Polyamine-Based Nanostructures Share Polyamine Transport Mechanisms with Native Polyamines and Their Analogues: Significance for Polyamine-Targeted Therapy

Abstract

Polyamines are small polycationic alkylamines involved in many fundamental cellular processes, including cell proliferation, survival, and protection from oxidative stress. Polyamine homeostasis is tightly regulated through coordinated biosynthesis, catabolism, and transport. Due to their continual proliferation, cancer cells maintain elevated intracellular polyamine pools. Both polyamine metabolism and transport are commonly dysregulated in cancer, and as such, polyamine analogues are a promising strategy for exploiting the increased polyamine requirement of cancer cells. One potential polyamine analogue resistance mechanism is the downregulation of the poorly defined polyamine transport system. Recent advances in nanomedicine have produced nanostructures with polyamine analogue-based backbones (nanopolyamines). Similar nanostructures with non-polyamine backbones have been shown to be transported by endocytosis. As these polyamine-based nanoparticles could be a method for polyamine analogue delivery that bypasses polyamine transport, we designed the current studies to determine the efficacy of polyamine-based nanoparticles in cells lacking intact polyamine transport. Utilizing polyamine transport-deficient derivatives of lung adenocarcinoma lines, we demonstrated that cells unable to transport natural polyamines were also resistant to nanopolyamine-induced cytotoxicity. This resistance was a result of transport-deficient cells being incapable of importing and accumulating nanopolyamines. Pharmacological modulation of polyamine transport confirmed these results in polyamine transport competent cells. These studies provide additional insight into the polyamine transport pathway and suggest that receptor-mediated endocytosis is a likely mechanism of transport for higher-order polyamines, polyamine analogues and the nanopolyamines.

Spider and Wasp Acylpolyamines: Venom Components and Versatile Pharmacological Leads, Probes, and Insecticidal Agents

“…Given the modularity and structural versatility of aliphatic and acylpolyamines, mul-tifunctional molecules can be designed and synthesized for the targeted delivery of therapeutics via a polyamine uptake system and receptors [ 108 ]. Thus, receptor-mediated endocytosis is an interesting cellular entry mechanism for complex polyam-ines, polyamine analogs, and nano polyamines to be further considered in the field [ 109 ].…”

A Non-Conventional Platinum Drug against a Non-Small Cell Lung Cancer Line

“…Although these polyamines are known to be closely related to neoplastic growth and cancer progression [ 25 , 26 , 27 , 28 , 29 ], this effect is not observed upon coordination to a metal center. Instead, they allow the formation of stable complexes with intermediate-to-soft transition ions (through nitrogen binding) that may be transported into the cell through the specific polyamine channels [ 30 , 31 ], which is an advantage for attaining a high bioavailability of the potential drugs at their pharmacological targets (namely DNA).…”

Editorial to the Special Issue on “Polyamine Metabolism in Health and Disease: Potential for Polyamine-Targeted Therapies and Prevention”

“…Along these same lines, Holbert and colleagues [ 6 ] compare the transport of spermine analogue-based nanoparticles with the parent molecules in human lung cancer cell lines. The nanoparticle strategy is based on the assumption that the polyamine transport system (used by the parent analogue) is independent of general endocytosis (used by nanoparticles).…”