RNAiとプラチナ基抗がん剤を組み合わせたときの相乗効果の最大化
Haihua Xiao1, Ruogu Qi1, Ting Li1
1Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.
Journal of the American Chemical Society
|February 7, 2017
まとめ
プラチナ ((II) 抗がん剤はsiRNAを急速にプラチナ化し,RNA干渉 (RNAi) の効率を低下させます. プラチナ (IV) とsiRNAを共配する新しいミセル戦略は,BCL-2 mRNA抑制を最大化し,抗がん効果を高める.
科学分野:
- 生化学と分子生物学
- 医療におけるナノテクノロジー
- ガン治療薬
背景:
- プラチナベースの化学療法と組み合わせたRNA干渉 (RNAi) は,プラチナによるsiRNA損傷のために課題に直面しています.
- プラチナ (II) 剤は,siRNAのグアノシン残留物でアダクトを形成し,典型的な実験濃度でRNAiの有効性を損なう.
- プラチナ (IV) アナログは直接のsiRNAプラチナ化を避けますが,細胞の吸収と効能が低下しています.
研究 の 目的:
- siRNAの完全性とRNAiの効率に対するプラチナ (II) 剤の影響を調査する.
- 組み合わせたRNAiとプラチナ化学療法のための新しい薬物投与システムを開発し評価する.
- BCL-2 siRNAとプラチナアナログのシナジスティックな配分を最適化してがん治療を強化する.
主な方法:
- プラチナ-siRNAアダクト形成を分析するためのスペクトロスクープの特徴化.
- siRNAとプラチナ剤を併用する生物分解性mPEG-b-PCL-b-PLLミセルの開発
- BCL- 2 mRNA抑制,細胞内プラチナ濃度,DNAアダクト形成,アポトーシス誘導,および抗増殖活性のインビトロ評価.
主要な成果:
- プラチナ (II) 剤は,BCL- 2 siRNAを急速にプラチナ化し,mRNAレベルを抑制する能力を著しく低下させた.
- BCL- 2 siRNAとプラチナ (IV) アナログをミセルで併封することで,最大限のBCL- 2 mRNA抑制を達成した (<10%).
- ミセル戦略は細胞内プラチナ濃度 (~4倍),DNAアダクト (~5倍),アポトーシス (~4倍),および抗増殖活性 (10~100倍) を高めました.
結論:
- プラチナ (II) 剤の標準的なin vitro濃度は,結合療法におけるsiRNA機能に有害である.
- プラチナ (IV) アナログとsiRNAを用いたミセルベースの共投与システムは,相乗効果のあるがん治療のための有望な戦略です.
- この一般化可能なアプローチは,治療応用と薬物スクリーニングのためのRNAiとプラチナベースの薬剤の間の相乗効果を最大化することができます.
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