Search

Intravascular brachytherapy requires advances in radio-embolization technologies that combine brilliant radiostability efficacy with a facile and green synthesis route. We report a hybrid-integrated radioactive microsphere strategy using phosphorylcholine-modified lutetium-177 coordinated polymeric microspheres (177Lu-PCMs) that were fabricated via radiation-induced graft polymerization for imaging-guided locoregional intravascular brachytherapy. The underlying formation mechanism of 177Lu-PCMs is elucidated using first-principles computations and density functional theory calculations and 177Lu loading mechanisms was investigated with Near-edge and extended X-ray absorption fine structure spectroscopy. The engineered 177Lu-PCMs exhibit excellent mechanical properties, good hydrophilicity, and controlled sphere diameter. These features provide advantages of ultra-stable and ultra-selective embolic radio-theranostics, which is demonstrated in different preclinical rodent models and isolated human liver tumor tissues. During locoregional intra-arterial brachytherapy, 177Lu-PCMs can be visualized via SPECT to validate the in vivo biodistribution and retention in real time, achieving precise delivery, effective anti-cancer treatment, and a distinguished safety profile without degradation, ectopic embolization, and adverse reactions. Therefore, this study may offer a new avenue for the development of a highly innovative and translational approach for precision intravascular brachytherapy.

Background: Neuropilin-1 (NRP-1) and integrin αvβ3 receptors are both overexpressed in breast cancer. Methods: We developed and synthesized a heterodimeric tracer consisting of Arg−Gly−Asp (RGD) and Ala-Thr-Trp-Leu-Pro-Pro-Arg (ATWLPPR) peptides that simultaneously targets integrin αvβ3 and NRP-1. We then investigated the diagnostic efficacy of RGD-ATWLPPR heterodimeric peptides in MCF-7 xenograft models in mice. DOTA-conjugated RGD-ATWLPPR peptides were then radiolabeled with 68Ga, and the receptor-binding characteristics and tumor-targeting efficacy of 68Ga-DOTA-RGD-ATWLPPR were investigated in vitro and in vivo. We also detected integrin αvβ3 and NRP-1 expression in MCF-7 cells and tumor tissues. Results: The peptide showed high stability in vitro. Static PET/CT imaging studies showed that MCF-7 tumors were clearly visible 30 min and 60 min after 68Ga-DOTA-RGD-ATWLPPR injection. Further, the heterodimer showed higher tumor uptake than 68Ga-DOTA-RGD or 68Ga-DOTA-ATWLPPR alone. High specificity was shown in blocking studies using RGD and ATWLPPR peptides. MicroPET/CT and biodistribution studies using 68Ga-DOTA-RGD-ATWLPPR showed that the tracer specifically targets NRP-1 and integrin ανβ3 receptors. Conclusions: Compared with 68Ga-DOTA-RGD and 68Ga-DOTA-ATWLPPR, 68Ga-DOTA-RGD-ATWLPPR has higher binding affinity, better targeting efficiency, and longer tumor retention time. It therefore has potential as an imaging probe for breast cancer detection.

Efforts have been devoted to select eligible candidates for PD-1/PD-L1 immune checkpoint blocker (ICB) immunotherapy based on radiopharmaceuticals. Here, we have observed a tracking-to-triggering (referred to as “T2T”) immunoediting effect of the employed radionuclides. In particular, we found the usefulness of 2-[18F]FDG in cancer ICB therapy. Given that the PD-L1 expression is upregulated after the administration of various radiotracers, the predictive result from PET/SPECT imaging should be treated with caution. Viewed positively, radiotracers are potential immunomodulators to create an immune-favorable microenvironment for tumor immunotherapy. Improving αPD-L1 mAb utilization and significant tumor growth delay are observed when the personalized therapeutic alliance of radiotracer stimulation and ICB are employed. This new paradigm has the potential to expand the traditional tumor theranostic model and implement precision cancer immunotherapy.