Abstract
Pancreatic cancer will gradually become the second leading cause of cancer death due to its poor suitability for surgical treatment, frequent recurrence and metastasis, and insensitivity to radiotherapy and chemotherapy. Strategies for precise early detection and effective targeted treatment of pancreatic cancer are urgently needed. Because of its unique advantages, molecular targeted contrast-enhanced ultrasound imaging (CEUI) has generated new opportunities to overcome this challenge. The aim of this study was to explore multifunctional nanobubbles named IR780-NBs-DTX as novel ultrasound contrast agents (UCAs) for dual-mode targeted imaging and photothermal ablation combined with chemotherapy for pancreatic cancer. An optimized “film hydration method” was used to prepare IR780-NBs-DTX in this research. The characteristics and ability of the new UCAs were detected via in vitro, in vivo and ex vivo experiments. The initial dose of 0.15 mg IR-780 iodide/1.0 mg DTX was considered to be the best formula for IR780-NBs-DTX, and the concentration of 6 ×106 bubbles/mL was best for CEUI. The excellent characteristics of IR780-NBs-DTX, including a uniform nanoscale particle size (349.8± 159.1 nm, n= 3), good performance in dual-mode imaging, high stability and reliable biocompatibility, were also proven. In the in vitro cell experiments, IR780-NBs-DTX targeted more pancreatic cancer cells than the control treatments, and the targeting rate was approximately 95.6± 1.7%. Under irradiation with an 808 nm laser, most cells died. Furthermore, the in vivo study demonstrated that IR780-NBs-DTX could precisely detect pancreatic cancer through near infrared fluorescence (NIRF) imaging and CEUI, and the tumor almost disappeared at 18 days after combined treatment. In ex vivo experiments, immunohistochemistry (IHC) and immunofluorescence (IF) showed that the expression of HSP70 increased and that of PCNA decreased, and many apoptotic tumor cells were observed by TUNEL staining in the IR780-NBs-DTX group. The newly prepared IR780-NBs-DTX are novel nanosized UCAs with high efficiency for dual-mode molecular targeted imaging and combined therapy, and they may have future potential applications in the precise detection and effective targeted therapy of small and metastatic lesions in the early stage of pancreatic cancer.
Highlights
Pancreatic cancer will gradually become the second leading cause of cancer death due to its poor suitability for surgical treatment, frequent recurrence and metastasis, and insensitivity to radiotherapy and chemotherapy
We prepared multifunctional nanobubbles named IR780-NBs-DTX as ultrasound contrast agents (UCAs); these NBs were used for pancreatic cancer diagnosis with dual-mode imaging and targeted treatment with photothermal therapy combined with chemotherapy
Different shell membranes of NBs were explored in previous s tudies[12], lipids were selected in this research; as the shell membranes of NBs are more conducive to contrast-enhanced ultrasound imaging (CEUI) and IR-780 iodide and DTX have liposoluble properties and are more carried in lipid shell membranes[10], the best formulations, with an initial dosage of 0.15 mg IR-780 iodide/1.0 mg DTX and an appropriate concentration (6 × 1 06 bubbles/mL) of IR780-NBs-DTX for CEUI, were verified in this study
Summary
Pancreatic cancer will gradually become the second leading cause of cancer death due to its poor suitability for surgical treatment, frequent recurrence and metastasis, and insensitivity to radiotherapy and chemotherapy. The aim of this study was to explore multifunctional nanobubbles named IR780-NBsDTX as novel ultrasound contrast agents (UCAs) for dual-mode targeted imaging and photothermal ablation combined with chemotherapy for pancreatic cancer. The in vivo study demonstrated that IR780-NBs-DTX could precisely detect pancreatic cancer through near infrared fluorescence (NIRF) imaging and CEUI, and the tumor almost disappeared at 18 days after combined treatment. The newly prepared IR780-NBs-DTX are novel nanosized UCAs with high efficiency for dual-mode molecular targeted imaging and combined therapy, and they may have future potential applications in the precise detection and effective targeted therapy of small and metastatic lesions in the early stage of pancreatic cancer. An increasing number of studies have verified that IR-780 iodide is effective in high-intensity NIRF imaging, with spontaneous accumulation in tumors and the ability to mediate cancer photothermal therapy (PTT) and photodynamic therapy (PDT)[19]. We loaded IR-780 iodide into NBs and preliminarily verified that the conjugates could target female tumor cells and glioma cells and performed NIRF and CEUI imaging and photothermal ablation of tumors for 15 d ays[18,24]
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