The classical photodynamic therapy (PDT) requires external light to activate photosensitizers for cancer treatment. However, limited tissue penetration of light has been a long-standing challenge for PDT to cure malignant tumors in deep tissues. Recently, Cerenkov radiation (CR) emitted by radiotracers such as F-fluorodeoxyglucose (F-FDG) has become an alternative and promising internal light source. Nevertheless, fluorine-18 (F-18) only releases 1.3 photons per decay in average; consequently, injection dose of F-18 goes beyond 10-30 times more than usual to acquire therapeutic efficacy because of its low Cerenkov productivity. Gallium-68 (Ga-68) is a favorable CR source owing to its ready availability from generator and 30-time higher Cerenkov productivity. Herein, we report, for the first time, the use of Ga-68 as a CR source to activate dextran-modified TiO nanoparticles (D-TiO NPs) for CR-induced PDT. Compared with F-FDG,Ga-labeled bovine serum albumin (Ga-BSA) inhibited the growth of 4T1 cells and exhibited significantly stronger DNA damage to tumor cells. In vivo studies showed that the tumor growth was almost completely inhibited when tumor-bearing mice were treated with a combination of D-TiO NPs and Ga-BSA. This study proved that Ga-68 is a more potent radionuclide for PDT than F-18 both in vitro and in vivo offered a promising strategy of using a diagnostic dose of radioactivity to achieve depth-independent cancer therapy without using any external light source.

Recently, metal−organic frameworks (MOFs) or coordination polymers have shown great potential for drug delivery, yet little has been done to study how particle size affects their tumor targeting and other in vivo features. This plight is probably due to two challenges: (1) the lack of a biocompatible method to precisely control the size of drugloaded MOFs and (2) the lack of a robust and facile radiolabeling technique to trace particles in vivo. Here, we report a one-pot, rapid, and completely aqueous approach that can precisely tune the size of drug-loaded MOF at room temperature. A chelator-free 64 Cu-labeled method was developed by taking the advantage of this rapid and aqueous synthesis. Cancer cells were found to take drug-loaded MOFs in a size-dependent manner. The in vivo biodistribution of drugloaded MOF was analyzed with positron emission tomography imaging, which, as far as we know, was used for the first time to quantitatively evaluate MOF in living animals, unveiling that 60 nm MOF showed longer blood circulation and over 50% higher tumor accumulation than 130 nm MOF. Altogether, this size-controlled method helps to find the optimal size of MOF as a drug carrier and opens new possibilities to construct multifunctional delivery systems for cancer theranostics.