Enhanced anti-metastatic therapy with down-regulation of heparinase expression by ROS-responsive micellar nanoparticles
Yicong Zhang, Yuai Li, Shiqi Huang, Hanming Zhang, Qing Lin, Tao Gong, Xun Sun, Zhirong Zhang, Ling Zhang
Abstract
Metastasis is a major sign of malignant tumors which plays a vital role in cancer-related death. Suppressing metastasis is an important way to improve the survival rate of cancer patients. Herein, multifunctional PEG-LAM-PPS nanoparticles (nPLPs) are fabricated as both nanocarriers and anti-metastatic agents for tumor treatment. In this system, laminarin sulfate (LAM) suppresses metastasis by reducing heparinase and protecting the extracellular matrix; the ROS-sensitive polypropylene sulfide (PPS) improves the release of the loaded drug in the tumor microenvironment. This is the first time that laminarin sulfate has been used as a carrier to inhibit the expression of heparinase and treat melanoma lung metastasis. The blank nanoparticles are excellently safe and showed high anti-metastatic efficacy in melanoma lung metastatic mouse models, reducing metastatic nodules by 60%. They significantly improved the anti-tumor efficacy of the loaded drug doxorubicin, provided ∼33% further reduction of the tumor volume and 50% further reduction of the metastatic nodule number compared with free doxorubicin. Thus, these simple and versatile micellar nanoparticles composed of biocompatible materials offer a promising vehicle for treating invasive solid tumors and metastases.