Release abilities of adenosine diphosphate from phospholipid vesicles with different membrane properties and their hemostatic effects as a platelet substitute

• Published in: Journal of controlled release Vol. 148; no. 3; pp. 373 - 379
• Main Authors: Okamura, Yosuke, Katsuno, Shunsuke, Suzuki, Hidenori, Maruyama, Hitomi, Handa, Makoto, Ikeda, Yasuo, Takeoka, Shinji
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier B.V 20.12.2010; Elsevier
• Subjects: Adenosine 5'-diphosphate (ADP); Adenosine Diphosphate - administration & dosage; Adenosine Diphosphate - pharmacology; Adenosine Diphosphate - therapeutic use; Amino Acid Sequence; Animals; Biological and medical sciences; Bleeding Time; Blood Platelets - drug effects; Blood Substitutes - administration & dosage; Blood Substitutes - pharmacology; Blood Substitutes - therapeutic use; Controlled release; General pharmacology; Hemostasis - drug effects; Humans; Lamellarity; Liposomes - chemistry; Liposomes - ultrastructure; Male; Medical sciences; Membrane flexibility; Peptides - chemistry; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Phospholipid vesicles; Phospholipids - chemistry; Platelet Aggregation - drug effects; Platelet substitute; Rats; Rats, Wistar; Thrombocytopenia - drug therapy; Platelet substitute; Phospholipid vesicles; Adenosine 5'-diphosphate (ADP); Lamellarity; Membrane flexibility; Controlled release; Vesicle; Purine nucleoside; Adenosine; Pharmaceutical technology; Controlled release form; Control release polymer; Phospholipid; Flexibility; Platelet; Hemostasis; Dosage form; Microparticle; Membrane; Diphosphates; Substitute; Release
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2010.09.013

We have constructed phospholipid vesicles with hemostatic activity as a platelet substitute. The vesicles were conjugated with a dodecapeptide (HHLGGAKQAGDV, H12), which is a fibrinogen γ-chain carboxy-terminal sequence (γ400–411). We have recently exploited these vesicles as a potential drug delivery system by encapsulation of adenosine 5'-diphosphate (ADP) (H12-(ADP)-vesicles). Here we explore the relationship between the ADP release from H12-(ADP)-vesicles with different membrane properties and their hemostatic effects. In total, we prepared five kinds of H12-(ADP)-vesicles with different lamellarities and membrane flexibilities. By radioisotope-labeling, we directly show that H12-(ADP)-vesicles were capable of augmenting platelet aggregation by releasing ADP in an aggregation-dependent manner. The amount of ADP released from the vesicles was dependent on their membrane properties. Specifically, the amount of ADP released increased with decreasing lamellarity and tended to increase with increasing membrane flexibility. Our in vivo results clearly demonstrated that H12-(ADP)-vesicles with the ability to release ADP exert considerable hemostatic action in terms of correcting prolonged bleeding time in a busulphan-induced thrombocytopenic rat model. We propose a recipe to control the hemostatic abilities of H12-(ADP)-vesicles by modulating ADP release based on membrane properties. We believe that this concept will be invaluable to the development of platelet substitutes and other drug carriers. [Display omitted]