Targeted delivery of a sialic acid-blocking glycomimetic to cancer cells inhibits metastatic spread

TY - JOUR

T1 - Targeted delivery of a sialic acid-blocking glycomimetic to cancer cells inhibits metastatic spread

AU - Büll, Christian

AU - Boltje, Thomas Jan

AU - van Dinther, Eric A W

AU - Peters, Timo

AU - de Graaf, Annemarie M A

AU - Leusen, Jeanette H W

AU - Kreutz, Martin

AU - Figdor, Carl G

AU - den Brok, Martijn H

AU - Adema, Gosse J

PY - 2015/1/27

Y1 - 2015/1/27

N2 - 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.

AB - 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.

KW - Animals

KW - Antibodies/chemistry

KW - Biomimetic Materials/chemistry

KW - Drug Carriers/chemistry

KW - Female

KW - Lactic Acid/chemistry

KW - Lung Neoplasms/secondary

KW - Melanoma, Experimental/pathology

KW - Membrane Glycoproteins/immunology

KW - Mice

KW - N-Acetylneuraminic Acid/antagonists & inhibitors

KW - Nanoparticles/chemistry

KW - Neoplasm Metastasis

KW - Polyglycolic Acid/chemistry

KW - Sialic Acids/chemistry

U2 - 10.1021/nn5061964

DO - 10.1021/nn5061964

M3 - Journal article

C2 - 25575241

SN - 1936-0851

VL - 9

SP - 733

EP - 745

JO - A C S Nano

JF - A C S Nano

IS - 1

ER -