title: Stapled endosome disrupting alginate particles for cytosolic delivery of cations.
abstract: Divalent cations, the most prevalent minerals in the body, are responsible for a wide variety of cellular functions including signaling, proliferation, differentiation and cell death, and therefore their transmembrane transportation is tightly regulated. Despite the importance of divalent cations in cell activity, there are currently no intracellular delivery methods for divalent cations or modulation of intracellular levels of minerals. Here, we describe endosome disrupting alginate nanoparticles termed Alginoketals, which can deliver divalent cations to the cytosol of the cells. Alginoketals are generated by crosslinking alginic acid with endosome disrupting ketals, and using divalent cations as the stapling or binding agent. We show that Alginoketals were able to deliver copper (II) in the cytosol of the cancer cells thereby disrupting copper homeostasis and inducing cell death via accumulation of hydrogen peroxide. Alginoketal-copper (II)-based particles act as superoxide dismutase mimics and are the first class of divalent cation delivery vehicles, with potential application in cancer therapy, regenerative medicine and drug delivery.
authors.affiliation: a Department of Chemical and Petroleum Engineering , University of Pittsburgh , Pittsburgh , PA , USA.
authors.forename: Abhinav P
authors.initials: AP
authors.lastname: Acharya
authors.affiliation: a Department of Chemical and Petroleum Engineering , University of Pittsburgh , Pittsburgh , PA , USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Little
mesh_terms: D000464:Alginates / Q000737:chemistry*; D000818:Animals; D002412:Cations / Q000008:administration & dosage; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003300:Copper / Q000008:administration & dosage*; D003432:Cross-Linking Reagents / Q000737:chemistry; D003600:Cytosol / Q000378:metabolism; D016503:Drug Delivery Systems; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D020723:Glucuronic Acid / Q000737:chemistry; D006603:Hexuronic Acids / Q000737:chemistry; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D051379:Mice; D053758:Nanoparticles
chemical_list: D000464:Alginates; D002412:Cations; D003432:Cross-Linking Reagents; D006603:Hexuronic Acids; D003300:Copper; D020723:Glucuronic Acid; D006861:Hydrogen Peroxide
keywords: Biomimetic; cancer therapy; nanoparticles; superoxide dismutase mimetic