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New Technology                                                                                                                                         67



                                                                                                    significant levels of PTX were present in the tumour clusters, including
                                                                                                results (Fig. 2b–e). The data did not contradict previous data obtained
                                                                                     following the accumulation of NK105 in the tumour was detected at
                                                                                           sections serial to those for MALDI-MS were also quantified by LCMS
                                                                                                  by HPLC14. The results of the MALDI-MS analysis demonstrate that
                                                                                       15 min as well as at 1, 24, 48, and 72 h after the administration of
                                                                                             (Fig. 2d, e), the results of which correlated with the drug imaging
                                                                                         NK105. The signal intensity was greatest at 24 h (Fig. 2c). Tissue
                                                                        A schematic illustration of the drug imaging system. The matrix-coated drug sample is ionised and then separated on the
                                                                      ɹɹɹ



                                                                                                      within the centre of the tumour tissue.            (a) Antitumour activity was examined in an animal model with BXPC3 xenografts. NK105, PTX, or saline (as a control) was  administered at a PTX equivalent dose of 50 mg/kg on days 0, 4, and 8. *P< 0.05 (PTX vs. NK105), ***P< 0.001 (saline vs.  NK105). Bar = SD. (b)(c) Imaging of PTX within the tumour was performed after PTX (b) or NK105 (c) administration at a dose of  100 mg/kg. The upper, middle, and lower columns display the optical images, reference substance (an arbitrary signal of m/z  824.6), and PTX (specific signal of m/z 892.3 [M + K] +  ), respectively. Bar, 1 mm. (d)(e) LC-MS a































                                                                      system. basis of its m/z. Images from MS or MS/MS analysis are recorded. Antitumour activity and visualisation of PTX and NK105  distribution within the tumour with MS analysis. NK105 or PTX was administered at a PTX equivalent dose of 50  mg/kg/day to mice bearing BxPC3 pancreatic cancer xenografts on  days 0, 4, and 8. NK105 showed significantly higher antitumour  activity than the control (saline) and free PTX (Fig. 2a). To confirm the  correlation of the distribution with the antitumour effect, the  corresponding tumour sections were subjected to MALDI-IMS. A drug  signal originating from PTX was detected in the tumours at 15 min  and 1 h after the administration of


                                                                      imaging


                                                                      Drug

                                                                      1.
                                                                      Fig.















                                                                         with that of PTX alone after injection into tumour-bearing mice. We demonstrated optically and quantitatively that NK105 delivered more PTX to the
                                                                       spectrometry (MALDI-IMS) with enhanced resolution and sensitivity, we compared the distribution of a paclitaxel (PTX)-incorporating micelle (NK105)
                                                                             treatment yielded a greater antitumour effect and less neural toxicity in mice than did PTX treatment. The use of high-resolution MALDI-IMS may be
                                            Masahiro Yasunaga 1 , Masaru Furuta 2 , Koretsugu Ogata 2 , Yoshikatsu Koga 1 , Yoshiyuki Yamamoto 1 , Misato Takigahira 1  & Yasuhiro
                                                                                                     In this study, we investigated the ability of our mass microscopy technique
                                                                                                   desorption/ionisation and quadruple ion trap time-of-flight (TOF) analyser.
                                                                                               We have developed a mass microscopy method in which a microscope is
                                                                     setting are desirable for evaluating drug effects and optimising drug design. Here, using matrix-assisted laser desorption ionisation imaging mass
                                                  1 Division of Therapeutics Development, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1
                                                                           tumour, including the centre of the tumour, while delivering less PTX to normal neural tissue, compared with injection with PTX alone. NK105
                                                                                                          formulation and obtain precise regional information about the drug
                                                                                                       to visualise the tissue distribution of unlabelled ACA and its micellar
                                                      2 Analytical & Measuring Instruments Division, Shimadzu Corporation, 1, Nishinokyo-Kuwabaracho, Nakagyo-ku, Kyoto
                                                                                                 coupled with a high-resolution atmospheric pressure-laser
                                                                                                            distribution in a specific anatomical area.  Results The drug imaging system and its application in PTX analysis on the   MALDI target. A schematic representation of our drug imaging system is shown in Fig. 1.  Imaging data were acquired using a mass microscope. In the analysis, mass  spectrometry (MS) and tandem mass spectrometry (MS/MS) were used for  quantification and validation, respectively (Fig. 1). Paclitaxel (PTX) is a mitotic inhibitor and an ACA that is used to treat  various cancers. However, PTX is associated with peripheral neuropathy, a  serious adverse affect 13 . NK105, a PTX-incorporating micelle, was  developed to































         global w430×h280        The significance of microscopic mass spectrometry with high resolution in the visualisation of drug distribution  Kashiwanoha, Kashiwa, Chiba 277-8577, Japan,  Correspondence and requests for materials should be addressed to Y.M. (yhmatsum@east.ncc.go.jp) The visualisation and quantitative analysis of the native drug distribution in a pre-clinical or clinical  an innovative approach for pharmacological evaluation and drug design support. Drug delivery, Pharmacokinetics, Pharmacodynamics, Biochemical assays  Advances in our understanding of cancer at the cellular and molecular  levels have promoted the development of new drugs 1,2 . Pharmacokinetic  (PK) and pharmacodynamic (PD) studies are very important t





                    New Technology            Matsumura 1  604-8511, Japan.  ABSTRACT  Key Words  Introduction                                   urgently required.        66
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