MP4, a new nonvasoactive PEG-Hb conjugate
Article first published online: 8 APR 2003
Volume 43, Issue 4, pages 509–516, April 2003
How to Cite
Vandegriff, K. D., Malavalli, A., Wooldridge, J., Lohman, J. and Winslow, R. M. (2003), MP4, a new nonvasoactive PEG-Hb conjugate. Transfusion, 43: 509–516. doi: 10.1046/j.1537-2995.2003.00341.x
4-PDS = 4,4′-dithiopyridine; 4-TP = 4-thiopyridone; p50 = partial pressure at half-saturation; SFH = stroma-free Hb; TFF = tangential flow filtration.
This work was supported, in part, by Grants R01 HL 64579-04, R43 HL64996-01, and R44 HL62818-03 from the NHLBI, NIH.
Disclaimer: The authors are employees of Sangart, Inc.
- Issue published online: 8 APR 2003
- Article first published online: 8 APR 2003
- Received for publication August 1, 2002; revision received October 30, 2002, and accepted November 18, 2002.
BACKGROUND: Vasoconstriction has been an obstacle to clinical development of Hb-based O2 carriers. It is proposed that this limitation can be overcome by increasing molecular size and oxygen affinity.
STUDY DESIGN AND METHODS: Surface-modified Hb (MP4) was designed, whose properties are consistent with the theory that cell-free Hb engages autoregulatory vasoconstrictive responses to Hb diffusion in the plasma space (“facilitated diffusion”). Human Hb was modified by reaction first with 2-iminothiolane to add sulfhydryl groups and then with monofunctional maleimide- activated 5-kDa PEG.
RESULTS: MP4 was found to have a molecular weight of 90 kDa, a molecular radius increased relative to native Hb (9.3 ± 1.4 vs. 3.2 nm), high oxygen affinity (p50∼ 5-6 mmHg), and a Bohr effect approximately half that of native human Hb (–0.24Δlogp50/ΔpH). At 4.2 g per dL in Ringer's lactate, its viscosity was 2.5 cP, and its oncotic pressure was 50 mmHg. The t50 of 14C-MP4 in rats was approximately 24 hours. No significant elevation in mean arterial pressure was observed.
CONCLUSION: MP4 appears to be free of a pressor effect, a major limitation to the development of a safe and effective RBC substitutes in the past.