The Therapeutic Potential of Nanoscale Sphingolipid Technologies

Abstract

Nanotechnologies, while small in size, widen the scope of drug delivery options for compounds with problematic pharmacokinetics, such as bioactive sphingolipids. We describe the development of historical sphingolipid nanotechnologies, such as nanoliposomes, and project future uses for a broad repertoire of nanoscale sphingolipid therapy formulations. In particular, we describe sphingo-nanotherapies for treatment of cancer, inflammatory disease, and cardiovascular disease. We conclude with a discussion of the challenges associated with regulatory approval, scale-up, and development of these nanotechnology therapies for clinical applications.

Sphingolipid metabolism determines the therapeutic efficacy of nanoliposomal ceramide in acute myeloid leukemia

“…Liposome generation, [14][15][16][17] apoptosis assays, 16 colony-forming assays, 16 lipidomics, 19 and animal therapeutic studies 15,20 were carried out as previously described. Additional study-specific information for these methods, as well as details on cell culture and statistical analyses can be found in the supplemental Methods.…”

“…13 Lip-C6 exerts anticancer efficacy across a spectrum of malignancies. 7,[13][14][15][16][17] This study evaluated the preclinical efficacy of Lip-C6 for AML with MDS-related changes (AML-MRC), which was uniquely sensitive to Lip-C6 because of its propensity to convert C6-ceramide to proapoptotic sphingolipid metabolites. In contrast, resistance to Lip-C6 by de novo AML (DN-AML) was overcome by using cotreatment with vinblastine, which restored this proapoptotic sphingolipid phenotype.…”

Therapeutic implications of bioactive sphingolipids: A focus on colorectal cancer

“…Ceramide has been encapsulated within nanoscale liposomes, calcium phosphosilicate nanocolloids, nanoemulsions, polyethyleneoxide-modified polyepsiloncaprolactone nanoparticles (PEO-PCL) and linear-dendritic nanoparticles. 110,111 One of these preclinical approaches, the C 6 -ceramide nanoliposome (CNL) has just entered the clinic for solid tumors under FDA IND 109471 (NCT 02834611). CNL is a homogeneous 85nM, ¡8mV, nanotechnology that intercalates 30 molar percent C 6 -ceramide within a 12 molar percent pegylated liposome.…”

Preclinical development of a C6-ceramide NanoLiposome, a novel sphingolipid therapeutic

“…In addition, several laboratories, besides our own, are now employing nanotechnologies to enhance pharmacokinetic and toxicology profiles of the synthetic sphingoid analogs. Nanoemulsions, calcium phosphosilicate nanoparticles, biodegradable linear-dendritic nanoparticles and biodegradable polymers have been used for delivering ceramide-based therapeutics to induce cell death selectively in cancer cells while sparing normal cells (Hankins et al, 2013). C 10 -ceramide-loaded calcium phosphate nanocomposite particles induce apoptosis in drug-sensitive and drug-resistant breast cancer and melanoma cells in vitro .…”