The Application Of Near Infrared Fluorescent Dye For Prostate Cancer Imaging And Therapy

The incidence of prostate cancer has ranked the top among all malignancies in male in the occidental world, posing great threat to men’s health. In our country, the incidence of prostate cancer is also rising up and there is a trend toward younger men in the patient population. Localized prostate cancer at an early stage can be treated by various methods including radical prostatectomy and radiation therapy. However, patients with early-stage prostate cancer often lack symptoms until disease progresses to adjacent tissue or even bone metastasis occurs. The delayed symptoms directly affect the therapeutic outcome. Therefore, improvements in early diagnosis and treatment are of great importance in the fight against prostate cancer.Burgeoning techniques of molecular imaging utilize target-specific probes to detect subtle changes at the cellular and molecular level, thereby realizing functional imaging analysis. Using probes with different targets, molecular imaging can reach multiple goals including early diagnosis, intraoperative imaging guidance, therapeutic monitoring and prognosis evaluation, exerting a critical role during all-course management of diseases. In comparison with conventional imaging techniques, molecular imaging displays higher sensitivity and accuracy, with huge advantages in distinguishing benign and malignant lesions, identifying minute tumor, delineating tumor border and functional imaging of tumor.Near infrared imaging is an optical imaging technique in molecular imaging that has attracted extensive attention in recent years, with distinct features of fast, portable and sensitive imaging without safety concerns about radiotoxicity. Compared to visible light, near infrared light presents with deeper tissue penetrance that allows for deep-tissue imaging. Near infrared probes with cancer targeting ability is crucial for cancer-specific imaging. Previous studies from our group have discovered a class of organic near infrared heptamethine carbocyanine dyes with excellent near infrared fluorescence imaging capability including IR780 and IR783. These dyes can accumulate in cancer cells without conjugating to specific targeting moieties. Herein the fluorescent characteristics of IR780 iodide and IR783 were determined. In vitro cell studies and prostate cancer models in nude mice were applied to fully evaluate whether these dyes are applicable for near infrared imaging of prostate cancer. The underlying mechanism of selective dye accumulation in cancer cells was also revealed. Finally, we sought to synthesize a novel multifunctional near infrared compound through the bioconjugation of IR780 iodide and abiraterone, a novel CYP17 inhibitor approved for treating metastatic castration-resistant prostate cancer. Two subjects in this study are as follows:1. Near infrared fluorescence imaging of prostate cancer using IR780 and IR783We first systemically determined the spectral properties of these two near infrared dyes, IR780 iodide and IR783, at various concentrations and in different solvents. Prostate cancer cells were stained by these dyes at different concentrations for fluorescence observance and cytotoxicity studies. The underlying mechanism of dye accumulation in cancer cells was analyzed. In the aim of evaluating the potential use of near infrared dyes in cytological analysis, blood samples from health volunteers were spiked with prostate cancer cells and then stained by these dyes to detect cancer cells. Different types of prostate cancer model were established using athymic nude mice. After that, near infrared dyes were injected to define whether near infrared live imaging of prostate cancer using these dyes are feasible and to observe in vivo bio-distribution of near infrared dyes. It was revealed that both IR780 iodide and IR783 displayed stable photophysical characteristics and favorable biocompatibility. Near infrared dyes realized selective cancer imaging at very low concentration. A subtype of organic anion transporting polypeptides OATP1B3 might implicate in the trans-membrane transportation of dyes. Cytological analysis using near infrared dyes identified a large population of cancer cells that mixed into blood samples. Results from in vivo live imaging documented that near infrared dyes are feasible for diagnostic imaging of prostate cancer.2. Synthesis of a novel multifunctional near infrared fluorescent compound Abi-780In the following study, we attempted to synthesize a novel multifunctional near infrared fluorescent compound through the bioconjugation of IR780 iodide and abiraterone, and then tested both imaging capability and anti-cancer effects of the new compound Abi-780. It was revealed that Abi-780 displayed fluorescence enhancement in serum and maintained excellent photophysical characteristics as well as favorable biocompatibility. Besides the capability of near infrared fluorescence imaging, Abi-780 exerted an inhibitory role on prostate cancer proliferation, migration and invasion potential. It also induced apoptosis in prostate cancer cells. The new compound Abi-780 could be applied for in vivo diagnostic imaging of prostate cancer, meanwhile, it remarkably inhibited the tumor growth in athymic nude mice without significant toxicity. All these suggested Abi-780 acts as an ideal multifunctional agent for both cancer imaging and therapy.In conclusion, near infrared fluorescence imaging of prostate cancer using IR780 and IR783 are safe and reliable. Constructing multifunctional theranostic probes based on near infrared fluorescent dyes can simultaneously realize diagnostic imaging, treatment and therapeutic evaluation of prostate cancer, which is conducive to improving treatment strategies and inspiring new thoughts for prostate cancer management.