Abstract
Liposome-encapsulated hemoglobin (LEH) is an erythrocyte substitute that is a potential resuscitative fluid for the in vivo delivery of oxygen. We have noninvasively imaged radiolabeled LEH in vivo with technetium-99m (99mTc) to study the biodistribution in an anesthetized rabbit. Rabbits (2.5 kg, n = 8) were infused with 30 ml of LEH (200 mg of phospholipid, 2.5 g of hemoglobin per kg of body weight) and imaged with a gamma camera continuously for 2 hr. At 20 hr postinfusion, the animals were imaged again and sacrificed; the organs were weighted and their radioactivity was determined for autopsy organ distribution. Organ uptake from the images was corrected for organ-associated blood pool, which was determined by infusion of 99mTc-labeled rabbit erythrocytes. Blood pool and decay-corrected biodistribution data reveal the kinetics of LEH distribution, with an initial rapid uptake by the liver, 8% at 30 min and 15% at 2 hr. The spleen accumulates less LEH initially, 3% at 30 min and 7% at 2 hr, with an apparent linear uptake of LEH over this time period. Image biodistribution data was also validated at 20 hr by tissue sampling. At 20 hr postinfusion, autopsy biodistribution data reveals approximately 42.6% of the total counts remaining in the blood, 15.4% in the liver, 18.1% in spleen, 3.2% in the lungs, 2.4% in muscle, 1.6% in urine, and trace levels in the kidney, brain, and heart (less than 1%). There is no evidence of hemoglobin release from LEH or kidney dysfunction (normal creatinine and blood urea nitrogen) at any time over the course of the study.
Full text
PDF




Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Ballinger J. R., Reid R. H., Gulenchyn K. Y. Technetium-99m HM-PAO stereoisomers: differences in interaction with glutathione. J Nucl Med. 1988 Dec;29(12):1998–2000. [PubMed] [Google Scholar]
- Dewanjee M. K. Binding of 99mTc ion to hemoglobin. J Nucl Med. 1974 Aug;15(8):703–706. [PubMed] [Google Scholar]
- Djordjevich L., Miller I. F. Synthetic erythrocytes from lipid encapsulated hemoglobin. Exp Hematol. 1980 May;8(5):584–592. [PubMed] [Google Scholar]
- Farmer M. C., Gaber B. P. Liposome-encapsulated hemoglobin as an artificial oxygen-carrying system. Methods Enzymol. 1987;149:184–200. doi: 10.1016/0076-6879(87)49056-3. [DOI] [PubMed] [Google Scholar]
- Farmer M. C., Rudolph A. S., Vandegriff K. D., Hayre M. D., Bayne S. A., Johnson S. A. Liposome-encapsulated hemoglobin: oxygen binding properties and respiratory function. Biomater Artif Cells Artif Organs. 1988;16(1-3):289–299. doi: 10.3109/10731198809132578. [DOI] [PubMed] [Google Scholar]
- Forssen E. A., Tökès Z. A. Use of anionic liposomes for the reduction of chronic doxorubicin-induced cardiotoxicity. Proc Natl Acad Sci U S A. 1981 Mar;78(3):1873–1877. doi: 10.1073/pnas.78.3.1873. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gabizon A., Dagan A., Goren D., Barenholz Y., Fuks Z. Liposomes as in vivo carriers of adriamycin: reduced cardiac uptake and preserved antitumor activity in mice. Cancer Res. 1982 Nov;42(11):4734–4739. [PubMed] [Google Scholar]
- Gregoriadis G. Targeting of drugs: implications in medicine. Lancet. 1981 Aug 1;2(8240):241–246. doi: 10.1016/s0140-6736(81)90486-4. [DOI] [PubMed] [Google Scholar]
- Hoffman S. J., Looker D. L., Roehrich J. M., Cozart P. E., Durfee S. L., Tedesco J. L., Stetler G. L. Expression of fully functional tetrameric human hemoglobin in Escherichia coli. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8521–8525. doi: 10.1073/pnas.87.21.8521. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lopez-Berestein G., Kasi L., Rosenblum M. G., Haynie T., Jahns M., Glenn H., Mehta R., Mavligit G. M., Hersh E. M. Clinical pharmacology of 99mTc-labeled liposomes in patients with cancer. Cancer Res. 1984 Jan;44(1):375–378. [PubMed] [Google Scholar]
- Lucignani G., Rossetti C., Ferrario P., Zecca L., Gilardi M. C., Zito F., Perani D., Lenzi G. L., Fazio F. In vivo metabolism and kinetics of 99mTc-HMPAO. Eur J Nucl Med. 1990;16(4-6):249–255. doi: 10.1007/BF00842776. [DOI] [PubMed] [Google Scholar]
- Neirinckx R. D., Canning L. R., Piper I. M., Nowotnik D. P., Pickett R. D., Holmes R. A., Volkert W. A., Forster A. M., Weisner P. S., Marriott J. A. Technetium-99m d,l-HM-PAO: a new radiopharmaceutical for SPECT imaging of regional cerebral blood perfusion. J Nucl Med. 1987 Feb;28(2):191–202. [PubMed] [Google Scholar]
- Ostro M. J., Cullis P. R. Use of liposomes as injectable-drug delivery systems. Am J Hosp Pharm. 1989 Aug;46(8):1576–1587. [PubMed] [Google Scholar]
- Perez-Soler R., Lopez-Berestein G., Kasi L. P., Cabanillas F., Jahns M., Glenn H., Hersh E. M., Haynie T. Distribution of technetium-99m-labeled multilamellar liposomes in patients with Hodgkin's disease. J Nucl Med. 1985 Jul;26(7):743–749. [PubMed] [Google Scholar]
- Poznansky M. J., Juliano R. L. Biological approaches to the controlled delivery of drugs: a critical review. Pharmacol Rev. 1984 Dec;36(4):277–336. [PubMed] [Google Scholar]
- Proffitt R. T., Williams L. E., Presant C. A., Tin G. W., Uliana J. A., Gamble R. C., Baldeschwieler J. D. Tumor-imaging potential of liposomes loaded with In-111-NTA: biodistribution in mice. J Nucl Med. 1983 Jan;24(1):45–51. [PubMed] [Google Scholar]
- Rabinovici R., Rudolph A. S., Feuerstein G. Characterization of hemodynamic, hematologic, and biochemical responses to administration of liposome-encapsulated hemoglobin in the conscious, freely moving rat. Circ Shock. 1989 Oct;29(2):115–132. [PubMed] [Google Scholar]
- Rabinovici R., Rudolph A. S., Feuerstein G. Improved biological properties of synthetic distearoyl phosphatidyl choline-based liposome in the conscious rat. Circ Shock. 1990 Mar;30(3):207–219. [PubMed] [Google Scholar]
- Rabinovici R., Rudolph A. S., Ligler F. S., Yue T. L., Feuerstein G. Liposome-encapsulated hemoglobin: an oxygen-carrying fluid. Circ Shock. 1990 Sep;32(1):1–17. [PubMed] [Google Scholar]
- Rabinovici R., Rudolph A. S., Yue T. L., Feuerstein G. Biological responses to liposome-encapsulated hemoglobin (LEH) are improved by a PAF antagonist. Circ Shock. 1990 Aug;31(4):431–445. [PubMed] [Google Scholar]
- Rahman A., Kessler A., More N., Sikic B., Rowden G., Woolley P., Schein P. S. Liposomal protection of adriamycin-induced cardiotoxicity in mice. Cancer Res. 1980 May;40(5):1532–1537. [PubMed] [Google Scholar]
- Rehani M. M., Sharma S. K. Site of Tc-99m binding to the red blood cell: concise communication. J Nucl Med. 1980 Jul;21(7):676–678. [PubMed] [Google Scholar]
- Rudolph A. S., Cliff R. O. Dry storage of liposome-encapsulated hemoglobin: a blood substitute. Cryobiology. 1990 Dec;27(6):585–590. doi: 10.1016/s0011-2240(05)80025-2. [DOI] [PubMed] [Google Scholar]
- Rudolph A. S. The freeze-dried preservation of liposome encapsulated hemoglobin: a potential blood substitute. Cryobiology. 1988 Aug;25(4):277–284. doi: 10.1016/0011-2240(88)90036-3. [DOI] [PubMed] [Google Scholar]
- Souhami R. L., Patel H. M., Ryman B. E. The effect of reticuloendothelial blockade on the blood clearance and tissue distribution of liposomes. Biochim Biophys Acta. 1981 May 18;674(3):354–371. doi: 10.1016/0304-4165(81)90366-4. [DOI] [PubMed] [Google Scholar]
- Stewart J. C. Colorimetric determination of phospholipids with ammonium ferrothiocyanate. Anal Biochem. 1980 May 1;104(1):10–14. doi: 10.1016/0003-2697(80)90269-9. [DOI] [PubMed] [Google Scholar]