Acidity-Activated Charge Conversion of 177Lu-Labeled Nanoagent for the Enhanced Photodynamic Radionuclide Therapy of Cancer

Nanomaterials in combination with radionuclide therapy (RNT) provide new opportunities for cancer treatment. However, nanomaterials with efficient tumor accumulation have been less exploited for effective radionuclide-based therapy. Here, we report glycol chitosan-based nanoparticles (GCP-NPs) with acidic pH-dependent surface charge conversion for efficient radionuclide-based combination therapy. The nanoplatform can change the surface charge of nanoparticles from slight negative to positive in the acidic tumor microenvironment, which facilitates cellular internalization and penetration and thus improves the tumor accumulation efficiency of nanomaterials. Radiolabeling of GCP-NPs with Tc-99m enables in vivo radioactive imaging in the mouse subcutaneous tumor model, showing 8.1-fold enhanced tumor uptake relative to pH-insensitive control nanoparticles (termed as GCOP-NPs). Afterward, therapeutic radioisotope Lu-177-labeled GCP-NPs (Lu-177-GCP-NPs) that utilize RNT synergistic with photodynamic therapy (PDT) derived from conjugated pyropheophorbide-a within nanoparticles endow superior antitumor efficacy in living cells and tumor-bearing mouse model. More importantly, the combination of RNT and PDT using Lu-177-GCP-NPs can effectively inhibit lung metastasis and eliminate splenomegaly, which is not possible for individual RNT or PDT. Therefore, this study proposes a facile radionuclidebased combination therapy strategy toward complete cancer remission.

Automated summary

This study presents glycol chitosan-based nanoparticles (GCP-NPs) with pH-dependent surface charge conversion for efficient radionuclide-based combination therapy. The nanoplatform can change the surface charge of nanoparticles in the acidic tumor microenvironment, enhancing tumor accumulation efficiency. The radiolabeling of GCP-NPs enables in vivo radioactive imaging and the therapeutic radioisotope Lu-177-labeled GCP-NPs show superior antitumor efficacy in combination with photodynamic therapy (PDT). The combination therapy effectively inhibits lung metastasis and eliminates splenomegaly.