Enhancing Cancer Therapy: Boron-Rich Polyboronate Ester Micelles for Synergistic Boron Neutron Capture Therapy and PD-1/PD-L1 Checkpoint Blockade

Abstract

Malignant cancers, known for their pronounced heterogeneity, pose substantial challenges to monotherapeutic strategies and contribute to the risk of metastasis. Addressing this, our study explores the synergistic potential of combining boron neutron capture therapy (BNCT) with immune checkpoint blockade to enhance cancer treatment efficacy. We synthesized boronrich block copolymer micelles as a novel boron drug for BNCT. Characterization was conducted using nuclear magnetic resonance, gelpermeation chromatography, transmission electron microscopy, and dynamic light scattering. These micelles, with an optimal size of 91.3 nm and a polydispersity index of 0.18, are suitable for drug delivery applications. In vitro assessments on B16F10 melanoma cells showed a 13fold increase in boron uptake with the micelles compared to borophenyl alanine (BPA), the conventional boron drug for BNCT. This resulted in a substantial increase in BNCT efficacy, reducing cell viability to 77% postirradiation in micelletreated cells, in contrast to 90% in BPAtreated cells. In vivo, melanomabearing mice treated with these micelles exhibited an 8fold increase in boron accumulation in tumor tissues versus those treated with BPA, leading to prolonged tumor growth delay (5.4 days with micelles versus 3.3 days with BPA). Moreover, combining BNCT with antiPDL1 immunotherapy further extended the tumor growth delay to 6.6 days, and enhanced Tcell infiltration and activation at tumor sites, thereby indicating a boosted immune response. This combination demonstrates a promising approach by enhancing cytotoxic Tcell priming and mitigating the immunosuppressive effects of melanoma tumors.