This primary focus of this project is to evaluate the pathophysiological mechanisms of thrombocytopenia induced by an infusion of liposome encapsulated hemoglobin (LEH) and to quantitate changes in oxygen uptake and oxygen delivery of LEH over time after administration in small animal models. We plan to investigate this LEH-induced thrombocytopenia using both in vitro and in vivo radiolabeled platelet studies in rat and rabbit models. The proposed in vivo studies will use non-invasive imaging of platelets labeled with indium- 111 to assess the effect of complement depletion, inhibition of arachidonic acid metabolism, and in vivo platelet aggregation inhibitors on platelet biodistribution following administration of LEH. Formulations of LEH less likely to cause thrombocytopenia will be investigated.
A second aim of this project is the investigation of LEH oxygen uptake and tissue delivery. Specifically, several new techniques based on the short lived positron emitting radioisotope of oxygen, oxygen-15 (15-O) (t 1/2 = 2.O2 minutes), will be used to investigate the ability of LEH to load oxygen from the lungs and deliver oxygen to the tissues in small animal models (rats and rabbits). Changes in oxygen carrying capacity and oxygen tissue extraction will be assessed over a period of time post-infusion and correlated with the clearance time course. Formulations of LEH that may potentially have prolonged circulation times, a longer effective oxygen carrying capacity, and efficient oxygen delivery to the tissues will be assessed using these new techniques. These studies will provide important information necessary for the development and continual improvement in the formulation of LEH as a safe and efficacious blood substitute. These studies will provide a better understanding of both the mechanisms of toxicity and the factors which govern the delivery of oxygen to the tissues. The tracer techniques described in this proposal will provide new tools that could generally be applied to the study of blood substitutes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL053052-03
Application #
2230797
Study Section
Special Emphasis Panel (ZHL1-CSR-S (M1))
Project Start
1994-08-01
Project End
1998-07-31
Budget Start
1996-08-01
Budget End
1998-07-31
Support Year
3
Fiscal Year
1996
Total Cost
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Awasthi, Vibhudutta; Goins, Beth; McManus, Linda et al. (2003) [99mTc] liposomes for localizing experimental colitis in a rabbit model. Nucl Med Biol 30:159-68
Awasthi, V D; Goins, B; Klipper, R et al. (2002) Accumulation of PEG-liposomes in the inflamed colon of rats: potential for therapeutic and diagnostic targeting of inflammatory bowel diseases. J Drug Target 10:419-27
Phillips, W T; Andrews, T; Liu, H et al. (2001) Evaluation of [(99m)Tc] liposomes as lymphoscintigraphic agents: comparison with [(99m)Tc] sulfur colloid and [(99m)Tc] human serum albumin. Nucl Med Biol 28:435-44
Phillips, W T; Klipper, R W; Awasthi, V D et al. (1999) Polyethylene glycol-modified liposome-encapsulated hemoglobin: a long circulating red cell substitute. J Pharmacol Exp Ther 288:665-70
Awasthi, V D; Goins, B; Klipper, R et al. (1998) Dual radiolabeled liposomes: biodistribution studies and localization of focal sites of infection in rats. Nucl Med Biol 25:155-60
Goins, B; Klipper, R; Martin, C et al. (1998) Use of oxygen-15-labeled molecular oxygen for oxygen delivery studies of blood and blood substitutes. Adv Exp Med Biol 454:643-52
Phillips, W T; Lemen, L; Goins, B et al. (1997) Use of oxygen-15 to measure oxygen-carrying capacity of blood substitutes in vivo. Am J Physiol 272:H2492-9
Phillips, W T; Klipper, R; Fresne, D et al. (1997) Platelet reactivity with liposome-encapsulated hemoglobin in the rat. Exp Hematol 25:1347-56
Goins, B; Phillips, W T; Klipper, R et al. (1997) Role of complement in rats injected with liposome-encapsulated hemoglobin. J Surg Res 68:99-105