CaCO3 nanoparticles as an ultra-sensitive tumor-pH-responsive nanoplatform enabling real-time drug release monitoring and cancer combination therapy

The exploration of stimuli-responsive nano-theranostics provides powerful tools for simultaneously enhancing the accuracy and efficiency of cancer therapies. Herein, we develop mono-dispersed CaCO3 nanoparticles modified with polyethylene glycol (PEG) as a multifunctional nano-carrier for efficient loading of both Mn2+-chelated chlorin e6 (Ce6(Mn)) as a photosensitizer, and doxorubicin (DOX) as a chemotherapy drug. Our CaCO3@Ce6(Mn)-PEG(DOX) nanoparticles, while being stable under physiological pH at 7.4, appear to be highly sensitive to reduced pH and would be rapidly degraded under slightly acidic environment, effectively releasing loaded therapeutic agents. Interestingly, owing to released Ce6(Mn), those nanoparticles show an interesting pH-dependent T1 signal enhancement under magnetic resonance (MR) imaging, which could be utilized for real-time monitoring of drug release. As discovered by MR and fluorescence imaging, intravenously (i.v.) injected CaCO3@Ce6(Mn)/DOX-PEG could gradually accumulate in the tumor, contributing to a superior synergistic anti-tumor effect in the combined photodynamic & chemotherapy. In conclusion, we have developed a tumor-pH-activated nanocarrier based on biodegradable CaCO3 nanoparticles, which may be an ideal cancer theranostic nanoplatform with substantial potential for future clinical translation.