Synthesis and Physicochemical Properties of Poly(2‐Alkyl‐2‐Oxazoline)‐Conjugated Hemoglobins as an Artificial O₂ Carrier: Comparison with Polyethylene Glycol Conjugates

Abstract Polyethylene glycol (PEG) is a biocompatible polymer extensively employed to prolong blood circulation and mitigate the immunogenicity of the protein therapeutics. Nonetheless, there are reports of anti‐PEG antibody production. Poly(2‐alkyl‐2‐oxazoline) (PROx) exhibits analogous immunological stealth properties and represents a potential substitute for PEG. This study details the synthesis of PROx‐conjugated hemoglobins (PROx m ‐Hbs, R = Me, Et) as artificial O 2 carriers, functioning as red blood cell (RBC) substitutes, and evaluates their O 2 affinities and solution properties. The average number of polymers bound is designed to be 6 or 11. The O 2 affinities ( P 50 ) of PMeOx m ‐Hbs and PEtOx m ‐Hbs are ascertained as 9 Torr, comparable to those of PEG‐conjugated Hbs (PEG m ‐Hbs). The PEtOx 6 ‐Hb T , synthesized under an N 2 atmosphere, exhibited a low O 2 affinity ( P 50 = 57 Torr). Through the admixture of PEtOx 6 ‐Hb and PEtOx 6 ‐Hb T , the P 50 value of the formulation to range from 9 to 57 Tor can be tailored as desired. The colloid osmotic pressures and viscosities of PMeOx m ‐Hb and PEtOx m ‐Hb solutions are lower than those of the corresponding PEG m ‐Hb solutions. Furthermore, the PROx conjugates evinced no cytotoxicity against normal cells. PMeOx m ‐Hbs and PEtOx m ‐Hbs, characterized by their appropriate O 2 affinities and solution properties, present themselves as promising alternative materials to RBCs.