MR-labelled liposomes and focused ultrasound for spatiotemporally controlled drug release in triple negative breast cancers in mice.
MR-labelled liposomes and focused ultrasound for spatiotemporally controlled drug release in triple negative breast cancers in mice.
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DOI：
10.7150/ntno.52168
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Thanou M
中科院分区：
文献类型：
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作者：
Amrahli M;Centelles M;Cressey P;Prusevicius M;Gedroyc W;Xu XY;So PW;Wright M;Thanou M
原理：图像引导、可重复的药物输送系统允许精确放置和高度局部化的抗癌治疗。它们包含用于空间映射和组织摄取跟踪的标签，为应用外部刺激以触发药物释放提供关键位置和定时信息。高强度聚焦超声（HIFU或FUS）是一种用于治疗小组织体积的非侵入性方法，并且在诱导药物从热敏纳米载体释放方面特别有效。在这里，我们提出了一种新的MR成像热敏脂质体（iTSL）的药物输送到三阴性乳腺癌（TNBC）。方法：将大环钆基磁共振成像（MRI）造影剂共价连接到脂质上。将其以30摩尔%掺入也包封阿霉素的热敏脂质体的脂质双层中。评估所得iTSL-DOX制剂的物理和化学性质、储存稳定性、钆或多柔比星的泄漏以及热或FUS诱导的药物释放。在体模中测试其对MRI弛豫时间的影响。使用具有肿瘤的小鼠进行研究以评估肿瘤分布和随时间的对比增强。脂质体中还包含脂质缀合的近红外荧光（NIRF）探针，以促进通过NIRF生物成像对肿瘤中iTSL分布和药物释放的真实的实时监测。然后使用TNBC（MDA-MB-231）荷瘤小鼠来证明延缓肿瘤生长和增加存活率的功效。结果：iTSL-DOX提供了快速的FUS诱导的药物释放，这取决于所施加的声功率。另外，发现其稳定，药物和钆泄漏到缓冲液中或在挑战性条件下最小。与通常建议的较长FUS治疗相反，我们鉴定了短暂（~3分钟）FUS显著增强了靶向肿瘤的iTSL-DOX摄取，并触发了包封的多柔比星的几乎全部释放，在TNBC小鼠模型中引起显著的生长抑制。肿瘤平均T1弛豫时间的明显减少归因于iTSL的积累。结论：我们证明，使用MRI跟踪肿瘤中的iTSL有助于FUS应用于精确的药物释放和治疗。
Rationale: Image-guided, triggerable, drug delivery systems allow for precisely placed and highly localised anti-cancer treatment. They contain labels for spatial mapping and tissue uptake tracking, providing key location and timing information for the application of an external stimulus to trigger drug release. High Intensity Focused Ultrasound (HIFU or FUS) is a non-invasive approach for treating small tissue volumes and is particularly effective at inducing drug release from thermosensitive nanocarriers. Here, we present a novel MR-imageable thermosensitive liposome (iTSL) for drug delivery to triple-negative breast cancers (TNBC). Methods: A macrocyclic gadolinium-based Magnetic Resonance Imaging (MRI) contrast agent was covalently linked to a lipid. This was incorporated at 30 mol% into the lipid bilayer of a thermosensitive liposome that was also encapsulating doxorubicin. The resulting iTSL-DOX formulation was assessed for physical and chemical properties, storage stability, leakage of gadolinium or doxorubicin, and thermal- or FUS-induced drug release. Its effect on MRI relaxation time was tested in phantoms. Mice with tumours were used for studies to assess both tumour distribution and contrast enhancement over time. A lipid-conjugated near-infrared fluorescence (NIRF) probe was also included in the liposome to facilitate the real time monitoring of iTSL distribution and drug release in tumours by NIRF bioimaging. TNBC (MDA-MB-231) tumour-bearing mice were then used to demonstrate the efficacy at retarding tumour growth and increasing survival. Results: iTSL-DOX provided rapid FUS-induced drug release that was dependent on the acoustic power applied. It was otherwise found to be stable, with minimum leakage of drug and gadolinium into buffers or under challenging conditions. In contrast to the usually suggested longer FUS treatment we identified that brief (~3 min) FUS significantly enhanced iTSL-DOX uptake to a targeted tumour and triggered near-total release of encapsulated doxorubicin, causing significant growth inhibition in the TNBC mouse model. A distinct reduction in the tumours' average T1 relaxation times was attributed to the iTSL accumulation. Conclusions: We demonstrate that tracking iTSL in tumours using MRI assists the application of FUS for precise drug release and therapy.