Real-Time Visualization and Quantitation of Vascular Permeability <em>In Vivo</em>: Implications for Drug Delivery

The leaky, heterogeneous vasculature of human tumors prevents the even distribution of systemic drugs within cancer tissues. However, techniques for studying vascular delivery systems in vivo often require complex mammalian models and time-consuming, surgical protocols. The developing chicken embryo is a well-established model for human cancer that is easily accessible for tumor imaging. To assess this model for the in vivo analysis of tumor permeability, human tumors were grown on the chorioallantoic membrane (CAM), a thin vascular membrane which overlays the growing chick embryo. The real-time movement of small fluorescent dextrans through the tumor vasculature and surrounding tissues were used to measure vascular leak within tumor xenografts. Dextran extravasation within tumor sites was selectively enhanced an interleukin-2 (IL-2) peptide fragment or vascular endothelial growth factor (VEGF). VEGF treatment increased vascular leak in the tumor core relative to surrounding normal tissue and increased doxorubicin uptake in human tumor xenografts. This new system easily visualizes vascular permeability changes in vivo and suggests that vascular permeability may be manipulated to improve chemotherapeutic targeting to tumors.人类肿瘤具有渗漏性且异质性的脉管系统，会阻碍全身性药物在癌组织内的均匀分布。然而，体内研究脉管递送系统的技术通常需要复杂的哺乳动物模型，以及耗时且繁琐的手术操作流程。发育中的鸡胚是已被广泛验证的人类癌症研究模型，且便于开展肿瘤成像实验。为评估该模型用于肿瘤通透性体内分析的可行性，研究人员将人类肿瘤种植于鸡胚绒毛尿囊膜（chorioallantoic membrane, CAM）——一种覆盖于发育中鸡胚表面的薄型脉管膜——之上。研究人员通过追踪小型荧光葡聚糖在肿瘤脉管系统及周围组织内的实时迁移过程，来测定肿瘤异种移植物中的脉管渗漏情况。肿瘤部位的葡聚糖外渗现象，可通过白细胞介素-2（interleukin-2, IL-2）肽片段或血管内皮生长因子（vascular endothelial growth factor, VEGF）进行选择性增强。VEGF处理可相较于周围正常组织，增强肿瘤核心区域的脉管渗漏，并提升人类肿瘤异种移植物对阿霉素（doxorubicin）的摄取量。该全新系统可直观呈现体内脉管通透性的变化，同时表明，可通过调控脉管通透性来提升化疗药物对肿瘤的靶向递送效果。