Remodeling Tumor Vasculature to Enhance Delivery of Intermediate-Sized Nanoparticles
Remodeling Tumor Vasculature to Enhance Delivery of Intermediate-Sized Nanoparticles
复制标题
重塑肿瘤脉管系统以增强中等尺寸纳米颗粒的递送
DOI：
10.1021/acsnano.5b02028
复制
发表时间：
2015-09-01
期刊：
影响因子：
17.1
通讯作者：
Kim, Betty Y. S.
中科院分区：
文献类型：
--
作者：
Jiang, Wen;Huang, Yuhui;Kim, Betty Y. S.
功能失调的肿瘤血管系统的恢复可以重建血管内和间质空间之间的压力梯度，这对于将纳米药物输送到实体瘤中至关重要。肿瘤血管的形态和功能正常化改善了组织灌注，以促进肿瘤内纳米颗粒递送。然而，这种重塑过程也降低了肿瘤血管的通透性，这可能会损害纳米颗粒的转运。尽管尺寸小于10 nm的纳米颗粒最大限度地受益于用于增强纳米药物递送的肿瘤血管正常化治疗，但小的颗粒尺寸严重限制了其适用性。在这里，我们发现中等大小的纳米颗粒（20-40 nm）也可以从肿瘤血管重塑中受益。我们证明了不同纳米颗粒尺寸的两阶段运输策略存在一个机会窗口。总体而言，肿瘤血管重塑增强了高达40 nm的中等尺寸纳米颗粒的经血管递送。然而，一旦在肿瘤基质内，较小的纳米颗粒经历显著较小程度的扩散阻碍，导致在肿瘤基质内更均匀的分布。这些发现表明，抗血管生成治疗和纳米颗粒设计可以以多阶段的方式结合，具有两组尺寸包含标准，以实现最佳的纳米药物递送到实体瘤中。
Restoration of dysfunctional tumor vasculature can reestablish the pressure gradient between intravascular and interstitial space that is essential for transporting nanomedicines into solid tumors. Morphologic and functional normalization of tumor vessels improves tissue perfusion to facilitate intratumoral nanoparticle delivery. However, this remodeling process also reduces tumor vessel permeability, which can impair nanoparticle transport. Although nanoparticles sized below 10 nm maximally benefited from tumor vessel normalization therapy for enhanced nanomedicine delivery, the small particle size severely limits its applicability. Here, we show that intermediate-sized nanoparticles (20-40 nm) can also benefit from tumor vasculature remodeling. We demonstrate that a window of opportunity exists for a two-stage transport strategy of different nanoparticle sizes. Overall, tumor vessel remodeling enhances the transvascular delivery of intermediate-size nanoparticles of up to 40 nm. Once within the tumor matrix, however, smaller nanoparticles experience a significantly lesser degree of diffusional hindrance, resulting in a more homogeneous distribution within the tumor interstitium. These findings suggest that antiangiogenic therapy and nanoparticle design can be combined in a multistage fashion, with two sets of size-inclusion criteria, to achieve optimal nanomedicine delivery into solid tumors.