Cancer-targeted pro-theranostic bi-metallic organocoordination nanoparticles

Rationale: Cancer remains a leading cause of mortality, with aggressive, treatment-resistant tumors posing significant challenges. Current combination therapies and imaging approaches often fail due to disparate pharmacokinetics and difficulties correlating drug delivery with therapeutic response. Methods: In this study, we developed radionuclide-activatable theranostic nanoparticles (NPs) comprising folate receptor-targeted bimetallic organo-nanoparticles (Gd-Ti-FA-TA NPs). Polyvalent tannic acid was used to coordinate titanium (Ti), a reactive oxygen species (ROS)-generating catalyst, gadolinium (Gd), a magnetic resonance imaging (MRI) contrast agent, and cypate, a near-infrared fluorescent dye. Results: The NPs exhibited higher magnetic field-dependent relaxivities (r1 = 20.8 mM^-1s-1, r2 = 72.1 mM^-1s-1) than Gd-DTPA (r1 = 4.8 mM^-1s-1, r2 = 4.9 mM^-1s-1) on a 3 T MRI scanner. Tannic acid coordination reduced the Ti band gap from 3.3 eV in TiO₂ NPs to 2.0 eV, tripling ROS generation under UV light exposure. In breast cancer models (4T1 and PyMT-Bo1), Cerenkov radiating radiopharmaceuticals activated Gd-Ti-FA-TA NPs in vitro and in vivo, generating cytotoxic ROS to inhibit tumor cell viability and prevent tumor progression. In vivo, the NPs selectively accumulated in 4T1 tumors and enhanced both T1 and T2 MRI contrast, highlighting a strategy to locally activate cytotoxic ROS generation with radiopharmaceuticals for cancer treatment, utilizing cross-modality PET/MRI and optical imaging for shallow and deep tissue visualization. Conclusion: The integrated nanoplatform allows direct imaging of drug delivery, providing guidance for the optimal timeline to activate therapeutic effects of pro-theranostic NPs via external triggers such as radionuclide-stimulated dynamic treatment.