MT1-MMP-Targeted Photoimmunotherapy via an IR700-Conjugated Bicyclic Peptide

Photoimmunotherapy (PIT) combines a photoabsorber conjugate with near-infrared light to trigger highly selective cancer cell destruction; however, current antibody-based agents remain expensive and exhibit slow systemic clearance. Here, a membrane-type 1 matrix metalloproteinase (MT1-MMP)-targeted bicyclic peptide was site-selectively conjugated with the photoabsorber IRDye700DX (bcMT1-IR700) to create a nonantibody scaffold for PIT. bcMT1-IR700 was chemically synthesized and confirmed by ESI-MS to possess a 1:1 peptide-to-dye ratio, and the absorption, excitation, and emission signatures of IR700 were maintained. In vitro, bcMT1-IR700 preferentially engaged MT1-MMP-overexpressing HT1080 cells, initially localized to the plasma membrane, and triggered rapid membrane blebbing and loss of viability upon 690 nm irradiation, whereas MT1-MMP-low A549 cells were largely unaffected except at the highest drug and light inputs. Following intravenous administration in HT1080 xenografts, bcMT1-IR700 accumulated rapidly within tumors and exhibited predominant renal clearance, and tumor-directed irradiation at 100 J/cm² significantly inhibited tumor growth relative to light-only and drug-only controls. These findings demonstrate that MT1-MMP-targeted bicyclic peptide-mediated PIT constitutes a viable nonantibody alternative, justifying further optimization of dosing, illumination parameters, and immunocompetent models to fully define its therapeutic potential.