MP4, a new nonvasoactive PEG‐Hb conjugate

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Abstract
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.

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