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Kang J.-H.,Advanced Medical Engineering Center | Tachibana Y.,Japan National Cardiovascular Center Research Institute | Kamata W.,Japan National Cardiovascular Center Research Institute | Mahara A.,Japan National Cardiovascular Center Research Institute | And 3 more authors.
Bioorganic and Medicinal Chemistry | Year: 2010

Recently, small interfering RNA (siRNA)-based therapeutics have been used to treat diseases. Efficient and stable siRNA delivery into disease cells is important in the use of this agent for treatment. In the present study, pullulan was introduced into polyethylenimine (PEI) for liver targeting. PEI/siRNA or pullulan-containing PEI/siRNA complexes were delivered into mice through the tail vein either by a hydrodynamics- or non-hydrodynamics-based injection. The incidence of mortality was found to increase with an increase in the nitrogen/phosphorus (N/P) ratio of PEI/siRNA complexes. Moreover, the hydrodynamics-based injection increased mice mortality. Introduction of pullulan into PEI dramatically reduced mouse death after systemic injection. After systemic injection, the PEI/fluorescein-labeled siRNA complex increased the level of fluorescence in the lung and the PEI-pullulan/siRNA complex led to an increased fluorescence level in the liver. These results suggest that the PEI-pullulan polymer may be a useful, low toxic means for efficient delivery of siRNA into the liver. © 2010 Elsevier Ltd. All rights reserved.

Matsubara K.,Nara Institute of Science and Technology | Watabe H.,Advanced Medical Engineering Center | Hayashi T.,Advanced Medical Engineering Center | Hayashi T.,RIKEN | And 2 more authors.
Transactions of Japanese Society for Medical and Biological Engineering | Year: 2010

Patlak analysis, which estimates the net FDOPA influx constant (Ki by linear regression of data acquired from [18F] FDOPA PET study, is widely employed in the diagnosis of neurological disorder, such as Parkinson's disease. In K estimation by Patlak analysis, it is assumed that the metabolites of radioligand do not diffuse out of the tissue during PET scan. However, [ 18F] F-Dopamine, synthesized from [18F] FDOPA, is rapidly metabolized and its metabolites diffuse from the tissue. We aimed at the evaluation of the effect of dopamine metabolism and the clearance of its metabolites on K estimated by Patlak analysis. For this purpose, we developed a model describing the detailed pathway of dopamine kinetics in the striatum, and a standard timeactivity curve (TAC) was generated based on this model and [ 18F] FDOPA PET data of a monkey. And TACs in case of altering the dopamine metabolism or the clearance of its metabolites were simulated.Then, we evaluated K1, values estimated by Patlak analysis for these simulated TACs. K was increased when the dopamine metabolism to DOPAC (κ dopac9) and the clearance of DOPAC and HVA (AfTc, k\?) were altered. The results suggest that K could be biased by the influence of the metabolism of dopamine and clearance of its metabolites. Therefore, it is important to consider these biases in the interpretation of K value estimated Patlak analysis.

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