Calcium-Mediated Cell Adhesion Enhancement-Based Antimetastasis and Synergistic Antitumor Therapy by Conjugated Polymer-Calcium Composite Nanoparticles.

Abstract

Strengthening tumor cellular adhesion through regulating the concentration of extracellular Ca²⁺ is highly challenging and promising for antimetastasis. Herein, a pH-responsive conjugated polymer-calcium composite nanoparticle (PFV/CaCO₃/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/CaCO₃/PDA@PEG is mainly equipped with conjugated poly(fluorene-<i>co</i>-vinylene) (PFV-COOH)-composited CaCO₃ nanoparticles, which can be rapidly decomposed under the tumor acidic microenvironment, effectively releasing Ca²⁺ and the photosensitizer PFV-COOH. The high extracellular Ca²⁺ 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 Ca²⁺ overload synergistic therapy. Furthermore, PFV/CaCO₃/PDA@PEG displayed superior <i>in vivo</i> 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.