Manipulating dynamic tumor vessel permeability to enhance polymeric micelle accumulation
Manipulating dynamic tumor vessel permeability to enhance polymeric micelle accumulation
复制标题
DOI：
10.1016/j.jconrel.2020.11.063
复制
发表时间：
2021-01-10
影响因子：
10.8
通讯作者：
Yamasoba, Tatsuya
中科院分区：
文献类型：
--
作者：
Inoue, Yuta;Matsumoto, Yu;Yamasoba, Tatsuya
选择性地将抗癌药物输送到实体瘤中，同时避免它们在健康组织中蓄积是聚合物胶束研究的主要目标。我们最近发现，聚合物胶束的外渗和渗透是以一种动态的方式发生的，其特征是血管破裂，随后液体短暂而有力地向外流动(称为纳米喷发)。纳米皮疹允许输送聚合物胶束相关药物，尽管在肿瘤之间和单个肿瘤内的输送可能是不同的，导致肿瘤内分布不佳。操纵纳米喷发有望提高药物输送系统(DDSS)的效率。通过使用影响肿瘤内环境的化合物，即转化生长因子-β抑制剂和氯喹，研究了操纵纳米皮疹以提高给药效率的可能性。这两种化合物都在GFP标记的胰腺肿瘤细胞的小鼠移植模型中进行了测试，方法是通过活体共聚焦激光扫描显微镜实时跟踪纳米喷发事件和大小调节的聚合物胶束的外溢。转化生长因子-β抑制剂增加了动态通气孔的数量，延长了持续时间，并产生了大小不等的动态通气孔。氯喹不影响纳米皮疹的发生频率，但增加了肿瘤血管直径、最大纳米皮疹面积和最大径向增加。转化生长因子-β抑制剂和氯喹都能促进纳米粒子通过肿瘤间质扩散聚合物胶束，并且这些药物对较大尺寸的聚合物胶束(即70 nm)的影响大于对直径为30 nm的较小聚合物胶束的影响。结果表明，转化生长因子-β抑制剂和氯喹通过不同的机制重塑DDSS在肿瘤内的分布。
Selectively delivering anticancer drugs to solid tumors while avoiding their accumulation in healthy tissues is a major goal in polymeric micelle research. We have recently discovered that the extravasation and permeation of polymeric micelles occur in a dynamic manner characterized by vascular bursts followed by a brief and vigorous outward flow of fluid (called "nano-eruptions"). Nano-eruptions allow delivery of polymeric micelle-associated drugs, though delivery can be heterogeneous both among tumors and within an individual tumor, leading to suboptimal intratumoral distribution. Manipulation of nano-eruptions is expected to improve the efficiency of drug delivery systems (DDSs). By using compounds that affect the intratumoral environment, i.e. a TGF-beta inhibitor and chloroquine, the possibility of manipulating nano-eruptions to improve delivery efficiency was investigated. Both compounds were tested in a mouse xenograft model of GFP-labeled pancreatic tumor cells by tracing nano-eruption events and extravasation of size-modulated polymeric micelles in real-time through intravital confocal laser scanning microscopy. The TGF-beta inhibitor increased the number of dynamic vents, extended duration time, and generated dynamic vents with a wide range of sizes. Chloroquine did not affect the frequency of nano-eruptions, but it increased tumor vessel diameter, maximum nano-eruption area, and maximum radial increase. Both the TGF-beta inhibitor and chloroquine augmented nano-eruptions to diffuse polymeric micelles through tumor stroma, and these medications had a greater effect on the polymeric micelles with larger size, i.e. 70-nm, than on the smaller polymeric micelles having a 30-nm diameter. The results indicate that TGF-beta inhibition and chloroquine refashion the intratumoral distribution of DDSs by different mechanisms.