Name: in vitro and in vivo delivery of magnetic nanoparticle hyperthermia using a custom-built delivery system
Uploaded: 2020-07-02T14:30:00
Description: Watch this Scientific Journal Video about In Vitro and In Vivo Delivery of Magnetic Nanoparticle Hyperthermia Using a Custom-Built Delivery System at JoVE.com

该研究由资助号资助：NCI P30 CA023108和NCI U54 CA151662。

达特茅斯学院动物护理和使用计划由美国实验动物护理认证协会（iAAALAC）认可，并遵守所有UDSA和NIH（实验动物福利办公室）指南和法规。所有体内研究均获得达特茅斯学院机构动物护理和使用委员会（IACUC）的批准。安乐死程序遵守 2020 年 AVMA 动物 安乐死指南。
1. 系统的仪表/设计
<ol><li>将定制的AMF天线（线圈）设计为闭环，选择形状以创建所需的磁场。使用发电机...

<ol>
	<li>Chen, X., Tan, L., Liu, T., Meng, X. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Micro-Nanomaterials+for+Tumor+Microwave+Hyperthermia:+Design,+Preparation,+and+Application.">Micro-Nanomaterials for Tumor Microwave Hyperthermia: Design, Preparation, and Application.</a> Current Drug Delivery. 14 (3), 307-322 (2016).</li><li>Luo, W., 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=Effects+of+radiofrequency+ablation+versus+other+ablating+techniques+on+hepatocellular+carcinomas:+A+systematic+review+and+meta-analysis.">Effects of radiofrequency ablation versus other ablating techniques on hepatocellular carcinomas: A systematic review and meta-analysis.</a> World Journal of Surgical Oncology. 15 (1), 126 (2017).</li><li>Ter Haar, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Heat+and+sound:+Focused+ultrasound+in+the+clinic.">Heat and sound: Focused ultrasound in the clinic.</a> International Journal of Hyperthermia. 31 (3), 223-224 (2015).</li><li>Salunkhe, A. 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R., Mohammad, F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Magnetic+nanomaterials+for+hyperthermia-based+therapy+and+controlled+drug+delivery.">Magnetic nanomaterials for hyperthermia-based therapy and controlled drug delivery.</a> Advanced Drug Delivery Reviews. 63 (9), 789-808 (2011).</li><li>Stigliano, R. V., 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=Mitigation+of+eddy+current+heating+during+magnetic+nanoparticle+hyperthermia+therapy.">Mitigation of eddy current heating during magnetic nanoparticle hyperthermia therapy.</a> International Journal of Hyperthermia. 32 (7), 735-748 (2016).</li><li>Johannsen, 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=Clinical+hyperthermia+of+prostate+cancer+using+magnetic+nanoparticles:+Presentation+of+a+new+interstitial+technique.">Clinical hyperthermia of prostate cancer using magnetic nanoparticles: Presentation of a new interstitial technique.</a> International Journal of Hyperthermia. 21 (7), 637-647 (2005).</li><li>Horsman, M. R., Overgaard, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Hyperthermia:+a+Potent+Enhancer+of+Radiotherapy.">Hyperthermia: a Potent Enhancer of Radiotherapy.</a> Clinical Oncology. 19 (6), 418-426 (2007).</li><li>Petryk, A. A., Giustini, A. J., Gottesman, R. E., Kaufman, P. A., Hoopes, P. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Magnetic+nanoparticle+hyperthermia+enhancement+of+cisplatin+chemotherapy+cancer+treatment.">Magnetic nanoparticle hyperthermia enhancement of cisplatin chemotherapy cancer treatment.</a> International Journal of Hyperthermia. 29 (8), 845-851 (2013).</li><li>Peeken, J. C., Vaupel, P., Combs, S. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Integrating+hyperthermia+into+modern+radiation+oncology:+What+evidence+is+necessary.">Integrating hyperthermia into modern radiation oncology: What evidence is necessary.</a> Frontiers in Oncology. 7, 132 (2017).</li><li>Petryk, A. A., Giustini, A. J., Gottesman, R. E., Trembly, B. S., Hoopes, P. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Comparison+of+magnetic+nanoparticle+and+microwave+hyperthermia+cancer+treatment+methodology+and+treatment+effect+in+a+rodent+breast+cancer+model.">Comparison of magnetic nanoparticle and microwave hyperthermia cancer treatment methodology and treatment effect in a rodent breast cancer model.</a> International Journal of Hyperthermia. 29 (8), 819-827 (2013).</li><li>Stigliano, R. V., Shubitidze, F., Petryk, A. A., Tate, J. A., Hoopes, P. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Magnetic+nanoparticle+hyperthermia:+predictive+model+for+temperature+distribution.">Magnetic nanoparticle hyperthermia: predictive model for temperature distribution.</a> Energy-based Treatment of Tissue and Assessment VII. 8584, 858410 (2013).</li><li>Dewhirst, M., Viglianti, B. L., Lora-Michiels, M., Hoopes, P. J., Hanson, M. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Thermal+dose+requirement+for+tissue+effect:+experimental+and+clinical+findings.">Thermal dose requirement for tissue effect: experimental and clinical findings.</a> Thermal Treatment of Tissue: Energy Delivery and Assessment II. 4954, 37 (2003).</li><li>Duval, K. E. A., 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=Immunogenetic+effects+of+low+dose+(CEM43+30)+magnetic+nanoparticle+hyperthermia+and+radiation+in+melanoma+cells.">Immunogenetic effects of low dose (CEM43 30) magnetic nanoparticle hyperthermia and radiation in melanoma cells.</a> International Journal of Hyperthermia. 36, 37-46 (2019).</li><li>Giustini, A. J., Petryk, A. A., Cassim, S. M., Tate, J. A., Baker, I., Hoopes, P. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Magnetic+Nanoparticle+Hyperthermia+in+Cancer+Treatment.">Magnetic Nanoparticle Hyperthermia in Cancer Treatment.</a> Nano LIFE. 01, 17-32 (2010).</li><li>Hoopes, P. J., 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=Intratumoral+iron+oxide+nanoparticle+hyperthermia+and+radiation+cancer+treatment.">Intratumoral iron oxide nanoparticle hyperthermia and radiation cancer treatment.</a> Thermal Treatment of Tissue: Energy Delivery and Assessment IV. 6440, (2007).</li><li>Semiatin, S. L., Zinn, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Coil+design+and+fabrication+basic+design+and+modifications.">Coil design and fabrication basic design and modifications.</a> Heat Treating. , 32-41 (1988).</li><li>Maxwell, J. 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该系统的设计和实施提供了进行准确和可重现的体外和体内磁性纳米颗粒热疗实验的能力。至关重要的是，该系统的设计使AMF频率和场强与磁性纳米颗粒类型，浓度以及所需的组织位置和温度充分匹配。此外，实时精确监测温度对于安全和计算准确的热剂量（43 °C/CEM 下的累积当量分钟）至关重要。如图1所示，探头的放置允许实时监测热剂量和核心体温，如图<strong class="xfig...

热疗历来用于癌症治疗，无论是单独使用还是与其他治疗联合使用。尽管它有很长的使用历史，但提供这种治疗的最有利方法仍在争论中，并且取决于疾病部位和位置。热疗方法包括微波、射频、聚焦超声、激光和金属纳米颗粒（如金或氧化铁）1，2，3，4。这些输送方法可以导致从发烧水平到数百摄氏度的一系列治疗温度。热疗的生物学效应主要取决于使用的温度和治疗的持续时间5。对于这份手稿和目的，我们专注于磁性纳米颗粒热疗（mNPH）。该方法允许使用无毒、FDA批准的氧化铁纳米颗粒进行集中，局部，良好监测和控制的温度变化。
其他热疗方式的一个缺陷是缺乏精确的细胞靶向;热疗没有固有的高治疗比例，因此，仔细的测温和靶向是必要的6.mNPH允许全身或肿瘤内注射mNPs，仅在mNPs所在的位置产生热量，从而直接针对肿瘤进行治疗。当磁性纳米颗粒位于细胞内部或外部时，mNPH可能有效。对于癌症治疗，mNPH的一般概述是注射磁性纳米颗粒（肿瘤内或静脉内），然后施加交变磁场，使纳米颗粒磁极不断重新排列，导致与纳米颗粒相关的细胞和组织的局部加热7，8.通过调整纳米颗粒的体积和交变磁场（AMF）的频率/强度，可以仔细控制组织内产生的温度。
这种治疗在靠近体表的肿瘤中效果很好，因为更深的肿瘤需要更强的AMF，因此涡流加热的风险增加9。有证据表明热疗在临床上被用作单一疗法，然而，通常热疗与放射治疗或化疗相结合，导致更有针对性的抗癌作用10，11，12。热疗与放疗联合使用的临床证据在先前的出版物13中进行了回顾。我们的实验室使用mNPH方法12，14，15成功治疗了各种动物，从小鼠到猪和自发性犬癌。该方案专为那些有兴趣研究局部热疗效果的人而设计，无论是单独使用还是与其他疗法联合使用。
热疗最重要的因素之一是能够实时测量和理解传递到靶标/肿瘤组织的热剂量。计算和比较剂量的标准方法是通过演示在43°C下加热的累积等效分钟数;该算法允许比较独立于输送系统、最高和最低温度（在特定范围内）和加热/冷却参数5，16 的剂量。CEM计算最适合39-57°C之间的温度5。例如，在我们进行的一些研究中，我们选择了CEM43 30的热剂量（即在43°C下30分钟）。选择这种剂量使我们能够在体外观察安全，有效的免疫遗传效应，无论是单独使用还是与单剂量辐射结合使用17。
对于磁性纳米颗粒热疗，在构建适当的输送系统时需要考虑几个因素。仪器设计包括重要的安全因素，例如使用冷却器来确保磁场输送设备即使在高功率下运行时也能保持冷却，以及故障安全程序，如果所有温度、功率评估和控制系统尚未激活，则防止系统打开。此外，对于体内和体外情况，需要考虑一些重要的生物学因素。使用培养细胞时，有必要在生长培养基中处理并保持一致的活温度，以避免可能影响结果的生理变化。对于单个纳米颗粒类型，在计算基于AMF的加热参数时，了解比吸收率（SAR）非常重要。同样，了解细胞和组织中的mNP / Fe浓度对于实现所需的加热是必需的也很重要。体内方法需要更加注重细节，因为在治疗期间必须将动物保持在麻醉下，并且在整个治疗过程中动物的核心体温保持在正常水平。允许动物的体温下降，就像在麻醉下发生的那样，会影响整体结果，相对于被治疗组织的热剂量。
在这篇手稿中，我们讨论了用于设计和构建多功能磁性纳米颗粒热疗系统的方法，以及需要考虑的重要使用因素。所描述的系统允许稳健、一致、生物学上适当、安全和控制良好的磁性纳米颗粒热疗输送。最后，应该注意的是，我们进行的mNPH研究通常涉及其他疗法，例如放疗，化学疗法和免疫疗法。为了使这些结果有意义，重要的是要确定传递的热量如何影响其他方式的功效和/或安全毒性（反之亦然）以及动物的健康。由于这个原因以及前面提到的剂量学和治疗情况，必须严格注意磁性纳米颗粒热疗的剂量精度以及连续的核心和目标温度测量。该协议的目标是为输送安全有效的磁性纳米颗粒热疗提供一种简单，一致的方法和描述。

<table>
	<tbody>
		<tr>
			<td>.25% Trypsin</td>
			<td>Corning</td>
			<td>45000-664</td>
			<td>available from many companies</td>
		</tr>
		<tr>
			<td>1.5 mL tubes</td>
			<td>Eppendorf</td>
			<td>Eppendorf 22363204</td>
			<td>available from many companies</td>
		</tr>
		<tr>
			<td>B16F10 murine melanoma cells</td>
			<td>American Type Culture Collection</td>
			<td>CRL-6475</td>
			<td></td>
		</tr>
		<tr>
			<td>C57/Bl6 mice</td>
			<td>Charles river</td>
			<td>027C57BL/6</td>
			<td>6-week-old female mice</td>
		</tr>
		<tr>
			<td>Chiller</td>
			<td>Thermal Care</td>
			<td>NQ 5 series</td>
			<td>chiller that cools the coil</td>
		</tr>
		<tr>
			<td>Coolant fluid</td>
			<td>Dow Chemical Company</td>
			<td>Dowtherm SR-1</td>
			<td>antenna cooling fluid</td>
		</tr>
		<tr>
			<td>Fetal Bovine serum</td>
			<td>Hyclone</td>
			<td>SH30071</td>
			<td>available from many companies</td>
		</tr>
		<tr>
			<td>fiber optic probes, software and chassis</td>
			<td>FISO</td>
			<td></td>
			<td>FISO evolution software used to read the temperatures</td>
		</tr>
		<tr>
			<td>IR camera</td>
			<td>Flir</td>
			<td></td>
			<td>infrared camera to monitor unintentional heating</td>
		</tr>
		<tr>
			<td>iron oxide nanoparticles</td>
			<td>micromod Partikeltechnologie GmbH</td>
			<td>Bionized NanoFerrite</td>
			<td>dextran coated iron oxide nanoparticles</td>
		</tr>
		<tr>
			<td>mouse coil, solenoid</td>
			<td>Fluxtrol</td>
			<td>custom built</td>
			<td></td>
		</tr>
		<tr>
			<td>penicillin/streptomycin</td>
			<td>Corning</td>
			<td>45000-652</td>
			<td>available from many companies</td>
		</tr>
		<tr>
			<td>RF generator</td>
			<td>Huttinger</td>
			<td>TIG 10/300</td>
			<td>power source</td>
		</tr>
		<tr>
			<td>RPMI media</td>
			<td>Corning</td>
			<td>45000-396</td>
			<td>available from many companies</td>
		</tr>
	</tbody>
</table>

in vitro and in vivo delivery of magnetic nanoparticle hyperthermia using a custom-built delivery system

热疗长期以来一直用于治疗癌症。技术从热铁棒的肿瘤内插入到全身递送的肿瘤抗体靶向磁性纳米颗粒，温度从39°C（发烧水平）到1，000°C（电灼），治疗时间从几秒钟到几小时不等。温度-时间关系（热剂量）决定了高热剂量导致组织消融和低热剂量导致亚致死效应的效果，例如血流量增加、药物积累和免疫刺激。目前最有前途的医学疗法之一是磁性纳米颗粒热疗（mNPH）。该技术涉及激活磁性纳米颗粒，该纳米颗粒可以通过非侵入性，无毒的交变磁场进行全身或肿瘤内递送。磁性纳米颗粒的大小、构造和关联以及磁场的频率和场强是主要的加热决定因素。我们开发了先进的仪器和技术，用于在大型和小型动物模型和培养细胞中提供可重复的磁性纳米颗粒热疗。这种方法在多个位置使用连续的实时温度监测，允许将明确定义的热剂量输送到目标组织（肿瘤）或细胞，同时限制非目标组织加热。精确控制和监测多个站点的温度，并使用行业标准算法（43 °C /CEM43 下的累积等效分钟数），可以准确测定和量化热剂量。我们的系统允许各种温度、热剂量和生物效应，是通过商业收购和内部工程和生物学开发相结合而开发的。该系统已经过优化，允许在离体、体外和体内技术之间快速转换。该协议的目标是演示如何设计，开发和实施有效的技术和系统，以提供可重复和准确的磁性纳米颗粒治疗（mNP）热疗。

体外研究 只有当磁性纳米颗粒/铁和AMF的量和浓度适当匹配时，细胞才能达到并保持所需的温度和热剂量。当使用磁性纳米颗粒在体外（和体内）加热细胞时，应该注意的是，为了在具有内化磁性纳米颗粒的细胞中实现热疗，需要特定水平的细胞内mNP / Fe，并且mNP负载细胞的数量和接近度将是必要的。如果靶细胞/组织中的mNP/Fe水平足以达到加热效果，则可以调节磁场频率和强度以达...

Watch this Scientific Journal Video about In Vitro and In Vivo Delivery of Magnetic Nanoparticle Hyperthermia Using a Custom-Built Delivery System at JoVE.com

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

该协议提供了使用复杂的输送和监测系统准确输送磁性纳米颗粒热疗所需的技术和方法。

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

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医学

Multi-modal Imaging of Angiogenesis in a Nude Rat Model of Breast Cancer Bone Metastasis Using Magnetic Resonance Imaging, Volumetric Computed Tomography and Ultrasound

利用磁共振成像，容积电脑断层扫描及超音波的裸鼠乳腺癌骨转移大鼠模型血管生成的多模态成像

Angiogenesis is an essential feature of cancer growth and metastasis formation. In bone metastasis, angiogenic factors are pivotal for tumor cell ...

Intramyocardial Cell Delivery: Observations in Murine Hearts

心肌内细胞交货：观察在小鼠心脏

Previous studies showed that cell delivery promotes cardiac function amelioration by release of cytokines and factors that increase cardiac tissue ...

Slow-release Drug Delivery through Elvax 40W to the Rat Retina: Implications for the Treatment of Chronic Conditions

通过40W的Elvax缓释给药的大鼠视网膜：对慢性疾病的治疗

Diseases of the retina are difficult to treat as the retina lies deep within the eye. Invasive methods of drug delivery are often needed to treat these ...

Intubation-mediated Intratracheal (IMIT) Instillation: A Noninvasive, Lung-specific Delivery System

Intubation-mediated Intratracheal IMIT Instillation: A Noninvasive, Lung-specific Delivery System

插管介导气管内（IMIT）灌输：一种无创，龙专用输送系统

Respiratory disease studies typically involve the use of murine models as surrogate systems. However, there are significant physiologic differences ...

Intrauterine Telemetry to Measure Mouse Contractile Pressure In Vivo

Intrauterine Telemetry to Measure Mouse Contractile Pressure In Vivo

宫内遥测来衡量鼠标收缩压力<em&gt;在体内</em

A complex integration of molecular and electrical signals is needed to transform a quiescent uterus into a contractile organ at the end of pregnancy. ...

Depletion of Mouse Cells from Human Tumor Xenografts Significantly Improves Downstream Analysis of Target Cells

从人类肿瘤异种移植的小鼠细胞的消耗显着改善靶细胞下游分析

The use of in vitro cell line models for cancer research has been a useful tool. However, it has been shown that these models fail to reliably mimic ...

Using Multi-fluorinated Bile Acids and In Vivo Magnetic Resonance Imaging to Measure Bile Acid Transport

Using Multi-fluorinated Bile Acids and In Vivo Magnetic Resonance Imaging to Measure Bile Acid Transport

使用多氟化胆汁酸和<em&gt;在体内</em&gt;磁共振成像来衡量胆汁酸运输

Along with their traditional role as detergents that facilitate fat absorption, emerging literature indicates that bile acids are potent signaling ...

Optimized LC-MS/MS Method for the High-throughput Analysis of Clinical Samples of Ivacaftor, Its Major Metabolites, and Lumacaftor in Biological Fluids of Cystic Fibrosis Patients

经优化的 LC/ms 方法对囊性纤维化患者 Ivacaftor 及其主要代谢物和 Lumacaftor 的高通量分析

Defects in the cystic fibrosis trans-membrane conductance regulator (CFTR) are the cause of cystic fibrosis (CF), a disease with life-threatening ...

Improved Method for the Establishment of an In Vitro Blood-Brain Barrier Model Based on Porcine Brain Endothelial Cells

Improved Method for the Establishment of an In Vitro Blood-Brain Barrier Model Based on Porcine Brain Endothelial Cells

一种基于猪脑内皮细胞的体外血脑屏障模型的改进方法

The aim of this protocol presents an optimized procedure for the purification and cultivation of pBECs and to establish in vitro blood-brain barrier (BBB) ...