1993 Fiscal Year Annual Research Report

薬物ターゲティングシステムの機能性評価法の確立と製剤特性-機能相関の体系化

Research Project

Project/Area Number	05452338
Research Institution	Kyoto University
Principal Investigator	橋田充京都大学, 薬学部, 教授 (20135594)
Co-Investigator(Kenkyū-buntansha)	高倉喜信京都大学, 薬学部, 助教授 (30171432)
Keywords	ターゲティング / 製剤特性 / 高分子運搬体システム / 臓器クリアランス / 臓器潅流実験系 / 微粒子性運搬体システム / ドラッグデリバリーシステム
Research Abstract	近年、薬物適用の最適化を目的として、薬物の体内挙動を制御し標的作用部位に選択的に伝達させる薬物ターゲティングが注目を集めている。中でも、優れた体内挙動特性を有する運搬体システムを各種製剤技術を利用して開発する試みが活発に行われているが、これらの大部分は試行錯誤的、経験主義的に進められ、運搬体システムの設計、開発の基盤となる学問体系は未だ確立されていない。そこで本研究では、標的指向の方法論の確立を最終目的として、(1)標的指向化の評価解析法の確立、(2)運搬体システムの製剤特性と体内挙動特性の関連の系統的整理の2つの方向から検討を行った。標的指向化の評価解析法として、クリアランスの概念を基礎とし、マウスを用いて各種運搬体システムの全身動態特性を速度論的に解析する系を確立してその有用性を確認した。また、臓器レベルでの標的指向性を評価する方法として、肝臓、腎臓、固形腫瘍などに対する臓器潅流実験系を確立し、併せて生理学的速度論の考えに基づいて臓器レベルと全身レベルの情報の結合を実現した。こうして確立した実験系を用い、各種高分子薬物運搬システムの体内動態特性を系統的に検討した結果、分子サイズや電荷と動態の関連が明らかになり、またその標的指向性を臓器レベルの動態パラメータを用いて定量的に比較検討することが可能となった。さらに以上の知見に基づき、活性酸素除去剤スパーオキサイドジスムターゼの肝臓、腎臓ターゲティングシステムを開発し、その治療効果を確認した。今後、リポソーム、マイクロエマルション、マイクロスフェアー等の微粒子性製剤について、同様の検討を進める予定である。

Research Products
(23 results)

All Other

All Publications (23 results)

[Publications] Nishikawa,M.: "Synthesis and pharmacokinetics of a new liver-specific carrier,glycosylated carboxymethyl-dextran,and its application to drug targeting" Pharm.Res.10. 1253-1264 (1993)
[Publications] Tokuda,H.: "Specific uptake of succinylated proteins via a scavenger receptor-mediated mechanism in cultured brain microvessel endothelial cells" Biochem.Biophys.Res.Commun.196. 18-24 (1993)
[Publications] Takino,T.: "Controlled biodistribution of highly lipophilic drugs with various parenteral" J.Drug Targeting. 1. 117-124 (1993)
[Publications] Mihara,K.: "Disposition characteristics of protein drugs in the perfused rat kidney" Pharm.Res.10. 823-827 (1993)
[Publications] Hashida,M.: "Targeting Delivery of protein drugs by chemical modification" Drug Dev.Ind.Pharm.20. 581-590 (1994)
[Publications] Takino,T.: "Long circulating emulsion carrier systems for highly lipophilic drugs" Biol.Pharm.Bull.17. 121-125 (1993)
[Publications] Ohe,Y.: "Combination effect of vaccination with IL2 and IL4 cDNA transfected cells on the induction of a therapeutic immune response against lewis lung carcinoma cells" Int.J.Cancer. 53. 432-437 (1993)
[Publications] Nishio,M.: "Pharmacokinetic re-evaluation and phase I study of high dose epirubicin in advanced non-small cell lung cancer" Jpn.J.Clin,.Oncol.23. 284-290 (1993)
[Publications] Karato,A.: "Phase I study of CPT-11 and etoposide in patients with refractory solid tumors" J.Clin.Oncol.11. 2030-2035 (1993)
[Publications] Sato,K.: "Granulocyte colony-stimulating factor produced by bladder carcinoma of a patient with leukemoid reaction did not affect proliferation of the tumor cells" J.Urol.(in press).
[Publications] Tanigawa,N.: "Thymidine uptake in vitro as a prognostic indicator for primary gastric cancer" Cancer. 72. 2883-2888 (1993)
[Publications] Tanigawa,N.: "Detection of P-glycoprotein in solid tumors by flow cytometry" Anti-cancer Res.13. 2171-2176 (1993)
[Publications] Tashiro,T.: "Mechanisms for reduced drug accumulation in cisplatin-resistant sublines of human small cell lung cancer cell lines" KURRI Prog.Rep.1992. 270-271 (1993)
[Publications] Naito,M.: "Enhancement of cellular accumulation of cyclosporine by anti-P-glycoprotein monoclonal antibody MRK-16 and synergistic modulation of multidrug resistance" J.Natl.Cancer Inst.85. 311-316 (1993)
[Publications] Naito,M.: "Enhancement of reversing effect of cyclosporin A on vincristine resistance by anti-P-glycoprotein monoclonal antibody MRK-16" Jpn.J.Cancer Res.84. 489-492 (1993)
[Publications] Noguchi,K.: "cDNA expression cloning of the 85-kDa protein overexpressed in adriamycin-resistant cells" Biochem.Biophys.Res.Commun.192. 88-95 (1993)
[Publications] Satoh,M.: "Modulation of both cisplatin nephrotoxicity and drug resistance in murine bladder tumor by controlling metallothionein synthesis" Cancer.Res.53. 1829-1832 (1993)
[Publications] Kondo,Y.: "Tissue-specific induction of metallothionein by bismuth as a promising protocol for chemotherapy with repeated administration of cis-diamminedichloroplatinum(II)against bladder tumor" Anticancer Res.12. 2303-2308 (1993)
[Publications] Satoh,M.: "Prevention of carcinogenicity of anticancer drugs by metallothionein induction" Cancer Res.53. 4767-4768 (1993)
[Publications] Sugimoto,Y.: "Molecular cloning and characterization of the complementary DNA for the Mr 85,000 Protein overexpressed in Adriamycin-resistant human tumor cells" Cancer Res.53. 2538-2543 (1993)
[Publications] Dranoff,G.: "Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent,specific,and long-lasting anti-tumor immunity" Proc.Natl.Acad.Sci.USA. 90. 3539-3543 (1993)
[Publications] Hashida,M.: "Drug targeting with macromolecular carrier systems.in"Perspectives in Medicinal Chemistry"(Eds.Testa,B,et al.)pp.545-558" Verlag Helvestica Chimica Acta,Basel, 644 (1993)
[Publications] Hanada,H.: "Strategies for immunogene therapy against cancer.in"Excerpta Medical International Congress Series"" Excerpta Medica,Tokyo, in press (1994)

1993 Fiscal Year Annual Research Report

薬物ターゲティングシステムの機能性評価法の確立と製剤特性-機能相関の体系化

Principal Investigator

橋田 充 京都大学, 薬学部, 教授 (20135594)

Research Products

[Publications] Nishikawa,M.: "Synthesis and pharmacokinetics of a new liver-specific carrier,glycosylated carboxymethyl-dextran,and its application to drug targeting" Pharm.Res.10. 1253-1264 (1993)

[Publications] Tokuda,H.: "Specific uptake of succinylated proteins via a scavenger receptor-mediated mechanism in cultured brain microvessel endothelial cells" Biochem.Biophys.Res.Commun.196. 18-24 (1993)

[Publications] Takino,T.: "Controlled biodistribution of highly lipophilic drugs with various parenteral" J.Drug Targeting. 1. 117-124 (1993)

[Publications] Mihara,K.: "Disposition characteristics of protein drugs in the perfused rat kidney" Pharm.Res.10. 823-827 (1993)

[Publications] Hashida,M.: "Targeting Delivery of protein drugs by chemical modification" Drug Dev.Ind.Pharm.20. 581-590 (1994)

[Publications] Takino,T.: "Long circulating emulsion carrier systems for highly lipophilic drugs" Biol.Pharm.Bull.17. 121-125 (1993)

[Publications] Ohe,Y.: "Combination effect of vaccination with IL2 and IL4 cDNA transfected cells on the induction of a therapeutic immune response against lewis lung carcinoma cells" Int.J.Cancer. 53. 432-437 (1993)

[Publications] Nishio,M.: "Pharmacokinetic re-evaluation and phase I study of high dose epirubicin in advanced non-small cell lung cancer" Jpn.J.Clin,.Oncol.23. 284-290 (1993)

[Publications] Karato,A.: "Phase I study of CPT-11 and etoposide in patients with refractory solid tumors" J.Clin.Oncol.11. 2030-2035 (1993)

[Publications] Sato,K.: "Granulocyte colony-stimulating factor produced by bladder carcinoma of a patient with leukemoid reaction did not affect proliferation of the tumor cells" J.Urol.(in press).

[Publications] Tanigawa,N.: "Thymidine uptake in vitro as a prognostic indicator for primary gastric cancer" Cancer. 72. 2883-2888 (1993)

[Publications] Tanigawa,N.: "Detection of P-glycoprotein in solid tumors by flow cytometry" Anti-cancer Res.13. 2171-2176 (1993)

[Publications] Tashiro,T.: "Mechanisms for reduced drug accumulation in cisplatin-resistant sublines of human small cell lung cancer cell lines" KURRI Prog.Rep.1992. 270-271 (1993)

[Publications] Naito,M.: "Enhancement of cellular accumulation of cyclosporine by anti-P-glycoprotein monoclonal antibody MRK-16 and synergistic modulation of multidrug resistance" J.Natl.Cancer Inst.85. 311-316 (1993)

[Publications] Naito,M.: "Enhancement of reversing effect of cyclosporin A on vincristine resistance by anti-P-glycoprotein monoclonal antibody MRK-16" Jpn.J.Cancer Res.84. 489-492 (1993)

[Publications] Noguchi,K.: "cDNA expression cloning of the 85-kDa protein overexpressed in adriamycin-resistant cells" Biochem.Biophys.Res.Commun.192. 88-95 (1993)

[Publications] Satoh,M.: "Modulation of both cisplatin nephrotoxicity and drug resistance in murine bladder tumor by controlling metallothionein synthesis" Cancer.Res.53. 1829-1832 (1993)

[Publications] Kondo,Y.: "Tissue-specific induction of metallothionein by bismuth as a promising protocol for chemotherapy with repeated administration of cis-diamminedichloroplatinum(II)against bladder tumor" Anticancer Res.12. 2303-2308 (1993)

[Publications] Satoh,M.: "Prevention of carcinogenicity of anticancer drugs by metallothionein induction" Cancer Res.53. 4767-4768 (1993)

[Publications] Sugimoto,Y.: "Molecular cloning and characterization of the complementary DNA for the Mr 85,000 Protein overexpressed in Adriamycin-resistant human tumor cells" Cancer Res.53. 2538-2543 (1993)

[Publications] Dranoff,G.: "Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent,specific,and long-lasting anti-tumor immunity" Proc.Natl.Acad.Sci.USA. 90. 3539-3543 (1993)

[Publications] Hashida,M.: "Drug targeting with macromolecular carrier systems.in"Perspectives in Medicinal Chemistry"(Eds.Testa,B,et al.)pp.545-558" Verlag Helvestica Chimica Acta,Basel, 644 (1993)

[Publications] Hanada,H.: "Strategies for immunogene therapy against cancer.in"Excerpta Medical International Congress Series"" Excerpta Medica,Tokyo, in press (1994)

橋田充京都大学, 薬学部, 教授 (20135594)