Biocompatible and long-acting polyphosphate inhibitors for the diagnosis and treatment of thrombosis and thromboembolism.

Polyphosphate (PolyP) is an emerging target for low-hemorrhagic antithrombotic therapy. However, as an inorganic polymer, PolyP is challenging to target using conventional small-molecule or protein-based drugs. Polyethyleneimine (PEI) and poly-l-lysine (PLL) have been proved to exhibit high efficacy in neutralizing PolyP's procoagulant activity in vitro, but are limited by rapid renal clearance and high toxicity in vivo. We herein chemically modified PEI and PLL with phthalocyanine (Pc), a near-infrared fluorescent compound with strong binding affinity to serum albumin. Modification with Pc firstly extended the in vivo circulation time and duration of antithrombotic effects of PEI and PLL by targeting albumin. Moreover, binding with albumin ameliorated PEI's toxicity both in vitro and in vivo. The antithrombotic activity of these PolyP inhibitors was significantly attenuated in FXI-/- mice, underscoring the dependence of their antithrombotic mechanism on the intrinsic coagulation system. Notably, Pc-PLL localized specifically to thromboemboli in a murine model of cerebral embolic stroke, enabling real-time in vivo thromboembolic imaging. This study proposes a new strategy for the diagnosis and therapy of thrombosis and thromboembolism by targeting PolyP.