Abstract
Polyamines are essential for the growth of eukaryotic cells and can be dysregulated in tumors. Here we describe a strategy to deplete polyamines through host–guest encapsulation using a peptide-pillar[5]arene conjugate (P1P5A, P1 = RGDSK(N3)EEEE) as a supramolecular trap. The RGD in the peptide sequence allows the molecule to bind to integrin αvβ3-overexpressing tumor cells. The negative charged glutamic acid residues enhance the inclusion affinities between the pillar[5]arene and cationic polyamines via electrostatic interactions and facilitate the solubility of the conjugate in aqueous media. The trap P1P5A efficiently encapsulates polyamines with association constants of 105–106 M−1. We show that P1P5A has a wide spectrum of antitumor activities, and induces apoptosis via affecting the polyamine biosynthetic pathway. Experiments in vivo show that P1P5A effectively inhibits the growth of breast adenocarcinoma xenografts in female nude mice. This work reveals an approach for suppressing tumor growth by using supramolecular macrocycles to trap polyamines in tumor cells.
Highlights
Polyamines are essential for the growth of eukaryotic cells and can be dysregulated in tumors
The RGD sequence was chosen because it is a known target of integrin αvβ[3], which is widely expressed on tumor cells
The percentage of apoptotic cells in the group treated with 25 μM P1P5A was about 46.7%, while that in the presence of 50 μM P1P5A was significantly higher at 73.0% (Fig. 3b, c). These results clearly indicate that P1P5A could effectively induce the apoptosis of tumor cells and that the apoptosis rate depended on the dosage
Summary
Polyamines are essential for the growth of eukaryotic cells and can be dysregulated in tumors. We describe a strategy to deplete polyamines through host–guest encapsulation using a peptide-pillar[5]arene conjugate (P1P5A, P1 = RGDSK(N3)EEEE) as a supramolecular trap. DMFO lacks clinical efficacy as a single agent in multiple clinical trials owing to its poor transport into cells and intracellular compensatory mechanisms[15,16,17]. Another methodology that has been reported is the use of polyamine analogs that are disparate enough from natural polyamines so that they can regulate physiological function, but not so different that they are not overly toxic to normal cells. It is very difficult to predict and control structural properties that favor both bioactivity and safety[18,19,20]
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