Limantrafin-BODIPY Conjugates Reduce Stemness and Metastatic Potential via Superoxide Driven Phototherapy in Triple...

Type-I photosensitizers are advantageous for treating hypoxic tumors compared to singlet oxygen (¹O₂)-based photodynamic therapy (PDT) agents. However, efficient and selective Type-I reactive oxygen species (ROS) generators remain scarce. Here, Limantrafin (Notch1 transcription inhibitor) conjugated BODIPY photosensitizer is reported that selectively produces superoxide radicals (O₂•⁻) upon green light irradiation and exhibits a significantly higher phototherapeutic index (PI) than its structural analog. Theoretical studies and delayed photoluminescence measurements indicate that efficient intersystem crossing from the singlet excited state (S₁) to an intermediate triplet (T₂), followed by relaxation to a long-lived triplet state (T₁), may facilitate effective electron transfer to molecular oxygen. In triple-negative breast cancer (TNBC) cells (MDA-MB-231), the lead compound shows significantly high PI (>3700) by low-intensity green light irradiation. Furthermore, encapsulation in glycopolymer-based nanoparticles enhances cancer cell selectivity and therapeutic efficacy. Interestingly, there is also a reduction in multiple stemness-associated gene expression and downregulation of Cluster of Differentiation 44 (CD44) and Intercellular Adhesion Molecule 1 (ICAM-1/CD54) surface protein markers that promote stemness and immune evasion in TNBC. This dual action may impair tumor aggressiveness, recurrence, and promote immunogenic cell death. The findings highlight that the conjugation of the Notch1 inhibitor, Limantrafin, with BODIPY widens the horizon of Type-I photosensitizers to design next-generation PDT agents.