A self-amplified necrotic targeting theranostic nanoparticle with deep tumor penetration for imaging-guided personalized chemo-photodynamic therapy

Abstract

Nano-based drug delivery system (NDDS) for photodynamic therapy (PDT) has emerged as an innovative strategy for enhanced anticancer treatment, however, the limited penetration depth of nanocarrier and poor therapeutic efficacy of PDT against hypoxic or necrotic cells might cause unsatisfactory outcomes such as tumor recurrence. Thus, developing a therapeutic modality that is highly penetrable and has synergistic effects with PDT in wiping out hypoxic tumorous cells is an unmet need. Herein, the hybrid Cy7-NO2/HPC/TPZ NPs were prepared by doping photosensitizer-hypericin (HPC), hypoxic activated chemotherapeutic prodrug-tirapazamine (TPZ), and hypoxic detection NIR probe Cy7-NO2. Aside from acting as the photosensitizer, the nanoparticles inherited the necrotic targeting ability from HPC, which allowed them to accumulate precisely at tumors with satisfactory penetration depth. Then, owing to the increasing tumor necrosis during the treatment, the ensuing positive feedback loop between necrotic degree and elevated tumor accumulation would occur. Besides, the contradictory demand of oxygen supported the enhanced anticancer efficacy by realizing chemo-co-photodynamic therapy with synergistic combination of HPC and TPZ. Due to the hypoxic heterogenicity in solid tumors, therapeutical outcomes of PDT and TPZ varied significantly under different circumstances. Thus, the Cy7-NO2 probe in NPs was applied to detect real-time hypoxic degree in advance for operators to adjust the optimal ratio of TPZ to HPC for different therapeutic scenarios and finally realized a specific and personalized dosing strategy. In summary, this synergistic chemophotodynamic nanomedicine proposed an innovative site-specific targeting strategy for improved tumor penetration via constructing a positive feedback loop between necrosis degree and tumor accumulation, as well as providing an option for imaging-guiding personalized theranostic strategy.