Evaluation for Peritoneal Injury at an Early Stage Using Dual Macromolecular Markers

Hirata, Haruna; Fumoto, Shintaro; Miyamoto, Hirotaka; Nakashima, Makoto; Nakayama, Morio; Nishida, Koyo

doi:10.1248/bpb.b15-01042

Biological & Pharmaceutical Bulletin

2016

DOI: 10.1248/bpb.b15-01042

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Evaluation for Peritoneal Injury at an Early Stage Using Dual Macromolecular Markers

Haruna Hirata

Shintaro Fumoto

Hirotaka Miyamoto

et al.

Abstract: Long-term peritoneal dialysis (PD) frequently produces morphological and functional changes of the peritoneum, making continuation of PD difficult. Therefore, it is necessary to evaluate peritoneal injury at an early stage and develop appropriate therapies. The aims of the present study were to evaluate peritoneal injury at an early stage and assess a drug for prevention of peritoneal injury using our previously developed novel evaluation method.

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Cited by 2 publications

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Organ surface application method-new DDS for digestive diseases

Nishida

Fumoto

2018

Official Journal of the Japan Society of Drug Delivery System

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For therapy of digestive diseases, generally drug treatment has been employed. There have been problems due to even drug distribution in the target and non-target organ. Since it is difficult to attain local drug activity after conventional administration such as intravenous and oral routes, we have tried to develop a new administration system utilizing drug absorption from the organ surface such as liver in the peritoneal cavity. As a non-invasive procedure, endoscopic surgery would enable us to achieve drug targeting to the diseased region in the peritoneal cavity. Although direct drug application to the organ surface could yield local drug availability, drug absorption characteristics from the organ surface such as liver surface had not been reported in the literature.Therefore, we first analyzed the efficiency of absorption of several organic anions and dextrans of various molecular weights, as marker compounds, following application to the rat liver surface in vivo employing a cylindrical diffusion cell. Each compound was absorbed from the rat liver surface with the different rates depending on the physicochemical properties. The absorption process from the liver surface might not obey an active transport system because of no detectable effect by dose and transport inhibitors. In addition, molecular weight and lipophilicity were found to be one of determinant factors of absorption through the liver surface. The ability of targeting to the desired region in the liver was enhanced significantly by application to the liver surface, compared to intravenous administration. Viscous additives, absorption enhancer, and vasomodulaters were proved to be effective to improve the drug availability in the target region. We also have obtained several expecting results from the application of this new drug delivery system for anticancer drugs. On the other hand, I have clarified the characteristics of drug absorption from the surfaces of the kidney, stomach, cecum and small intestine, and expect to apply the physiological findings to other fields. Furthermore, it is possible to apply the organ surface administration to genetic medicine. We successfully enhanced transgene expression onto the organ surface based on various strategies. 消化器疾患の治療では、全身および非病巣への薬物分布による重篤な副作用が大きな障壁となっている。この問題を解決するための、消化器疾患に対する新たな DDS 手段として、腹腔内の臓器表面から薬物を浸透させる臓器表面投与法を考案した。円筒状の拡散セルにより吸収部位が肝臓表面に限定された実験系を新たに構築して、腹腔内の消化器の代表例として肝臓表面からの薬物吸収性を検討した。物性の異なる各種マーカー化合物は、分子量や脂溶性などの物理化学的性質に基づいて、肝臓表面より良好に吸収される可能性を初めて証明した。さらに、抗がん薬に対する本投与形態の適用に関して、肝臓内の投与部位近傍における5 -FU の高度な分布を認めた。他の腹腔内臓器である腎臓や消化管漿膜表面からの薬物吸収性や臓器分布についても検討を加えている。また、臓器表面投与法は遺伝子医薬品にも応用可能で、さまざまな戦略により遺伝子発現を促進できることも明らかにした。

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Organ surface application method-new DDS for digestive diseases

Nishida

Fumoto

2018

Official Journal of the Japan Society of Drug Delivery System

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Suppression of Peritoneal Fibrosis by Sonoporation of Hepatocyte Growth Factor Gene-Encoding Plasmid DNA in Mice

et al. 2021

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Gene therapy is expected to be used for the treatment of peritoneal fibrosis, which is a serious problem associated with long-term peritoneal dialysis. Hepatocyte growth factor (HGF) is a well-known anti-fibrotic gene. We developed an ultrasound and nanobubble-mediated (sonoporation) gene transfection system, which selectively targets peritoneal tissues. Thus, we attempted to treat peritoneal fibrosis by sonoporation-based human HGF (hHGF) gene transfection in mice. To prepare a model of peritoneal fibrosis, mice were intraperitoneally injected with chlorhexidine digluconate. We evaluated the preventive and curative effects of sonoporation-based hHGF transfection by analyzing the following factors: hydroxyproline level, peritoneum thickness, and the peritoneal equilibration test. The transgene expression characteristics of sonoporation were also evaluated using multicolor deep imaging. In early-stage fibrosis in mice, transgene expression by sonoporation was observed in the submesothelial layer. Sonoporation-based hHGF transfection showed not only a preventive effect but also a curative effect for early-stage peritoneal fibrosis. Sonoporation-based hHGF transfection may be suitable for the treatment of peritoneal fibrosis regarding the transfection characteristics of transgene expression in the peritoneum under fibrosis.

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Evaluation for Peritoneal Injury at an Early Stage Using Dual Macromolecular Markers

Cited by 2 publications

References 26 publications

Organ surface application method-new DDS for digestive diseases

Organ surface application method-new DDS for digestive diseases

Suppression of Peritoneal Fibrosis by Sonoporation of Hepatocyte Growth Factor Gene-Encoding Plasmid DNA in Mice

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