Is Exercise Treadmill Time or Reduction in Myocardial Ischemia the Appropriate Primary Endpoint to Assess Success of Percutaneous Coronary Intervention in Stable Angina (ORBITA)?

Abstract

1 Objectives: In vivo fluorescence imaging in the second near-infrared window region (NIR-II, 1,000-1,700 nm) holds great promise for providing deeper tissue penetration, higher spatial resolution and signal-to-noise ratios than those obtained at the conventional near-infrared window I region (NIR-I, 650-900 nm), because of its reduced tissue autofluorescence and photon scattering, and low levels of photon absorption of long-wavelength photons. Developing semiconducting polymer nanoparticles (NPs) with a strong absorption peak at 808 nm, excellent photostability and biocompatibility will be highly important and find broad uses for efficient in vivo NIR II imaging. Methods: A diketopyrrolopyrrole-based semiconducting polymer NP (PDFT1032) as a novel NIR-II fluorescent probe has been developed for the first time. The versatile use of PDFT1032 for several important biomedical applications in NIR-II window have been demonstrated, including NIR-II optical imaging of tumor using subcutaneous osteosarcoma model, assessing of vascular embolization therapy of tumor, and sentinel lymph node biopsy (SLNB) with high spatial and temporal resolution. Results: Hydrophobic PDFT were encapsulated with the amphiphilic PEGylated phospholipid to provide excellent water-soluble and biocompatible PDFT1032 NP, with high monodispersity, homogeneity, particle size 68 nm in PBS, a unique absorption peak at 809 nm, and fluorescence emission peak at 1,032 nm. No apparent cytotoxicity of PDFT1032 to NIH3T3 cells was observed even with the concentration up to 150 μg/mL. In addition, the H&E staining of the major organs, including heart, liver, spleen, lung, and kidney, at 21 days after intravenous injection of PDFT1032 (1 mg/kg) demonstrated no obvious damages and necrotic lesions. Further NIR-II imaging showed that the nanoprobe clearly visualized the subcutaneous osteosarcoma up to 3 days with high tumor-to-background ratio (TBR, up to 3.4 ± 0.16 for lateral position and 2.4 ± 0.15 for prone position). Ex vivo fluorescent images also demonstrated the favorable contrast between tumor and skin because of the low fluorescence signal of skin. Lastly, with the help of NIR-II imaging and PDFT1032 nanoprobe, the axillary lymph node was clearly identified within short time and dissected from the ambient tissue and then confirmed by histological analysis. Conclusions: Excellent biocompatibility, favorable hydrophilicity, and desirable chemical and optical properties render NIR-II PDFT1032 a highly promise probe with a potential of being widely applicable in clinical imaging and surgical treatment of malignancy.