Targeted photodynamic elimination of HER2 + breast cancer cells mediated by antibody-photosensitizer fusion proteins.

Breast cancer has emerged as the leading cause of cancer death in women worldwide. The high recurrence and metastasis rates of malignant tumors impose significant limitations on existing mainstream treatments, including surgery, chemotherapy, and radiotherapy. Photodynamic therapy (PDT) is a clinically validated approach for cancer treatment. PDT requires three elements, photosensitizer, light, and oxygen, and mainly relies on the production of singlet oxygen (¹O₂) to elicit damage to the cancer tissue. In this study, we explored targeted photodynamic elimination of breast cancer cells overexpressing human epidermal growth factor receptor 2 (HER2). HER2 is enriched on the surface of certain cancer cells and targeted by commercially available monoclonal antibodies, including Trastuzumab, in the treatment of breast and stomach cancers. We engineered chimeric fusion proteins composed of Trastuzumab and genetically encoded photosensitizers, including SOPP3 and miniSOG. The production of ¹O₂ by these fusion proteins was directly measured by near-infrared spectroscopy centered at 1270 nm and further evaluated in the assay of targeted photodynamic neutralizations of SARS-CoV-2 pseudoviruses. To enhance the internalization of the antibody-photosensitizer fusion protein, cell-penetrating peptides (CPPs) were added to the fusion protein. HER2-positive (HER2⁺) cancer cells were incubated with the antibody-photosensitizer fusion protein and then exposed to light illumination. Cell viability assays revealed an over 50% reduction in cancer cell survival, with minimal impacts on the cells from the control group. In addition, we observed a long-lasting, over 24-h inhibition of the growth of the cancer cells after photodynamic treatment. Thus, based on these assays at the molecular and cellular levels, this study established a targeted photodynamic approach that can potentially be developed as an effective PDT for cancer treatment.