Fan Zhang

NIR-II bioluminescence for in vivo high contrast imaging and in situ ATP-mediated metastases tracing

AbstractBioluminescence imaging has been widely used in life sciences and biomedical applications. However, conventional bioluminescence imaging usually operates in the visible region, which hampers the high-performance in vivo optical imaging due to the strong tissue absorption and scattering. To address this challenge, here we present bioluminescence probes (BPs) with emission in the second near infrared (NIR-II) region at 1029 nm by employing bioluminescence resonance energy transfer (BRET) and two-step fluorescence resonance energy transfer (FRET) with a specially designed cyanine dye FD-1029. The biocompatible NIR-II-BPs are successfully applied to vessels and lymphatics imaging in mice, which gives ~5 times higher signal-to-noise ratios and ~1.5 times higher spatial resolution than those obtained by NIR-II fluorescence imaging and conventional bioluminescence imaging. Their capability of multiplexed imaging is also well displayed. Taking advantage of the ATP-responding character, the NIR-II-BPs are able to recognize tumor metastasis with a high tumor-to-normal tissue ratio at 83.4.

SN-38 Sensitizes BRCA-Proficient Ovarian Cancers to PARP Inhibitors through Inhibiting Homologous Recombination Repair

As a multifunctional protein posttranslational modification enzyme in eukaryotic cells, Poly-ADP-ribose polymerase (PARP) acts as a DNA damage sensor, which helps to repair DNA damage through recruiting repair proteins to the DNA break sites. PARP inhibitors offer a significant clinical benefit for ovarian cancer with BRCA1/2 mutations. However, the majority of ovarian cancer patients harbor wild-type (WT) BRCA1/2 status, which narrows its clinical application. Here, we identified a small compound, SN-38, a CPT analog, which sensitizes BRCA-proficient ovarian cancer cells to PARP inhibitor treatment by inhibiting homologous recombination (HR) repair. SN-38 treatment greatly enhanced PARP inhibitor olaparib induced DNA double-strand breaks (DSBs) and DNA replication stress. Meanwhile, the combination of SN-38 and olaparib synergistically induced apoptosis in ovarian cancer. Furthermore, combination administration of SN-38 and olaparib induced synergistic antitumor efficacy in an ovarian cancer xenograft model in vivo. Therefore, our study provides a novel therapeutic strategy to optimize PARP inhibitor therapy for patients with BRCA-proficient ovarian cancer.

Molecular Imaging of Ovarian Follicles and Tumors With Near‐Infrared II Bioconjugates

AbstractFollicular tracking is typically conducted using ultrasound technology, but its effectiveness is constrained by limited resolution. High‐resolution imaging of deep tissues can be accomplished using luminescence imaging in the near‐infrared II window (NIR‐II, 1000–1700 nm); however, the contrast agents that are used lack specificity. Here, it is reported that the FDA‐approved indocyanine green (ICG)‐conjugated recombinant human chorionic gonadotropin (hCG) protein can target early follicles with long‐term effectiveness. A novel high‐resolution NIR‐II imaging approach is developed for monitoring follicular development as well as ovulation using multi‐color imaging of ovarian vessels with a combination of non‐overlapping downconversion nanoparticles (DCNPs). The results showed that the ability to monitor early follicles of around 50 µm in diameter exceeded the spatial and temporal resolution of ultrasound or MRI without the reproductive damage associated with computed tomography radiation, and this enabled the clinical identification of the follicular reserve in patients with infertility diseases such as polycystic ovary syndrome (PCOS). In addition, NIR‐II imaging clearly targeted ovarian tumors and showed micro‐metastatic lesions, thus providing a new tool for monitoring tumors in vivo and guiding surgical resection.