Enhancement in blood-tumor barrier permeability and delivery of liposomal doxorubicin using focused ultrasound and microbubbles: evaluation during tumor progression in a rat glioma model.
Enhancement in blood-tumor barrier permeability and delivery of liposomal doxorubicin using focused ultrasound and microbubbles: evaluation during tumor progression in a rat glioma model.
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DOI：
10.1088/0031-9155/60/6/2511
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发表时间：
2015-03-21
影响因子：
3.5
通讯作者：
McDannold N
中科院分区：
文献类型：
--
作者：
Aryal M;Park J;Vykhodtseva N;Zhang YZ;McDannold N
由于“血肿瘤屏障”（BTB）的异质渗透性沿着其他因素，如增加的间质压力和药物外排泵，向脑肿瘤有效递送药物通常具有挑战性。聚焦超声（FUS）结合微泡可以增强BTB在脑肿瘤中的渗透性，以及周围组织中的血脑屏障。在这项研究中，动态对比增强MRI（DCE-MRI）被用来表征FUS诱导的渗透性变化的BTB在大鼠胶质瘤模型在植入后的不同时间。将9 L胶质肉瘤细胞植入雄性大鼠的两个半球。在植入后第9、14或17天，在每只动物的一个肿瘤中使用690 kHz超声和Depletion微泡进行FUS诱导的BTB破坏。在FUS之前，以5.67 mg/kg的剂量给予脂质体阿霉素。这种化疗剂以前被证明可以提高动物胶质瘤模型的存活率。超声处理前后通过DCE-MRI测量描述MRI造影剂Gd-DTPA外渗的传递系数Ktranss。我们发现，在第9、14和17天，对照肿瘤中的肿瘤多柔比星浓度单调增加（823±600、1817±732和2432±448 ng/g）。随着FUS诱导的BTB破坏，阿霉素浓度显著增加（分别在第9、14和17天P<0.05、P<0.01和P<0.0001），并且无论肿瘤生长的阶段如何，都比对照肿瘤高两倍或更多（2222±784、3687±796和5658±821 ng/g）。与对照肿瘤相比，转移系数Ktranss仅在第9天显著（p<0.05）增强，但在第14或17天没有增强。这些结果表明，FUS诱导的肿瘤药物递送增强随时间推移相对一致，至少在该肿瘤模型中是如此。这些结果对于使用大型药物载体是令人鼓舞的，因为它们表明即使是大型/晚期肿瘤也可以从FUS诱导的药物增强中受益。在大/晚期肿瘤中发现Ktransen 100 ts的相应增强是可变的，并且与对照组没有显著差异，这可能反映了脂质体药物（~100 nm）和Gd-DTPA（分子量：938 Da;流体动力学直径：~2 nm）之间的尺寸不匹配。当使用大型药物载体（如脂质体）时，可能需要使用较大的MRI造影剂，以有效评价大型/晚期肿瘤中超声诱导的增强透化。
Effective drug delivery to brain tumors is often challenging because of the heterogeneous permeability of the “blood tumor barrier” (BTB) along with other factors such as increased interstitial pressure and drug efflux pumps. Focused ultrasound (FUS) combined with microbubbles can enhance the permeability of the BTB in brain tumors, as well as the blood-brain barrier in the surrounding tissue. In this study, dynamic contrast-enhanced MRI (DCE-MRI) was used to characterize the FUS-induced permeability changes of the BTB in a rat glioma model at different times after implantation. 9L gliosarcoma cells were implanted in both hemispheres in male rats. At day 9, 14, or 17 days after implantation, FUS-induced BTB disruption using 690 kHz ultrasound and Definity microbubbles was performed in one tumor in each animal. Before FUS, liposomal doxorubicin was administered at a dose of 5.67 mg/kg. This chemotherapy agent was shown previously to improve survival in animal glioma models. The transfer coefficient Ktrans describing extravasation of the MRI contrast agent Gd-DTPA was measured via DCE-MRI before and after sonication. We found that tumor doxorubicin concentrations increased monotonically (823±600, 1817±732 and 2432±448 ng/g) in the control tumors at 9, 14 and 17 days. With FUS-induced BTB disruption, the doxorubicin concentrations were enhanced significantly (P<0.05, P<0.01, and P<0.0001 at days 9, 14, and 17, respectively) and were greater than the control tumors by a factor of two or more (2222±784, 3687±796 and 5658±821 ng/g) regardless of the stage of tumor growth. The transfer coefficient Ktrans was significantly (p<0.05) enhanced compared to control tumors only at day 9 but not at day 14 or 17. These results suggest that FUS-induced enhancements in tumor drug delivery are relatively consistent over time, at least in this tumor model. These results are encouraging for the use of large drug carriers, as they suggest that even large/late-stage tumors can benefit from FUS-induced drug enhancement. Corresponding enhancemen100 ts in Ktrans were found variable in large/late-stage tumors and not significantly different than controls, perhaps reflecting the size mismatch between the liposomal drug (~100 nm) and Gd-DTPA (molecular weight: 938 Da; hydrodynamic diameter: ~2 nm). It may be necessary to use a larger MRI contrast agent to effectively evaluate the sonication-induced enhanced permeabilization in large/late-stage tumors when a large drug carrier such as a liposome is used.
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影响因子：
19.7
作者：
Hynynen, K;McDannold, N;Jolesz, FA
通讯作者：
Jolesz, FA
影响因子：
11.2
作者：
McDannold N;Arvanitis CD;Vykhodtseva N;Livingstone MS
通讯作者：
Livingstone MS
DOI：
10.1016/j.jconrel.2012.09.007
发表时间：
2012-11-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Park EJ;Zhang YZ;Vykhodtseva N;McDannold N
通讯作者：
McDannold N
DOI：
10.1016/j.jconrel.2013.04.007
发表时间：
2013-07-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Aryal M;Vykhodtseva N;Zhang YZ;Park J;McDannold N
通讯作者：
McDannold N
DOI：
10.1073/pnas.0604318103
发表时间：
2006-08-01
影响因子：
11.1
作者：
Kinoshita, Manabu;McDannold, Nathan;Hynynen, Kullervo
通讯作者：
Hynynen, Kullervo