Abstract Heparan sulfate (HS) are linear polysaccharides conjugated to proteins, heparan sulfate proteoglycans (HSPGs), located on the cell surface and extracellular matrix. The HS chains display varying degrees of sulfation. These sulfate clusters mediate the interaction of polynuclear platinum complexes (PPCs) with HSPG through a “sulfate clamp.” Such PPC-HS interactions can be conceptualized as “polyarginine” mimics. Strong HS-PPC binding protects the oligosaccharide against sulfate loss through metalloshielding. The biological consequences of PPCs metalloshielding HS will in principle affect HS interactions with relevant enzymes and proteins such as heparanase and growth factors, similar in concept to inhibition of DNA-protein binding through modification of DNA structure and conformation. HSPGs, associated growth factors, and heparanase promote tumor progression by facilitating invasion, angiogenesis, and metastasis. High heparanase expression correlates with increased metastatic potential and poor clinical prognosis. PPC-HS interactions inhibit cleavage of a model pentasaccharide by heparanase and further modulated bFGF binding to HS, and bFGF-induced migration and signaling in colon cancer cells. The end-point of functional modulation of HS interactions is inhibition of angiogenesis and metastasis. We report proof-of-principle of strong in vivo anti-metastatic activity of PPCs in triple negative breast cancer (TNBC) models. Further, we examine the anti-metastatic and anti-angiogenic effects of PPC-HS metalloshielding in these in vivo models through multiple growth factor signaling pathways (bFGF, HB-EGF, VEGF), and heparanase activity in breast cancer and endothelial cells. PPCs represent a novel class of intrinsically dual-function agents combining platinum cytotoxicity through DNA targeting with anti-angiogenic effects through glycan targeting. Chicago 14-17 April 2018 Citation Format: Samantha J. Katner, James D. Hampton, Erica J. Peterson, Eriko Katsuta, Megan R. Sayyad, Kazuaki Takabe, Jennifer Koblinski, Nicholas P. Farrell. Heparan sulfate, a new target for platinum in metastatic TNBC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3941.