纵向临床前成像在健康和白血病骨髓血管微环境中描绘了放射治疗后细胞外药物积累。
Longitudinal Preclinical Imaging Characterizes Extracellular Drug Accumulation After Radiation Therapy in the Healthy and Leukemic Bone Marrow Vascular Microenvironment.
机构信息
Department of Radiation Oncology, City of Hope, Duarte, California; Department of Radiation Oncology, University of Minnesota, Minneapolis, Minnesota.
Department of Pathology, City of Hope, Duarte, California.
出版信息
Int J Radiat Oncol Biol Phys. 2022 Mar 15;112(4):951-963. doi: 10.1016/j.ijrobp.2021.10.146. Epub 2021 Nov 9.
PURPOSE
Recent initial findings suggest that radiation therapy improves blood perfusion and cellular chemotherapy uptake in mice with leukemia. However, the ability of radiation therapy to influence drug accumulation in the extracellular bone marrow tissue is unknown, due in part to a lack of methodology. This study developed longitudinal quantitative multiphoton microscopy (L-QMPM) to characterize the bone marrow vasculature (BMV) and drug accumulation in the extracellular bone marrow tissue before and after radiation therapy in mice bearing leukemia.
METHODS AND MATERIALS
We developed a longitudinal window implant for L-QMPM imaging of the calvarium BMV before, 2 days after, and 5 days after total body irradiation (TBI). Live time-lapsed images of a fluorescent drug surrogate were used to obtain measurements, including tissue wash-in slope (WIS) to measure extracellular drug accumulation. We performed L-QMPM imaging on healthy C57BL/6 (WT) mice, as well as mice bearing acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).
RESULTS
Implants had no effects on calvarium dose, and parameters for wild-type untreated mice were stable during imaging. We observed decreased vessel diameter, vessel blood flow, and WIS with the onset of AML and ALL. Two to 10 Gy TBI increased WIS and vessel diameter 2 days after radiation therapy in all 3 groups of mice and increased single-vessel blood flow in mice bearing ALL and AML. Increased WIS was observed 5 days after 10 Gy TBI or 4 Gy split-dose TBI (2 treatments of 2 Gy spaced 3 days apart).
CONCLUSIONS
L-QMPM provides stable functional assessments of the BMV. Nonmyeloablative and myeloablative TBI increases extracellular drug accumulation in the leukemic bone marrow 2 to 5 days posttreatment, likely through improved blood perfusion and drug exchange from the BMV to the extravascular tissue. Our data show that neo-adjuvant TBI at doses from 2 Gy to 10 Gy conditions the BMV to improve drug transport to the bone marrow.
目的
最近的初步研究结果表明，放射治疗可改善白血病小鼠的血液灌注和细胞化学药物摄取。然而，由于缺乏方法学，放射治疗影响细胞外骨髓组织中药物积累的能力尚不清楚。本研究开发了纵向定量多光子显微镜（L-QMPM），以在患有白血病的小鼠接受放射治疗前后，对颅骨骨髓血管（BMV）和细胞外骨髓组织中的药物积累进行定性和定量分析。
方法与材料
我们开发了一种纵向窗口植入物，用于在全身照射（TBI）前、后 2 天和后 5 天对颅骨 BMV 进行 L-QMPM 成像。使用荧光药物示踪剂的实时延时图像进行测量，包括组织内药物积累的组织内药物冲洗斜率（WIS）。我们对健康的 C57BL/6（WT）小鼠以及患有急性淋巴细胞白血病（ALL）和急性髓系白血病（AML）的小鼠进行了 L-QMPM 成像。
结果
植入物对颅骨剂量没有影响，并且在成像过程中，未处理的野生型小鼠的参数保持稳定。我们观察到随着 AML 和 ALL 的发生，血管直径、血管血流和 WIS 降低。在所有 3 组小鼠中，2 至 10 Gy TBI 在放射治疗后 2 天增加了 WIS 和血管直径，并增加了 ALL 和 AML 小鼠的单血管血流。在接受 10 Gy TBI 或 4 Gy 分割剂量 TBI（2 次 2 Gy 治疗，间隔 3 天）后 5 天观察到增加的 WIS。
结论
L-QMPM 可提供 BMV 的稳定功能评估。非骨髓清除性和骨髓清除性 TBI 在治疗后 2 至 5 天内增加白血病骨髓中的细胞外药物积累，可能通过改善血液灌注和药物从 BMV 向血管外组织的交换来实现。我们的数据表明，2 Gy 至 10 Gy 剂量的新辅助 TBI 使 BMV 适应以改善药物向骨髓的输送。
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