Pharmacokinetic Study of the Structural Components of Adenosine Diphosphate-Encapsulated Liposomes Coated with Fibrinogenγ-Chain Dodecapeptide as a Synthetic Platelet Substitute

Abstract

Fibrinogen g-chain (dodecapeptide HHLGGAKQAGDV, H12)-coated, ADP-encapsulated liposomes [H12-(ADP)-liposomes] were developed as a synthetic platelet alternative that specifically accumulates at bleeding sites as the result of interactions with activated platelets via glycoprotein IIb/IIIa and augments platelet aggregation by releasing ADP. The aim of this study is to characterize the pharmacokinetic properties of H12-(ADP)-liposomes and structural components in rats, and to predict the blood retention of H12-(ADP)-liposomes in humans. With use of H12-(ADP)-liposomes in which the encapsulated ADP and liposomal membrane cholesterol were radiolabeled with 14 C and 3 H, respectively, it was found that the time courses for the plasma concentration curves of 14 C and 3 H radioactivity showed that the H12-(ADP)-liposomes remained intact in the blood circulation for up to 24 hours after injection, and were mainly distributed to the liver and spleen. However, the 14 C and 3 H radioactivity of H12-(ADP)-liposomes disappeared from organs within 7 days after injection. The encapsulated ADP was metabolized to allantoin, which is the final metabolite of ADP in rodents, and was mainly eliminated in the urine, whereas the cholesterol was mainly eliminated in feces. In addition, the half-life of the H12-(ADP)-liposomes in humans was predicted to be approximately 96 hours from pharmacokinetic data obtained for mice, rats, and rabbits using an allometric equation. These results suggest that the H12-(ADP)-liposome has potential with proper pharmacokinetic and acceptable biodegradable properties as a synthetic platelet substitute.

Effect of Repeated Injections of Adenosine Diphosphate-Encapsulated Liposomes Coated with a Fibrinogen γ-Chain Dodecapeptide Developed as a Synthetic Platelet Substitute on Accelerated Blood Clearance in a Healthy and an Anticancer Drug-Induced Thrombocytopenia Rat Model

“…(b) The hepatic distribution of 14 C and 3 H radioactivity at 2 h after the first injection (closed bar) or the second injection (open bar) of 3 H , 14 C radiolabeled H 12‐( ADP )‐liposome at a dose of 10 mg lipid/kg to healthy rats. The data for the first injection were cited from our previously reported paper . Each point represents the mean ± SD ( n = 4).…”

“…14 C, 3 H double‐labeled H12‐(ADP)‐liposomes were prepared as previously reported . The diameter and zeta‐potential of the 14 C‐labeled H12‐(ADP)‐liposomes used in this study were in the range of 250 ± 50 nm and −10 ± 0.9 mV, respectively.…”

“…In fact, it was reported that these modifications enable the liposomes to accumulate at the site of an injury in vivo by specifically binding to glycoprotein IIb/IIIa on activated platelet membranes, thus decreasing bleeding time in a dose‐dependent manner in both thrombocytopenic rat and rabbit models . Furthermore, we recently reported that H12‐(ADP)‐liposomes have an adequate circulation time in the blood to permit them to function as a platelet substitute in healthy animals and a thrombocytopenic model rat . Because of these characteristics, H12‐(ADP)‐liposomes show hemostatic effects comparable to platelet‐rich plasma and also result in an improved survival in rabbits with acute thrombocytopenia …”

Pharmacokinetic Properties of Single and Repeated Injection of Liposomal Platelet Substitute in a Rat Model of Red Blood Cell Transfusion-Induced Dilutional Thrombocytopenia

“…1,5‐Dihexadecyl‐ N ‐succinyl‐ l ‐glutamate (DHSG) and H12‐PEG‐Glu2C18 were synthesized as reported previously . 14 C‐, 3 H‐abeled H12‐(ADP)‐liposomes were prepared, as described in a previous report . The diameter and zeta potential of the H12‐(ADP)‐liposomes used in this study were in the range of 250 ± 50 nm and −10 ± 0.9 mV, respectively.…”

“…In fact, previous in vitro and in vivo studies clearly showed that the modification of H12‐(ADP)‐liposomes such as H12 and encapsulation with ADP enables them to specifically interact with the glycoproteins IIb/IIIa on activated PLT and stimulate PLT aggregation. Furthermore, a pharmacokinetic study of H12‐(ADP)‐liposomes in healthy animals showed that they have an adequate circulation time in the blood to permit them to function as a PLT substitute and that they have acceptable biodegradable properties . Taken together with these characteristics of H12‐(ADP)‐liposomes in preclinical trials, H12‐(ADP)‐liposomes are promising candidates for use as a PLT substitute in clinical applications.…”