Abstract
The hemoglobin vesicle (HbV) is an artificial oxygen carrier encapsulating a concentrated hemoglobin solution in a liposome of which the surface is covered with polyethylene glycol (PEG). It was recently reported that repeated injections of PEGylated liposomes induce the accelerated blood clearance (ABC) phenomenon, in which serum anti-PEG IgM plays an essential role. To examine this issue, we investigated whether HbV induces the ABC phenomenon in mice at a dose of 0.1 mg Hb/kg, a dose that is generally known to induce the ABC phenomenon, or at 1400 mg Hb/kg, which is proposed for clinical use. At 7 days after the first injection of nonlabeled HbV (0.1 mg Hb/kg), the mice received HbV in which the Hb had been labeled with 125I. After a second injection, HbV was rapidly cleared from the circulation, and uptake clearances in liver and spleen were significantly increased. In contrast, at a dose of 1400 mg Hb/kg, the pharmacokinetics of HbV was negligibly affected by repeated injection. It is interesting to note that IgM against HbV was produced 7 days postinjection at both of the above doses, and their recognition site was determined to be 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine-N-PEG in HbV. These results suggest that a clinical dose of HbV does not induce the ABC phenomenon, and that suppression of ABC phenomenon is caused by the saturation of phagocytic processing by the mononuclear phagocyte system. Thus, we conclude that induction of the ABC phenomenon would not be an issue in the dose regimen used in clinical settings.
- PEG, polyethylene glycol
- ABC, accelerated blood clearance
- HbV, hemoglobin vesicle
- Hb, hemoglobin
- PLP, pyridoxal 5′-phosphate
- MPS, mononuclear phagocyte system
- DPPC, 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine
- DHSG, 1,5-bis-O-hexadecyl-N-succinyl-l-glutamate
- DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine-N-PEG
- rHSA, recombinant human serum albumin
- 125I-HbV, 125I-labeled hemoglobin vesicle
- BSA, bovine serum albumin
- ELISA, enzyme-linked immunosorbent assay
- CLuptake, uptake clearance
- AUC, area under the concentration-time curve
- CL, clearance.
Footnotes
-
This work was supported in part by Health Sciences Research grants (Health Science Research including Drug Innovation) from the Ministry of Health, Labor, and Welfare, Japan.
-
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.109.028852
- Received June 6, 2009.
- Accepted August 10, 2009.
- Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|