title: Targeted delivery of a sialic acid-blocking glycomimetic to cancer cells inhibits metastatic spread.
abstract: Sialic acid sugars are overexpressed by cancer cells and contribute to the metastatic cascade at multiple levels. Therapeutic interference of sialic acids, however, has been difficult to pursue because of the absence of dedicated tools. Here we show that a rationally designed sialic acid-blocking glycomimetic (P-3F(ax)-Neu5Ac) successfully prevents cancer metastasis. Formulation of P-3F(ax)--Neu5Ac into poly(lactic-co-glycolic acid nanoparticles coated with antityrosinase-related protein-1 antibodies allowed targeted delivery of P-3F(ax)--Neu5Ac into melanoma cells, slow release, and long-term sialic acid blockade. Most importantly, intravenous injections of melanoma-targeting P-3F(ax)--Neu5Ac nanoparticles prevented metastasis formation in a murine lung metastasis model. These findings stress the importance of sialoglycans in cancer metastasis and advocate that sialic acid blockade using rationally designed glycomimetics targeted to cancer cells can effectively prevent cancer metastases. This targeting strategy to interfere with sialic acid-dependent processes is broadly applicable not only for different types of cancer but also in infection and inflammation.
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Geert Grooteplein 28, 6525 GA Nijmegen, The Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Büll
authors.forename: Thomas Jan
authors.initials: TJ
authors.lastname: Boltje
authors.forename: Eric A W
authors.initials: EA
authors.lastname: van Dinther
authors.forename: Timo
authors.initials: T
authors.lastname: Peters
authors.forename: Annemarie M A
authors.initials: AM
authors.lastname: de Graaf
authors.forename: Jeanette H W
authors.initials: JH
authors.lastname: Leusen
authors.forename: Martin
authors.initials: M
authors.lastname: Kreutz
authors.forename: Carl G
authors.initials: CG
authors.lastname: Figdor
authors.forename: Martijn H
authors.initials: MH
authors.lastname: den Brok
authors.forename: Gosse J
authors.initials: GJ
authors.lastname: Adema
mesh_terms: D000818:Animals; D000906:Antibodies / Q000737:chemistry / Q000276:immunology; D040761:Biomimetic Materials / Q000737:chemistry* / Q000494:pharmacology*; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D019344:Lactic Acid / Q000737:chemistry; D008175:Lung Neoplasms / Q000556:secondary; D008546:Melanoma, Experimental / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D019158:N-Acetylneuraminic Acid / Q000037:antagonists & inhibitors*; D053758:Nanoparticles / Q000737:chemistry; D009362:Neoplasm Metastasis; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D012794:Sialic Acids / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000906:Antibodies; D004337:Drug Carriers; D008562:Membrane Glycoproteins; C588396:P-3F(ax)-Neu5Ac; D012794:Sialic Acids; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D019158:N-Acetylneuraminic Acid
keywords: PLGA nanoparticles; cancer; glycomimetic; metastasis; sialic acids