A dual receptors-targeting and size-switchable 'cluster bomb' co-loading chemotherapeutic and transient receptor potential ankyrin 1 (TRPA-1) inhibitor for treatment of triple negative breast cancer
Autor: | Mou Wang, Sheng Yin, Zhirong Zhang, Qin He, Yiliang Yang, Shanshan Xu, Man Li, Yashi Wang, Lin Mei, Xuan He |
---|---|
Rok vydání: | 2020 |
Předmět: |
Ankyrins
Pharmaceutical Science Triple Negative Breast Neoplasms Vimentin 02 engineering and technology medicine.disease_cause Metastasis Mice 03 medical and health sciences In vivo Cell Line Tumor medicine Animals Humans TRPA Receptor TRPA1 Cation Channel Micelles 030304 developmental biology Drug Carriers 0303 health sciences biology Chemistry 021001 nanoscience & nanotechnology medicine.disease In vitro Doxorubicin biology.protein Cancer research 0210 nano-technology Oxidative stress Nanogel |
Zdroj: | Journal of Controlled Release. 321:71-83 |
ISSN: | 0168-3659 |
Popis: | Oxidative-stress defense system stands for the vulnerability of tumor cells because of the stronger oxidative stress existing in tumor sites. TRPA-1 has been found to be overexpressed in various tumors, related to the tumor proliferation and metastasis, and promote reactive oxygen species (ROS) and chemotherapy tolerance through Ca2+-dependent anti-apoptotic pathway in recent studies, which provides a new anti-tumor approach to target oxidative-stress defense system. However, there are few studies on the mechanisms of TRPA-1 inhibition increasing the effectiveness of chemotherapy and inhibiting tumor metastasis. Here, in order to deliver drugs to the deep tumor where is full of stronger oxidative stress, a dual receptors-targeting and size-switchable “cluster bomb” co-loading doxorubicine (DOX) and TRPA-1 inhibitor AP-18 (DA-tMN) was designed. DSPE-PEG2000 micelles (M, ~10 nm) were connected to the master core of hyaluronic acid nanogels (N, ~100 nm) to realize HAase-responsive size-switchable and acquired targeting characteristics. Besides, tumor homing peptide tLyP-1 (t) was modified on the surface of micelles to further increase tumor accumulation. Our study showed that tLyP-1 modification enhanced tumor-targeting delivery of tLyP-1-modified micelles @ nanogels (tMN) in vitro and in vivo. Then, HAase responsive nanogel core realized the deep penetration of tMN in 4 T1 3D tumor spheres models and 4 T1 tumor-bearing mice models. In vitro anti-tumor and anti-metastasis mechanism studies indicated that AP-18 increased the sensitivity of tumor cells to DOX by inhibiting Ca2+ influx and AKT phosphorylation caused by DOX. Compared with DOX-loaded tLyP-1-modified micelles @ nanogels (D-tMN), DA-tMN had the enhanced anti-tumor and anti-metastasis effect in vitro and vivo. Furthermore, the further anti-metastasis mechanism studies showed that TRPA-1 inhibition downregulate the expression of N-cadherin and vimentin and upregulate the expression of E-cadherin, which suggested that metastases inhibition caused by TRPA-1 inhibition may be related to the inhibition of epithelial-mesenchymal transition (EMT) process. |
Databáze: | OpenAIRE |
Externí odkaz: |