Calcium carbonate nanoparticles stimulate tumor metabolic reprogramming and modulate tumor metastasis

Aim: CaCO₃ nanoparticles (nano-CaCO₃) can neutralize the acidic pHe of solid tumors, but the lack of intrinsic imaging signal precludes noninvasive monitoring of pH-perturbation in tumor microenvironment. We aim to develop a theranostic version of nano-CaCO₃ to noninvasively monitor pH modulation and subsequent tumor response. Materials & methods: We synthesized ferromagnetic core coated with CaCO₃ (magnetite CaCO₃). Magnetic resonance imaging (MRI) was used to determine the biodistribution and pH modulation using murine fibrosarcoma and breast cancer models. Results: Magnetite CaCO₃-MRI imaging showed that nano-CaCO₃ rapidly raised tumor pHe, followed by excessive tumor-associated acid production after its clearance. Continuous nano-CaCO₃ infusion could inhibit metastasis. Conclusion: Nano-CaCO₃ exposure induces tumor metabolic reprogramming that could account for the failure of previous intermittent pH-modulation strategies to achieve sustainable therapeutic effect.