Purpose

When doxorubicin (DOX) is administered via lyso-thermosensitive liposomes (LTLD), mild hyperthermia enhances localized delivery to heated vs. unheated tumors. The optimal LTLD dose and the impact of different doses on systemic drug distribution are unknown.

Materials and methods: In this study, we evaluated local and systemic DOX delivery with three LTLD doses (0.1, 0.5, and 2.5 mg/kg) in a Vx2 rabbit tumor model. Temporally and spatially accurate controlled hyperthermia was achieved using a clinical MR-HIFU system for the intended heating duration (40 min).

Results: DOX concentration in tissues delivered from LTLD combined with MR-HIFU mild hyperthermia are dose-dependent, including heated/unheated tumor, heart, and other healthy organs. Higher DOX accumulation and tumor-to-heart drug concentration ratio, defined as the ratio of DOX delivered into the tumor vs the heart, were observed in heated tumors compared to unheated tumors in all three tested doses. The DOX uptake efficiency for each mg/kg of LTLD injected IV of heated tumor was significantly higher than that of unheated tumor and heart within the tested dose range (0.1-2.5 mg/kg). The DOX uptake for the heart linearly scaled up as a function of dose while that for the heated tumor showed some evidence of saturation at the high dose of 2.5 mg/kg.

Conclusions: These results provide guidance on clinical protocol design of hyperthermia-triggered drug delivery.

中文翻译：

---

在使用MR-HIFU轻度高温和热敏脂质体的Vx2兔肿瘤模型中，注射剂量对局部肿瘤累积和阿霉素心脏摄取的影响。

目的

当通过溶酶热敏感性脂质体（LTLD）施用阿霉素（DOX）时，温和的高温会增强局部递送至加热或未加热的肿瘤。LTLT的最佳剂量和不同剂量对全身药物分布的影响尚不清楚。

材料和方法：在这项研究中，我们评估了Vx2兔肿瘤模型中三种LTLD剂量（0.1、0.5和2.5 mg / kg）的局部和全身DOX递送。使用临床MR-HIFU系统在预期的加热时间（40分钟）内实现了时间和空间上精确的受控热疗。

结果： LTLD与MR-HIFU轻度高热相结合的组织中的DOX浓度是剂量依赖性的，包括加热/未加热的肿瘤，心脏和其他健康器官。在所有三种测试剂量下，与未加热的肿瘤相比，在加热的肿瘤中观察到较高的DOX积累和肿瘤与心脏药物的浓度比（定义为传递到肿瘤中的DOX与心脏的比例）。在测试剂量范围（0.1-2.5 mg / kg）内，经加热的肿瘤静脉注射LTLD的每mg / kg的DOX吸收效率显着高于未加热的肿瘤和心脏。心脏的DOX吸收随剂量呈线性增加，而加热的肿瘤的DOX吸收在2.5 mg / kg的高剂量下显示出饱和的迹象。

结论：这些结果为热疗触发药物递送的临床方案设计提供了指导。