PO.TB02.02 · 肿瘤生物学
利用跨体素交换模型（Cross-Voxel eXchange Model）和DCE-MRI对肿瘤转运动力学进行新型表征
Novel characterization of tumor transport dynamics using Cross-Voxel eXchange Model and DCE-MRI
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摘要 Abstract
中文摘要
尽管肿瘤学取得了重大进展，肿瘤异质性仍持续导致对新兴疗法的应答不一致。肿瘤微环境（TME）的生物物理特征——尤其是升高的组织间液压（IFP）和降低的水力传导率（K）——产生向外的对流，限制了药物和示踪剂的转运，从而促成耐药。改进对这些参数的表征对于理解不同肿瘤部位由TME介导的屏障至关重要。在本研究中，评估了多样化的ME180肿瘤微环境，以检验跨体素交换模型（CVXM）量化转运特性并阐明TME与药代动力学之间动态相互作用的能力。ME180宫颈癌异种移植瘤分别在免疫缺陷NRG小鼠的原位、肌内和皮下部位建立。将CVXM应用于7T DCE-MRI（Biospec，Bruker），获得逐体素的外渗、对流（速度）、扩散和水力传导率估计值。使用固态传感器直接测量的IFP和离体水力传导率测量值被用于验证CVXM推导的K。一部分原位肿瘤接受分次放疗（RT）：5×5 Gy（SmART+，Precision），并采集放疗后五天的DCE-MRI以评估CVXM对放疗诱导的TME变化的敏感性。CVXM生成了各肿瘤模型中关键转运参数（外渗、示踪剂速度、扩散和水力传导率）的空间图。外渗范围为0.002–0.084 min⁻¹，外周速度为0.91–6.8 μm/s，平均扩散为168–250 μm²/s，均在报道的生理范围内。CVXM推导的K与对流推导的速度强相关（R² = 0.49–0.65，p < 0.001），平均值范围为9.96×10⁻⁸至3.88×10⁻⁷ cm²/(mmHg·s)，与先前发表的ME180测量值一致。放疗后，原位肿瘤在放疗后五天表现出IFP下降12%，同时示踪剂速度下降49%，CVXM推导的K下降29%。这些数据表明，CVXM提供了一种非侵入性手段来表征肿瘤内的转运行为并检测治疗导致的生物物理变化。这些发现证明，CVXM提供了一个非侵入性、基于成像的平台，用于量化肿瘤转运特性并检测治疗诱导的TME生物物理变化。通过将放射学转运指标与潜在生理学联系起来，CVXM为监测治疗应答以及识别与药物递送和放疗疗效相关的生物物理生物标志物提供了一种转化工具。
查看英文原文 English abstract
Despite significant advances in oncology, tumor heterogeneity continues to drive inconsistent responses to emerging therapeutics. Biophysical features of the tumor microenvironment (TME) - particularly elevated interstitial fluid pressure (IFP) and reduced hydraulic conductivity (K) generate outward convective flow that limits drug and tracer transport, contributing to resistance. Improved characterization of these parameters is essential for understanding TME-mediated barriers across tumor sites. In this work, the diverse ME180 tumor microenvironments were evaluated to test the ability of the Cross-Voxel eXchange Model (CVXM) to quantify transport properties and elucidate dynamic interactions between the TME and pharmacokinetics.ME180 cervical carcinoma xenografts were established in orthotopic, intramuscular, and subcutaneous sites in immunodeficient NRG mice. CVXM applied to 7T DCE-MRI (Biospec, Bruker) yielded voxel-wise estimates of extravasation, convection (velocity), diffusion, and hydraulic conductivity. Direct IFP measured with a solid-state transducer and ex vivo hydraulic conductivity measurements were used to validate CVXM-derived K. A subset of orthotopic tumors received fractionated radiotherapy (RT): 5×5 Gy (SmART+, Precision), and DCE-MRI acquired five days post-RT was used to assess CVXM sensitivity to RT-induced TME changes.CVXM produced spatial maps of key transport parameters (extravasation, tracer velocity, diffusion, and hydraulic conductivity) across tumor models. Extravasation ranged from 0.002-0.084min⁻¹, peripheral velocity from 0.91-6.8μm/s and mean diffusion from 168-250μm²/s, all within reported physiological ranges. CVXM-derived K strongly correlated with convection-derived velocity (R² = 0.49-0.65, p < 0.001), with mean values ranging from 9.96×10⁻ 8 to 3.88×10⁻⁷cm²/(mmHg·s), consistent with previously published ME180 measurements. Following RT, orthotopic tumors exhibited a 12% reduction in IFP, accompanied by a 49% decrease in tracer velocity and a 29% decrease in CVXM-derived K at five days post-RT. These data indicate that CVXM provides a non-invasive means to characterize transport behavior within tumors and to detect biophysical changes resulting from treatment.These findings demonstrate that CVXM provides a non-invasive, imaging-based platform for quantifying tumor transport properties and detecting treatment-induced shifts in TME biophysics. By linking radiologic transport metrics with underlying physiology, CVXM offers a translational tool for monitoring therapy response and identifying biophysical biomarkers relevant to drug delivery and radiation efficacy.
利益披露 Disclosure
J. Kim, None..
N. Sinno, None..
M. Milosevic, None..
C. Coolens, None.