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
Summary
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。
Abstract
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。
Introduction
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。
Protocol
Representative Results
Discussion
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…
Divulgations
The authors have nothing to disclose.
Acknowledgements
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.
Materials
| Rotary evaporator | Heidolph Instruments GmbH & Co.KG | Laborota 4000 | |
| High pressure extruder | Northern Lipids Inc. | T.001 | 10 mL thermobarrel |
| Heating circulator | VWR International LLC. | 11305 | Connected to extruder |
| Polycarbonate membrane filter | Whatman | 110605;110606 | |
| Differential scanning calorimeter (DSC) | TA Instruments | Q100 | |
| Inductively coupled plasma-atomic emission spectrometer (ICP-AES) | PerkinElmer | Optima 7300DV | |
| Zetasizer | Malvern Instruments Ltd. | Nano-ZS | |
| Cell incubator | NuAire Inc. | NU-5800 | |
| Autoclip wound clip applier | Becton Dickinson | 427630 | |
| Autoclip wound clip remover | Becton Dickinson | 427637 | |
| Wound clips | Becton Dickinson | 427631 | 9 mm |
| 763 nm Laser device | Biolitec | Ceralas CD 403 laser | |
| Laser probe | Thorlabs Inc. | FT400EMT | With SMA and flat cleave connectors |
| Spectralon (illuminator) | Labsphere Inc. | FAST-SL-5CMX5CM | |
| CSTM-SL-5CMX5CM | |||
| 7 Tesla prelinical magnetic resonance (MR) imaging system | Bruker Corporation | Biospec 70/30 | |
| Fiber optic temperature sensor | LumaSense Technologies Inc. | Luxtron FOT Lab Kit | |
| Integrating sphere | Newport Corporation | 819C | |
| Optical power meter | Newport Corporation | 1830-R |
References
- Maeda, H., Wu, J., Sawa, T., Matsumura, Y., Hori, K. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Releas. 65 (1-2), 271-284 (2000).
- Simard, P., Leroux, J. C., Allen, C., Meyer, O. Liposomes for Drug Delivery. Nanoparticles for Pharmaceutical Application. , (2007).
- O’Brien, M. E. R., et al. 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. Ann Onco. 15 (3), 440-449 (2004).
- White, S. C., et al. Phase II study of SPI-77 (sterically stabilised liposomal cisplatin) in advanced non-small-cell lung cancer. Br J Cancer. 95 (7), 822-828 (2006).
- Laginha, K. M., Verwoert, S., Charrois, G. J. R., Allen, T. M. Determination of doxorubicin levels in whole tumor and tumor nuclei in murine breast cancer tumors. Clin Cancer Res. 11 (19), 6944-6949 (2005).
- Baronzio, G. F., Hager, E. D. . Hyperthermia in cancer treatment: a primer. , (2006).
- Landon, C. D., Park, J. Y., Needham, D., Dewhirst, M. W. 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. Open Nanomed. 3, 38-64 (2011).
- Koning, G. A., Eggermont, A. M., Lindner, L. H., ten Hagen, T. L. Hyperthermia and thermosensitive liposomes for improved delivery of chemotherapeutic drugs to solid tumors. Pharm Res. 27 (8), 1750-1754 (2010).
- Viglianti, B. L., et al. In vivo monitoring of tissue pharmacokinetics of liposome/drug using MRI: illustration of targeted delivery. Magn Reson Me. 51 (6), 1153-1162 (2004).
- Ponce, A. M., et al. Magnetic resonance imaging of temperature-sensitive liposome release: drug dose painting and antitumor effects. J Natl Cancer Ins. 99 (1), 53-63 (2007).
- Kong, G., et al. Efficacy of liposomes and hyperthermia in a human tumor xenograft model: importance of triggered drug release. Cancer Res. 60 (24), 6950-6957 (2000).
- Yarmolenko, P. S., et al. Comparative effects of thermosensitive doxorubicin-containing liposomes and hyperthermia in human and murine tumours. Int J Hyperthermia. 26 (5), 485-498 (2010).
- Wang, L. H., Jacques, S. L., Zheng, L. Q. MCML-Monte Carlo modeling of photon transport in multi-layered tissues. Comput Meth Prog Bio. 47, 131-146 (1995).
- Rieke, V., Butts Pauly, K. MR thermometry. J Magn Reson Imaging. 27 (2), 376-390 (2008).
- Dou, Y. N., et al. Heat-activated thermosensitive liposomal cisplatin (HTLC) results in effective growth delay of cervical carcinoma in mice. J Control Release. 178, 69-78 (2014).
- Lammers, T., Kiessling, F., Hennink, W. E., Storm, G. Nanotheranostics and image-guided drug delivery: current concepts and future directions. Mol Pharm. 7 (6), 1899-1912 (2010).
- Lee, H., et al. A novel 64Cu-liposomal PET agent (MM-DX-929) predicts response to liposomal chemotherapeutics in preclinical breast cancer models. Thirty-Fifth Annual CTRC-AACR San Antonio Breast Cancer Symposium. , (2012).
