around 120 nm. Twenty-four hr post-intravenous injection of porphysomes, the local temperature of the tumor increased from 30 &deg;C to 62 &deg;C rapidly upon one minute exposure of 750 mW (1.18 W/cm2), 671 nm laser irradiation. Following the complete thermal ablation of the tumor, eschars formed and healed within 2 weeks, while in the control groups the tumors continued to grow and all reached the defined end point within 3 weeks. These data show how porphysomes can be used as potent photothermal therapy (PTT) agents.

We developed novel intrinsic multifunctional nanovesicles called porphysomes, which have structure-dependent fluorescence self-quenching and unique photothermal properties, thus functioning as potent photothermal therapy agents. We formulated porphysomes using high pressure extrusion and investigated their photothermal therapy efficacy in a xenograft tumor model.

一分钟，小一瓦光热消融肿瘤使用Porphysomes，内在多功能纳米囊泡

We recently developed porphysomes as intrinsically multifunctional nanovesicles. A photosensitizer, pyropheophorbide &alpha;, was conjugated to a ...

科研

生物工程

Controllable Nucleation of Cavitation from Plasmonic Gold Nanoparticles for Enhancing High Intensity Focused Ultrasound Applications

In this study, plasmonic gold nanoparticles were simultaneously exposed to pulsed near-infrared laser light and high intensity focused ultrasound (HIFU) for the controllable nucleation of cavitation in tissue-mimicking gel phantoms. This in vitro protocol was developed to demonstrate the feasibility of this approach, for both enhancement of imaging and therapeutic applications for cancer. The same apparatus can be used for both imaging and therapeutic applications by varying the exposure duration of the HIFU system. For short duration exposures (10 &#181;s), broadband acoustic emissions were generated through the controlled nucleation of inertial cavitation around the gold nanoparticles. These emissions provide direct localization of nanoparticles. For future applications, these particles may be functionalized with molecular-targeting antibodies (e.g. anti-HER2 for breast cancer) and can provide precise localization of cancerous regions, complementing routine diagnostic ultrasound imaging. For continuous wave (CW) exposures, the cavitation activity was used to increase the localized heating from the HIFU exposures resulting in larger thermal damage in the gel phantoms. The acoustic emissions generated from inertial cavitation activity during these CW exposures was monitored using a passive cavitation detection (PCD) system to provide feedback of cavitation activity. Increased localized heating was only achieved through the unique combination of nanoparticles, laser light and HIFU. Further validation of this technique in pre-clinical models of cancer is necessary.

This protocol demonstrates the controllable nucleation of cavitation in gel phantoms, through simultaneous exposure to both near-infrared pulsed laser light and high intensity focused ultrasound (HIFU). The cavitation activity can then be used for enhancing imaging and/or therapeutic uses of HIFU.

等离子金纳米粒子空化的可控核增强高强度聚焦超声应用

In this study, plasmonic gold nanoparticles were simultaneously exposed to pulsed near-infrared laser light and high intensity focused ultrasound (HIFU) ...

工程学

Synthesis of Gold Nanoparticle Integrated Photo-responsive Liposomes and Measurement of Their Microbubble Cavitation upon Pulse Laser Excitation

Photo-responsive nanoparticles (NPs) have received considerable attention because of their potential in providing spatial, temporal, and dosage control over the drug release. However, most of the relevant technologies are still in the development process and are unprocurable by clinics. Here, we describe a facile fabrication of these photo-responsive NPs with commercially available gold NPs and thermo-responsive liposomes. Calcein is used as a model drug to evaluate the encapsulation efficiency and the release kinetic profile upon heat/light stimulation. Finally, we show that this photo-triggered release is due to the membrane disruption caused by microbubble cavitation, which can be measured with hydrophone.

This protocol describes a simple preparation method for gold nanoparticle integrated photo-responsive liposomes with the commercially available materials. It also shows how to measure the microbubble cavitation process of the synthesized liposomes upon the treatment of pulsed laser.

在脉冲激光激发金纳米粒子集成光电响应脂质体及其微泡空化的测量的合成

Photo-responsive nanoparticles (NPs) have received considerable attention because of their potential in providing spatial, temporal, and dosage control ...

Magnetic Resonance-Guided High Intensity Focused Ultrasound Generated Hyperthermia: A Feasible Treatment Method in a Murine Rhabdomyosarcoma Model

Magnetic resonance-guided high intensity focused ultrasound (MRgHIFU) is an established method for producing localized hyperthermia. Given the real-time imaging and acoustic energy modulation, this modality enables precise temperature control within a defined area. Many thermal applications are being explored with this noninvasive, nonionizing technology, such as hyperthermia generation, to release drugs from thermosensitive liposomal carriers. These drugs can include chemotherapies such as doxorubicin, for which targeted release is desired due to the dose-limiting systemic side effects, namely cardiotoxicity. Doxorubicin is a mainstay for treating a variety of malignant tumors and is commonly used in relapsed or recurrent rhabdomyosarcoma (RMS). RMS is the most common solid soft tissue extracranial tumor in children and young adults. Despite aggressive, multimodal therapy, RMS survival rates have remained the same for the past 30 years. To explore a solution for addressing this unmet need, an experimental protocol was developed to evaluate the release of thermosensitive liposomal doxorubicin (TLD) in an immunocompetent, syngeneic RMS mouse model using MRgHIFU as the source of hyperthermia for drug release.

Presented here is a protocol to use controlled hyperthermia, generated by magnetic resonance-guided high intensity focused ultrasound, to trigger drug release from temperature-sensitive liposomes in a rhabdomyosarcoma mouse model.

磁共振引导的高强度聚焦超声产生热疗:小鼠横纹肌肉瘤模型中的可行治疗方法

Magnetic resonance-guided high intensity focused ultrasound (MRgHIFU) is an established method for producing localized hyperthermia. Given the real-time ...

癌症研究

An Immunocompetent Murine Model for Laser Interstitial Thermal Therapy of Glioblastoma

Glioblastoma (GB), the most aggressive form of primary brain cancer, accounts for approximately half of all high-grade primary brain tumors in adults and has no cure. Laser interstitial thermal therapy (LITT) is a Food and Drug Administration (FDA)-approved treatment for GB and is used in patients who may not be candidates for conventional surgical resection. While the clinical efficacy of LITT has been established, research beyond clinical case studies and case series is limited and hindered by the lack of an established animal model. This protocol uses C57BL/6 mice and syngeneic CT2A glioma cancer cell line to closely recapitulate human GB&#160;while also using a 1064 nm Neodymium-doped Yttrium Aluminum Garnet (Nd:YAG) laser, such as is used in one of the two FDA-approved LITT systems, providing excellent pre-clinical relevance. The successful establishment of this LITT murine model will provide a valuable platform for investigating the unique features of LITT ablation and its effects on the tumor microenvironment, potentially leading to improved therapeutic strategies.

Glioblastoma is a devastating form of primary brain cancer, and laser interstitial thermal therapy is emerging as a promising alternative to conventional surgical resection for inoperable glioblastoma. This protocol describes an optimized pre-clinical mouse model that can be used to study treatment effects or adjuvant and combinatorial treatments.

Glioblastoma (GB), the most aggressive form of primary brain cancer, accounts for approximately half of all high-grade primary brain tumors in adults and ...

Microfluidic Production of Lysolipid-Containing Temperature-Sensitive Liposomes

The presented protocol enables a high-throughput continuous preparation of low temperature-sensitive liposomes (LTSLs), which are capable of loading chemotherapeutic drugs, such as doxorubicin (DOX). To achieve this, an ethanolic lipid mixture and ammonium sulfate solution are injected into a staggered herringbone micromixer (SHM) microfluidic device. The solutions are rapidly mixed by the SHM, providing a homogeneous solvent environment for liposomes self-assembly. Collected liposomes are first annealed, then dialyzed to remove residual ethanol. An ammonium sulfate pH-gradient is established through buffer exchange of the external solution by using size exclusion chromatography. DOX is then remotely loaded into the liposomes with high encapsulation efficiency (&#62; 80%). The liposomes obtained are homogenous in size with Z-average diameter of 100 nm. They are capable of temperature-triggered burst release of encapsulated DOX in the presence of mild hyperthermia (42 &#176;C). Indocyanine green (ICG) can also be co-loaded into the liposomes for near-infrared laser-triggered DOX release. The microfluidic approach ensures high-throughput, reproducible and scalable preparation of LTSLs.

The protocol presents the optimized parameters for preparing thermosensitive liposomes using the staggered herringbone micromixer microfluidics device. This also allows co-encapsulation of doxorubicin and indocyanine green into the liposomes and the photothermal-triggered release of doxorubicin for controlled/triggered drug release.

含脂脂的微流体生产-温度敏感脂质体

The presented protocol enables a high-throughput continuous preparation of low temperature-sensitive liposomes (LTSLs), which are capable of loading ...

Magnetic-, Acoustic-, and Optical-Triple-Responsive Microbubbles for Magnetic Hyperthermia and Pothotothermal Combination Cancer Therapy

The precision delivery of anti-cancer agents which aim for targeted and deep-penetrated delivery as well as a controlled release at the tumor site has been challenged. Here, we fabricate iron oxide nanoparticle shelled microbubbles (NSMs) through self-assembly, synergizing magnetic, acoustic, and optical responsiveness in one nanotherapeutic platform. Iron oxide nanoparticles serve as both magnetic and photothermal agents. Once intravenously injected, NSMs can be magnetically guided to the tumor site. Ultrasound triggers the release of iron oxide nanoparticles, facilitating the penetration of nanoparticles deep into the tumor due to the cavitation effect of microbubbles. Thereafter, magnetic hyperthermia and photothermal therapy can be performed on the tumor for combinational cancer therapy, a solution for cancer resistance due to the tumor heterogeneity. In this protocol, the synthesis and characterization of NSMs including structural, chemical, magnetic and acoustic properties were performed. In addition, the anti-cancer efficacy by thermal therapy was investigated using in vitro cell cultures. The proposed delivery strategy and combination therapy holds great promise in cancer treatment to improve both delivery and anticancer efficacies.

Presented here is a protocol for the fabrication of iron oxide nanoparticle-shelled microbubbles (NSMs) through self-assembly, synergizing magnetic, acoustic, and optical responsiveness in one nanotherapeutic platform for magnetic hyperthermia and photothermal combination cancer therapy.

磁性、声学和光学三响应性微泡，用于磁性高温和波托托热组合癌症治疗

The precision delivery of anti-cancer agents which aim for targeted and deep-penetrated delivery as well as a controlled release at the tumor site has ...

A High-Throughput Image-Guided Stereotactic Neuronavigation and Focused Ultrasound System for Blood-Brain Barrier Opening in Rodents

The blood-brain barrier (BBB) has been a major hurdle for the treatment of various brain diseases. Endothelial cells, connected by tight junctions, form a physiological barrier preventing large molecules (&#62;500 Da) from entering the brain tissue. Microbubble-mediated focused ultrasound (FUS) can be used to induce a transient local BBB opening, allowing larger drugs to enter the brain parenchyma.
In addition to large-scale clinical devices for clinical translation, preclinical research for therapy response assessment of drug candidates requires dedicated small animal ultrasound setups for targeted BBB opening. Preferably, these systems allow high-throughput workflows with both high-spatial precision as well as integrated cavitation monitoring, while still being cost effective in both initial investment and running costs.
Here, we present a bioluminescence and X-ray guided stereotactic small animal FUS system that is based on commercially available components and fulfills the aforementioned requirements. A particular emphasis has been placed on a high degree of automation facilitating the challenges typically encountered in high-volume preclinical drug evaluation studies. Examples of these challenges are the need for standardization in order to ensure data reproducibility, reduce intra-group variability, reduce sample size and thus comply with ethical requirements and decrease unnecessary workload. The proposed BBB system has been validated in the scope of BBB opening facilitated drug delivery trials on patient-derived xenograft models of glioblastoma multiforme and diffuse midline glioma.

The blood-brain barrier (BBB) can be temporarily disrupted with microbubble-mediated focused ultrasound (FUS). Here, we describe a step-by-step protocol for high-throughput BBB opening in vivo using a modular FUS system accessible for non-ultrasound experts.

高通量图像引导立体定向神经导航和聚焦超声系统，用于在啮齿动物中打开血脑屏障

The blood-brain barrier (BBB) has been a major hurdle for the treatment of various brain diseases. Endothelial cells, connected by tight junctions, form a ...

神经科学

Real-Time Magnetic Resonance Guided Focused Ultrasound for Painful Bone Metastases

Bones are one of the most common sites of cancer metastasis, which usually causes pain and impairs quality of life. Radiation therapy combined with opioids is the standard treatment for painful bone metastases. This treatment achieves effective pain control in 60&#8722;74% of patients, but limited treatment choices with limited benefits are available for recurrent or residual painful bone metastases after radiotherapy. More than 40% of patients still experience moderate to severe bone pain after reirradiation. Magnetic resonance-guided focused ultrasound (MRgFUS) combines high-intensity focused ultrasound, which achieves thermal ablation of bone metastases and subsequent pain reduction, with real-time magnetic resonance (MR) thermometry to monitor the temperature of anatomic MR images, with an accuracy of 1 &#176;C, spatial resolution of 1 mm, and temporal resolution within 3 s. As well as being increasingly used clinically for controlling metastatic bone pain, the use of MRgFUS for other diseases has also been tested. However, the use of MR software as a thermometer is the only technique available to verify the accuracy of the software and assure energy delivery. Here, we describe an efficient method of quality assurance we developed for thermal detection and energy delivery before each MRgFUS treatment and also propose a modified workflow to expedite the treatment course as well as to reduce patients&#39; pain during the procedure.

Magnetic resonance could offer real-time monitoring of the position and temperature of focused ultrasound in thermal ablation for painful bone metastases, regardless of cancer type or previous local treatments. Our innovative method of quality assurance could facilitate the application of this effective and safe treatment.

Bones are one of the most common sites of cancer metastasis, which usually causes pain and impairs quality of life. Radiation therapy combined with ...

医学

In Vitro and In Vivo Delivery of Magnetic Nanoparticle Hyperthermia Using a Custom-Built Delivery System

Hyperthermia has long been used in the treatment of cancer. Techniques have varied from the intra-tumoral insertion of hot iron rods, to systemically delivered tumor antibody-targeted magnetic nanoparticles, at temperatures from 39 &#730;C (fever-level) to 1,000 &#730;C (electrocautery) and treatment times from seconds to hours. The temperature-time relationship (thermal dose) dictates the effect with high thermal doses resulting in the tissue ablation and lower thermal doses resulting in sublethal effects such as increased blood flow, accumulation of drugs and immune stimulation. One of the most promising current medical therapies is magnetic nanoparticle hyperthermia&#160; (mNPH). This technique involves activating magnetic nanoparticles, that can be delivered systemically or intratumorally, with a non-invasive, non-toxic alternating magnetic field. The size, construct and association of the magnetic nanoparticles and the frequency and field strength of the magnetic field are major heating determinants. We have developed sophisticated instrumentation and techniques for delivering reproducible magnetic nanoparticle hyperthermia in large and small animal models and cultured cells. This approach, using continuous, real time temperature monitoring in multiple locations, allows for the delivery of well-defined thermal doses to the target tissue (tumor) or cells while limiting non-target tissue heating. Precise control and monitoring of temperature, in multiple sites, and use of the industry standard algorithm (cumulative equivalent minutes at 43 &#730;C /CEM43), allows for an accurate determination and quantification of thermal dose. Our system, which allows for a wide variety of temperatures, thermal doses, and biological effects, was developed through a combination of commercial acquisitions and inhouse engineering and biology developments. This system has been optimized in a manner that allows for the rapid conversion between ex vivo, in vitro, and in vivo techniques. The goal of this protocol is to demonstrate how to design, develop and implement an effective technique and system for delivering reproducible and accurate magnetic nanoparticle therapy (mNP) hyperthermia.

This protocol presents techniques and methodology necessary for the accurate delivery of magnetic nanoparticle hyperthermia using a sophisticated delivery and monitoring system.

使用定制的输送系统进行磁性纳米颗粒热疗的体外和体内输送

Hyperthermia has long been used in the treatment of cancer. Techniques have varied from the intra-tumoral insertion of hot iron rods, to systemically ...