Targeting Delivery of Platelets Inhibitor to Prevent Tumor Metastasis

Abstract

Activated platelets have a high affinity for tumor cells, and consequently, they can protect tumor cells from environmental stress and immune attacks. Therefore, preventing platelet−tumor cell interaction can lead to the elimination of circulating tumor cells via natural killer cells and finally metastasis inhibition. It is also shown that CREKA (Cys-Arg-Glu-Lys-Ala), a tumor-homing pentapeptide, targets fibrin−fibronectin complexes that are found on the tumor stroma and the vessel walls. In this study, we linked CREKA to Ticagrelor, a reversible antagonist of the P2Y 12 receptor on platelets.In vitro experiments indicated that CREKA-Ticagrelor could not only inhibit the platelet-induced migration of tumor cells with an invasive phenotype but also prevent tumor−platelet interaction. In vivo antitumor and antimetastasis results of this drug showed that CREKA-Ticagrelor could specifically target the tumor tissues within 24 h post intravenous injection and suppress lung metastasis. Meanwhile, by having this antiplatelet drug targeted, its side effects were minimized, and bleeding risk was decreased. Thus, CREKA-Ticagrelor offers an efficient antimetastatic agent.

Platelet-Cancer Interplay: Molecular Mechanisms and New Therapeutic Avenues

“…This result further supported a new anti-cancer strategy. A tumor-homing pentapeptide that targets fibrin-fibronectin complexes in the tumor stroma and the vascular wall is called CREKA, coupled to Ticagrelor ( 260 ). This CREKA-Ticagrelor complex effectively inhibited platelet-induced migration of tumor cells, and also prevented tumor-platelet interaction thereby suppressing lung metastasis ( 260 ).…”

P2Y12 Inhibition beyond Thrombosis: Effects on Inflammation

“…CREKA-ticagrelor inhibited platelet-induced migration of 4T1 tumor cells and prevented tumor-platelet interaction. In vivo, it suppressed lung metastasis in a mouse model injected with breast cancer cells [171]. This finding opens the way to innovative antimetastatic agents.…”

Targeted Inhibition of Tumor Inflammation and Tumor-Platelet Crosstalk by Nanoparticle-Mediated Drug Delivery Mitigates Cancer Metastasis

“…As revealed by tail bleeding assay and hematological analysis (Figures A and B), administration of free ticagrelor resulted in salient bleeding complications and thrombocytopenia, compared with the saline group ( P < 0.01). We attributed this phenomenon to the antiplatelet and antithrombotic effects of platelet inhibitors, which would inevitably produce hematological toxicity when applied systemically. ,, In contrast, there were limited alterations of the bleeding time or platelet counts in mice following six IV injections of multiple nanoparticles (Figures A and B). In addition, the whole blood routine analysis as well as serum biochemical examination also confirmed the outstanding biological safety of the nanoformulations (see Figure C, as well as Figure S20 in the Supporting Information).…”