ABSTRACT
Objective:To investigate the effect of self-made phase-change nanodroplets IR780/FA-Nds-DTX as molecular targeted ultrasound contrast agents for accurate diagnosis and combined targeted therapy of pancreatic cancer.Methods:Pancreatic cancer cell lines were cultured in vitro and 50 tumor bearing nude mouse models were established. The experimental group (IR780/ FA-NdS-DTX) and four control groups[ normal saline, Nds(FITC), FA-Nds (FITC) and IR-780] were divided to verify dual-mode targeted imaging. The imaging using the IVIS Imaging System verified the high-efficiency targeted detection ability and near-infrared fluorescence imaging of IR780/FA-Nds-DTX for tumors in vivo, phase transformation induced by low-intensity focused ultrasound and further contrast-enhanced ultrasound imaging verified the high-efficiency aggregation of IR780/FA-Nds-DTX in local tumors and accurate evaluation of tumor contour. The therapeutic effect was observed in the experimental group (IR780/FA-Nds-DTX) and four control groups (FA-Nds-IR780, FA-Nds-DTX, FA-Nds and normal saline). After low-intensity focused ultrasound irradiation for 30s induced microbubble blasting after phase transformation in each group, 808nm photothermal therapy apparatus was used to irradiate tumor area in each group. Two-dimensional ultrasound was used to monitor the changes in tumor volume in each group before and at 3 d, 9 d, 15 d after treatment, and the changes in tumor volume rate and inhibition in each group were statistically analyzed and compared.Results:The amount of IR780/ FA-Nds-DTX locally targeted aggregation was the largest, and the average fluorescence intensity of tumor in the experimental group was significantly higher than that of the control groups: IR780/ FA-Nds-DTX group compared with Nds(FITC) group[(5.12±0.69)×10 7 vs (1.06±0.23)×10 7, P<0.05], IR780/FA-Nds-DTX group compared with FA-Nds (FITC) group [(5.12±0.69)×10 7 vs (2.98±0.34)×10 7, P<0.05], IR780/FA-Nds-DTX group compared with IR-780 group [(5.12±0.69)×10 7 vs (1.54±0.42)×10 7, P<0.05], and there was no fluorescence in tumor area in saline group. Further contrast-enhanced ultrasound imaging after nanodroplet phase transformation could more accurately locate the tumor boundary. After 15 days of photothermal ablation combined with chemotherapy, the growth rate of tumor volume in the IR780/ FA-Nds-DTX treatment group was significantly lower than that in the control groups: IR780/FA-Nds-DTX group compared with FA-Nds-IR780 group[(0.105±0.075) vs (0.405±0.175), P<0.05], IR780/ FA-Nds-DTX group compared with FA-Nds-DTX group [(0.105±0.075) vs (1.385±0.035), P<0.05], IR780/ FA-Nds-DTX group compared with FA-Nds group [(0.105±0.075) vs (2.255±0.105), P<0.05], IR780/ FA-Nds-DTX group compared with normal saline group [(0.105±0.075) vs (2.185±0.155), P<0.05]. And the tumor inhibition rate increased significantly: IR780/ FA-Nds-DTX group compared with FA-Nds-IR780 group [(0.93±0.06) vs (0.48±0.17), P<0.05], IR780/ FA-Nds-DTX group compared with FA-Nds-DTX group [(0.93±0.06) vs (-0.51±0.105), P<0.05], IR780/ FA-Nds-DTX group compared with FA-Nds group [(0.93±0.06) vs (-1.63±0.115), P<0.05], IR780/ FA-Nds-DTX group compared with normal saline[(0.93±0.06) vs (-1.35±0.245), P<0.05]. Conclusions:The self-made phase-change ultrasound contrast agents IR780/FA-Nds-DTX have good potential clinical value in targeted detection and combined therapy of pancreatic cancer with small lesions or even metastases.
ABSTRACT
Pancreatic cancer is the seventh most common cause of cancer deaths worldwide.Although more and more progress of oncotherapy has been achieved in recent years,very few progress has been achieved in pancreatic cancer.This review summarizes the molecular signaling pathway and relevant targeting drug,their recent clinical and experimental findings of this disease.It also presents the situation and future development of targeting treatment in pancreatic cancer.
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Detection of biomarkers benefited many advanced non-small cell lung cancer (NSCLC ) patients .In recent years ,epidermal growth factor (EGFR) tyrosine kinase inhibitors (TKIs) represented by Gefitinib ,Erlotinib ,Afatinib and an-aplastic lymphoma kinase (ALK) TKIs represented by Crizotinib have remarkable efficacy .However ,the efficacy for most first-generation EGFR-TKI and ALK-TKI is weakened due to secondary resistance .Currently ,the third-generation EGFR-TKI which successfully against drug resistance is based on research and development of the second-generation .In addition ,there are many other targeted inhibitors of mutation sites for advanced NSCLC .Unfortunately ,the largest proportion of Kirsten rat sar-coma viral oncogene homolog (K-RAS) mutation is not targetable with small molecule inhibitors currently .Therefore ,based on mechanisms exploration of tumor driven gene mutation ,its target drug research and development will be greatly addressed in the future .
ABSTRACT
RSK2 is a downstream signaling protein of ERK1 and ERK2 and plays a key role in physiological homeostasis. For this reason, RSK2 is a highly conserved protein among the p90RSK family members. In its location in the signaling pathway, RSK2 is a kinase just upstream of transcription and epigenetic factors, and a few kinases involved in cell cycle regulation and protein synthesis. Moreover, activation of RSK2 by growth factors is directly involved in cell proliferation, anchorage-independent cell transformation and cancer development. Direct evidences regarding the etiological roles of RSK2 in cancer development in humans have been published by our research group illustrating that elevated total- and phospho-RSK2 protein levels mediated by ERK1 and ERK2 are higher in skin cancer tissues compared to normal skin tissues. Notably, it has been shown that RSK2 ectopic expression in JB6 Cl41 cells induces cell proliferation and anchorage-independent cell transformation. Importantly, knockdown of RSK2 suppresses Ras-mediated foci formation and anchorage-independent colony growth of cancer cells. Kaempferol is a one of the natural compounds showing selectivity in inhibiting RSK2 activity in epidermal growth factor-induced G1/S cell cycle transition and cell transformation. Thus, ERKs/RSK2 signaling axis is an important target signaling molecule in chemoprevention.