Regulation of transport pathways in tumor vessels: Role of tumor type and microenvironment
Regulation of transport pathways in tumor vessels: Role of tumor type and microenvironment
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DOI：
10.1073/pnas.95.8.4607
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发表时间：
1998-04-14
影响因子：
11.1
通讯作者：
Jain, RK
中科院分区：
文献类型：
--
作者：
Hobbs, SK;Monsky, WL;Jain, RK
新型的抗肿瘤药物，如基因靶向载体和包封载体，体积相当大（直径约100- 300nm）。了解经血管途径的功能大小和生理调节对于优化这些药物的递送是必要的。在此，我们分析了跨血管转运的功能限制及其微环境对其的调节。将1例人和5例小鼠肿瘤（包括乳腺癌和结直肠癌、肝癌、胶质瘤和肉瘤）植入背侧皮肤褶腔或颅窗，并测定孔切断大小，这是跨血管间隙大小的功能指标。微环境被调节：(i)空间上，通过皮下或颅骨位置的肿瘤生长；（ii）时间上，通过诱导激素依赖性肿瘤的血管消退。皮下生长的肿瘤具有200 nm至1.2 μ m的特征性孔切断尺寸。在颅骨生长的肿瘤或激素消退后的肿瘤中，这种孔切断尺寸减小。含碱性成纤维细胞生长因子凝胶诱导血管的孔截止尺寸为200nm。白蛋白渗透性与孔截止尺寸无关。这些结果对治疗药物的递送有三个主要含义：(1)在颅肿瘤中的递送效率可能低于皮下肿瘤，(2)在激素消融引起的肿瘤消退期间递送可能减少，以及(3)只要分子直径远小于孔径，分子的渗透性与孔切断大小无关。
Novel anti-neoplastic agents such as gene targeting vectors and encapsulated carriers are quite large (approximately 100-300 nm in diameter). An understanding of the functional size and physiological regulation of transvascular pathways is necessary to optimize delivery of these agents. Here we analyze the functional limits of transvascular transport and its modulation by the microenvironment. One human and five murine tumors including mammary and colorectal carcinomas, hepatoma, glioma, and sarcoma were implanted in the dorsal skin-fold chamber or cranial window, and the pore cutoff size, a functional measure of transvascular gap size, was determined. The microenvironment was modulated: (i) spatially, by growing tumors in subcutaneous or cranial locations and (ii) temporally, by inducing vascular regression in hormone-dependent tumors. Tumors grown subcutaneously exhibited a characteristic pore cutoff size ranging from 200 nm to 1.2 mu m. This pore cutoff size was reduced in tumors grown in the cranium or in regressing tumors after hormone withdrawal. Vessels induced in basic fibroblast growth factor containing gels had a pore cutoff size of 200 nm. Albumin permeability was independent of pore cutoff size. These results have three major implications for the delivery of therapeutic agents: (i) delivery may be less efficient in cranial tumors than in subcutaneous tumors, (ii) delivery may be reduced during tumor regression induced by hormonal ablation, and (iii) permeability to a molecule is independent of pore cutoff size as long as the diameter of the molecule is much less than the pore diameter.