Thrombin‐inhibiting liposomes as a targeted therapeutic for the treatment of acute thrombosis

Abstract

We propose the conjugation of D‐phenylalanyl‐L‐prolyl‐L‐arginyl‐chloromethyl ketone (PPACK) to the surface of a liposome as a high affinity, site‐specific inhibitor of thrombin for the treatment of acute thrombosis. The formulated PPACK‐liposomes exhibited a diameter of 150.55 ± 4.52 nm and zeta potential of −6.255 ± 0.869 mV. The in vitro activity of the PPACK‐liposomes was tested against a chromogenic substrate, resulting in a KI’ of 172.6 nM. In vivo activity of the PPACK‐liposomes was tested in a model of mouse carotid artery injury. PPACK‐liposomes prolonged the time to occlusion versus the control (85 ± 18.5 min for control liposomes; n=4, 140 ± 20 min for PPACK‐Liposomes; P = 0.002, n=6). Activated partial thromboplastin time (APTT) used to examine systemic activity of the PPACK‐liposomes revealed a rapid return to normal APTT values within 50 minutes of initial exposure (Figure 1, * P < 0.05). In summary, our results demonstrate persistent local thrombin inhibition at a site of injury but rapid abatement of systemic anticoagulant effect in acute thrombosis.