Calcium-Mediated Cell Adhesion Enhancement-Based Antimetastasis and Synergistic Antitumor Therapy by Conjugated Polymer–Calcium Composite Nanoparticles
Junni He, Yuze Wang, Yuxin Ren, Qiong Yuan, Ziqi Zhang, Ling Li, Benkai Bao, Wenhua Jia, Xinyi Zhang, Meiqi Li, Yanli Tang
Abstract
Strengthening tumor cellular adhesion through regulating the concentration of extracellular Ca 2+ is highly challenging and promising for antimetastasis. Herein, a pH-responsive conjugated polymer–calcium composite nanoparticle (PFV/CaCO 3 /PDA@PEG) is developed for calcium-mediated cell adhesion enhancement-based antimetastasis and reactive oxygen species (ROS)-triggered calcium overload and photodynamic therapy (PDT) synergistic tumor treatment. PFV/CaCO 3 /PDA@PEG is mainly equipped with conjugated poly(fluorene- co -vinylene) (PFV-COOH)-composited CaCO 3 nanoparticles, which can be rapidly decomposed under the tumor acidic microenvironment, effectively releasing Ca 2+ and the photosensitizer PFV-COOH. The high extracellular Ca 2+ concentration facilitates the generation of dimers between two adjacent cadherin ectodomains, which greatly enhances cell–cell adhesion and suppresses tumor metastasis. The inhibition rates are 97 and 87% for highly metastatic tumor cells 4T1 and MCF-7, respectively. Such a well-designed nanoparticle also contributes to realizing PDT, mitochondrial dysfunction, and ROS-triggered Ca 2+ overload synergistic therapy. Furthermore, PFV/CaCO 3 /PDA@PEG displayed superior in vivo inhibition of 4T1 tumor growth and demonstrated a marked antimetastatic effect by both intravenous and intratumoral injection modes. Thus, this study provides a powerful strategy for calcium-mediated metastasis inhibition for tumor therapy.