Dongban Duan,Hui Liu,Yang Xu,Yuxiang Han,Mengxin Xu,Zhengchu Zhang,Zhibo Liu
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 18F-fluorodeoxyglucose (18F-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 TiO2 nanoparticles (D-TiO2 NPs) for CR-induced PDT. Compared with 18F-FDG, 68Ga-labeled bovine serum albumin (68Ga-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-TiO2 NPs and 68Ga-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.
Traditional photodynamic therapy (PDT) suffers from poor tissue penetration due to using external light as excitation source. Cerenkov radiation (CR) from radionuclides can serve as an internal light source to activate photosensitizers inside lesion tissues. Using CR instead of external light in PDT is thought to be an effective way to overcome the shortcoming of traditional PDT. However, the weakness of CR emission limits the outcomes of CR-induced PDT (CR-PDT). We anticipated that CR-induced combined therapy could effectively enhance the therapeutic outcome of CR-PDT. Herein, a ROS-responsive Chemo-PDT agent ( TTC ) was synthesized by conjugation of tetraphenylporphyrin (photosensitizer) with camptothecin (chemotherapeutic drug) through a ROS-cleavable thioketal linker. Under activation by CR emission from gallium-68 ( 68 Ga), the porphyrin moiety could generate ROS , which then cleaves the thioketal linker to induce the subsequent release of CPT. Using [ 68 Ga]Ga-NOTA-Nb109 as an intracellular CR emitter, in comparison with its non-cleavable analogue ( TUC ) only displaying phototoxicity, TTC exhibited much higher cytotoxicity toward A375-hPD-L1 cells due to its combined effect of PDT and chemotherapy. Our work presents a new strategy to use ROS-responsive Chemo-PDT agent to improve the outcomes of CR-PDT.
Prostate-specific membrane antigen (PSMA) is a prostate cancer target that plays a crucial role in prostate cancer diagnosis and therapy. Herein, a novel dual-targeted imaging probe, [68Ga]Ga-FAPI-PSMA, was prepared by radiolabeling conjugated DOTA-FAPI-PSMA with the short half-life radionuclide gallium-68 (68Ga), which is dedicated to prostate cancer diagnostic imaging. In vitro, [68Ga]Ga-FAPI-PSMA had higher affinity for the PSMA and FAP high-expressing cell lines 22Rv1 and U87 MG with IC50 values of 4.73 and 2.10 nM, respectively, than in the corresponding negative expression cell lines PC3 and A549, and significant differences in cell uptake were also observed. In vivo, [68Ga]Ga-FAPI-PSMA was rapidly cleared from the body, and the estimated radiation dose was relatively low compared with several other FAPI probes. In 22Rv1 and U87 MG tumor xenografts, [68Ga]Ga-FAPI-PSMA rapidly accumulated in tumors after administration, and the best images can be obtained at 1 h postinjection. In conclusion, the dual-targeted probe [68Ga]Ga-FAPI-PSMA was successfully prepared for in vivo prostate cancer PET/CT imaging.
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