Abstract
Synthesizing polycationic polymers directly from existing drugs overcomes the drug-loading limitations often associated with pharmacologically inert nanocarriers. We recently described nanocarriers formed from a first-generation polyamine analogue, bis(ethyl)norspermine (BENSpm), that could simultaneously target polyamine metabolism while delivering therapeutic nucleic acids. In the current study, we describe the synthesis and evaluation of self-immolative nanocarriers derived from the second-generation polyamine analogue PG-11047. Polyamines are absolutely essential for proliferation and their metabolism is frequently dysregulated in cancer. Through its effects on polyamine metabolism, PG-11047 effectively inhibits tumor growth in cancer cell lines of multiple origins as well as in human tumor mouse xenografts. Promising clinical trials have been completed verifying the safety and tolerance of this rotationally restricted polyamine analogue. We therefore used PG-11047 as the basis for Nano11047, a biodegradable, prodrug nanocarrier capable of targeting polyamine metabolism. Following exposure of lung cancer cell lines to Nano11047, uptake and intracellular degradation into the parent compound PG-11047 was observed. The release of PG-11047 highly induced the polyamine catabolic enzyme activities of spermidine/spermine N1-acetyltransferase (SSAT) and spermine oxidase (SMOX). By contrast, the activity of ornithine decarboxylase (ODC), a rate-limiting enzyme in polyamine biosynthesis and a putative oncogene, was decreased. Consequently, intracellular levels of the natural polyamines were depleted concurrent with tumor cell growth inhibition. This availability of Nano11047 as a novel drug form and potential nucleic acid delivery vector will potentially benefit and encourage future clinical studies.
Highlights
The naturally occurring eukaryotic polyamines are essential for cellular proliferation, differentiation, and survival [1], and fluctuations in their intracellular levels can influence important cellular processes such as nucleosome formation, DNA replication, gene transcription, protein synthesis, membrane stability, ion channel regulation, and free radical scavenging [2,3,4,5]
We previously reported the development of self-immolative nanocarriers based on a polyamine analogue, (N1,N11)-bis(ethyl)norspermine (BENSpm) [28,29,30]
We further developed the concept of nanocarriers that target polyamine metabolism to the next-generation polyamine analogue PG-11047
Summary
The naturally occurring eukaryotic polyamines (spermine, spermidine, and putrescine) are essential for cellular proliferation, differentiation, and survival [1], and fluctuations in their intracellular levels can influence important cellular processes such as nucleosome formation, DNA replication, gene transcription, protein synthesis, membrane stability, ion channel regulation, and free radical scavenging [2,3,4,5]. Polyamines are observed at elevated intracellular concentrations in proliferating cells, cancer cells, due to dysregulation of their metabolism. As these elevated polyamine levels are required by tumor cells to maintain proliferation, polyamine analogues have been developed to exploit polyamine-sensitive feedback mechanisms as potential therapies for cancer and other hyperproliferative conditions [6,7,8]. As versions of the natural polyamines that can function in the regulation of polyamine metabolism, but not in the growth supporting functions, the symmetrically substituted bis(ethyl) class of polyamine analogues utilize the polyamine transport machinery to gain entry into cells, where they commonly upregulate the polyamine catabolic enzymes spermidine/spermine N1-acetyltransferase (SSAT) and/or spermine oxidase (SMOX), while down-regulating biosynthesis and uptake, thereby depleting the cells of the natural polyamines and causing growth arrest (Fig 1). In cells that respond to analogue treatment with an induction of SMOX, generation of the reactive oxygen species hydrogen peroxide (H2O2) can result in apoptotic cell death [7,8,9]
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