Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center , Houston, Texas, United States.
The Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the Collaborative Innovation Center of Hematology, Soochow University , China.
ACS Nano. 2015 Sep 22;9(9):8689-96. doi: 10.1021/acsnano.5b02028. Epub 2015 Jul 31.
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.
功能失调的肿瘤血管的恢复可以重建血管内和细胞外间隙之间的压力梯度，这对于将纳米药物输送到实体瘤中是至关重要的。肿瘤血管的形态和功能正常化可以改善组织灌注，从而促进肿瘤内纳米颗粒的输送。然而，这种重塑过程也会降低肿瘤血管的通透性，从而影响纳米颗粒的运输。虽然小于 10nm 的纳米颗粒最大程度地受益于肿瘤血管正常化治疗以增强纳米药物的输送，但小粒径严重限制了其适用性。在这里，我们表明，中等大小的纳米颗粒（20-40nm）也可以受益于肿瘤血管重塑。我们证明了不同纳米颗粒大小的两阶段输送策略存在一个机会窗口。总的来说，肿瘤血管重塑增强了最大可达 40nm 的中等大小纳米颗粒的跨血管输送。然而，一旦进入肿瘤基质，较小的纳米颗粒经历的扩散阻碍程度要小得多，导致在肿瘤间质中分布更加均匀。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，采用两套大小包含标准，以实现实体瘤中最佳的纳米药物输送。
