Self-Immolative Polycations as Gene Delivery Vectors and Prodrugs Targeting Polyamine Metabolism in Cancer

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• 作者：Yu Zhu ; Jing Li ; Shrey Kanvinde ; Zhiyi Lin ; Stuart Hazeldine ; Rakesh K. Singh ; David Oupick媒
• 刊名：Molecular Pharmaceutics
• 出版年：2015
• 出版时间：February 2, 2015
• 年：2015
• 卷：12
• 期：2
• 页码：332-341
• 全文大小：525K
• ISSN：1543-8392

文摘

Polycations are explored as carriers to deliver therapeutic nucleic acids. Polycations are conventionally pharmacological inert with the sole function of delivering therapeutic cargo. This study reports synthesis of a self-immolative polycation (DSS-BEN) based on a polyamine analogue drug N¹,N¹¹-bisethylnorspermine (BENSpm). The polycation was designed to function dually as a gene delivery carrier and a prodrug targeting dysregulated polyamine metabolism in cancer. Using a combination of NMR and HPLC, we confirm that the self-immolative polycation undergoes intracellular degradation into the parent drug BENSpm. The released BENSpm depletes cellular levels of spermidine and spermine and upregulates polyamine catabolic enzymes spermine/spermidine N¹-acetyltransferase (SSAT) and spermine oxidase (SMO). The synthesized polycations form polyplexes with DNA and facilitate efficient transfection. Taking advantage of the ability of BENSpm to sensitize cancer cells to TNF伪-induced apoptosis, we show that DSS-BEN enhances the cell killing activity of TNF伪 gene therapy. The reported findings validate DSS-BEN as a dual-function delivery system that can deliver a therapeutic gene and improve the outcome of gene therapy as a result of the intracellular degradation of DSS-BEN to BENSpm and the subsequent beneficial effect of BENSpm on dysregulated polyamine metabolism in cancer.