Nucleus-targeting near-infrared nanoparticles based on TAT peptide-conjugated IR780 for photo-chemotherapy of breast cancer

Breast cancer is the most common malignant tumor in women. Phototherapy, mainly including photothermal therapy (PTT) and photodynamic therapy (PDT), shows many advantages such as high spatial selectivity, noninvasive nature, and negligible drug resistance for breast cancer treatment. Additionally, recent investigations have shown that nucleus-targeted PTT can kill cancer cells more directly and more efficiently by "burning" cell nuclei closely. In this study, we developed a nucleus-targeting nanoparticle system for combining PTT/PDT and chemotherapy to treat breast cancer. IR780, a near-infrared (NIR) fluorescence dye that has potent anticancer efficacy of PTT and PDT, was firstly conjugated with TAT peptide through substitution reaction between chlorine atom and sulfhydryl group, thus obtained a conjugate TAT-IR780 with notably enhanced water solubility and optical stability. Next, chemotherapeutic drug doxorubicin (DOX) and TAT-IR780 self-assembled in aqueous medium to form TID nanoparticles with a small size of approximately 100 nm. Both in vitro and in vivo, TID nanoparticles showed greatly enhanced PTT/PDT efficiencies as compared with free IR780. Through the mediation of TAT peptide, TID nanoparticles significantly improved the cellular internalization of IR780 in breast cancer cells and delivered it mostly to the perinuclear region. Upon laser irradiation at 785 nm, TID nanoparticles rapidly destroyed the genetic substances and potently induced the apoptosis of breast cancer cells. In the mice bearing breast cancer, intratumoral injection of TID nanoparticles with local laser irradiation realized fluorescence and photothermal imaging-guided combination treatment of nucleus-targeted PTT/PDT and chemotherapy, and achieved significant synergistic effects on breast tumor ablation and recurrence. In summary, this study provides a nucleus-targeting nanoplatform for dual imaging-guided photo-chemotherapy for breast cancer treatment.