title: Self-immolative polycations as gene delivery vectors and prodrugs targeting polyamine metabolism in cancer.
abstract: 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 N(1),N(11)-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 N(1)-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 TNFα-induced apoptosis, we show that DSS-BEN enhances the cell killing activity of TNFα 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.
authors.affiliation: Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, and ‡Department of Pathology and Microbiology, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhu
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Shrey
authors.initials: S
authors.lastname: Kanvinde
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Lin
authors.forename: Stuart
authors.initials: S
authors.lastname: Hazeldine
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Singh
authors.forename: David
authors.initials: D
authors.lastname: Oupický
mesh_terms: D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000737:chemistry; D006801:Humans; D051379:Mice; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000378:metabolism; D011073:Polyamines / Q000737:chemistry*; D000071228:Polyelectrolytes; D011355:Prodrugs / Q000737:chemistry*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013096:Spermine / Q000737:chemistry; D000097667:Polyamine Oxidase
chemical_list: D000123:Acetyltransferases; D000587:Oxidoreductases Acting on CH-NH Group Donors; D011073:Polyamines; D000071228:Polyelectrolytes; D011355:Prodrugs; D013096:Spermine; D000097667:Polyamine Oxidase
keywords: TNFα; bisethylnorspermine; combination therapy; gene delivery; polyamine metabolism; polymeric prodrugs; self-immolative linker