Hemoglobin-vesicles for a Transfusion Alternative and Targeted Oxygen Delivery

Abstract

Hb-vesicles (HbV) are artificial oxygen carriers that encapsulate purified Hb solution (35 g/dl) in unilamellar phospholipid vesicles (liposomes). The dispersion stability of HbV is attained using surface-modification with polyethylene glycol (PEG), so that the deoxygenated HbV can be stored at room temperature for years. Moreover, the intravenously injected HbV does not induce aggregation when contacted with blood components. Animal experiments have verified the safety and efficacy of HbV as a transfusion alternative. One advantage of HbV is that the O(2) affinity (P(50)) of HbV can be regulated easily to that of RBC (28 torr) and to other values by manipulating the amount of the allosteric effectors, such as pyridoxal 5'-phosphate, coencapsulated in HbV. It is possible that HbV with a lower P(50) (higher O(2) affinity) would retain O(2) in the normal tissue while unloading O(2) to a targeted hypoxic tissue. Small HbV (250-280 nm diameter) is distributed homogeneously in the plasma phase, and HbV would transport oxygen through collateral arteries in the ischemic tissues. Results of in vitro and in vivo experiments of the domestic and international collaborations have confirmed the possibility of targeted O(2) delivery by HbV.

Ring-Opening Polymerization of Hemoglobin

“…55 Reportedly, HBOCs with a high oxygen affinity are effective for targeted oxygen delivery to a hypoxic tissue. 56,57 Consequently, XL-poly(Hb−PEG) will eventually be applicable as other HBOCs with high oxygen affinity for such clinical use.…”

Liposome‐Encapsulated Hemoglobin, TRM‐645: Current Status of the Development and Important Issues for Clinical Application

“…Furthermore, effects of controlling oxygen affinity have been reported for HbV (39–41). One of the advantages of LEH is that its oxygen affinity is easy control of internal aqueous phase conditions as discussed regarding LEH (42). However, the optimal characteristics of oxygen affinity for AOCs may vary with physiological conditions.…”

Hemoglobin Vesicles, Polyethylene Glycol (PEG)ylated Liposomes Developed as a Red Blood Cell Substitute, Do Not Induce the Accelerated Blood Clearance Phenomenon in Mice

“…There are some distinct advantages for HbV to exist in a liposomal structure; the oxygen affinity (P 50 ) of HbV can be easily regulated by manipulating the content of an allosteric effector such as pyridoxal 5Ј-phosphate (PLP) (Sakai and Tsuchida, 2007). Furthermore, the diameter of HbV liposomes can be tailored to approximately 250 nm, and further modification by PEG leads to an enhanced lifetime in the blood circulation compared with other types of hemoglobin-based oxygen carriers (t 1/2 for cell-free Hb and PEGylated Hb in rats of 1.5 and 10.9 h, respectively) (Goins et al, 1995;Lee et al, 2006) because the encapsulation of Hb completely suppresses renal excretion, although HbVs in the circulation are eventually captured by phagocytes in the mononuclear phagocyte system (MPS) (Sakai et al, 2001).…”