Design of high molecular weight polymerized hemoglobins for use in transfusion medicine and monocyte/macrophage hemoglobin-based drug delivery systems.

摘要

Hemoglobin (Hb) is a unique protein with both the ability to transport oxygen and to target monocytes and macrophages. Therefore, Hb could be used in the design of oxygen delivery systems and targeted drug delivery systems. This dissertation dedicates two chapters to each of the aforementioned areas. Chapters 2 and 3 discuss the ability of Hb to transport oxygen, in the form of polymerized Hb. In contrast, Chapters 4 and 5 describe the ability of Hb to deliver drugs towards monocytes and macrophages, in the form of Hb-drug conjugates and Hb surface conjugated liposomes.;Although polymerized Hb solutions have long been studied as red blood cell substitutes, concerns about their side-effects have never been adequately addressed. Recent studies have demonstrated that these side-effects arise from the low molecular weight (MW) Hb components in solution. Therefore, to eliminate these side-effects, it is important to synthesize polymerized Hbs without these low MW fractions in solution. Chapter 2 shows that the novel cross-linking agent, 1,11-bis(maleimido)triethylene glycol, can be used to polymerize Hb without the presence of low MW fractions. Chapter 3 demonstrates the synthesis of high molecular weight glutaraldehyde polymerized Hb in a defined quaternary state, without low MW fractions. In contrast, the remaining chapters are devoted to the use of Hb as a targeted drug delivery ligand towards monocytes and macrophages.;The Hb-haptoglobin complex is a natural ligand for the CD163 receptor on the surface of monocytes and macrophages. This unique characteristic makes Hb a natural ligand for developing a drug delivery system to target monocytes and macrophages. Chapter 4 shows that Hb can deliver drugs into monocytes and macrophages by chemically conjugating the surface of Hb with drug molecules. In a similar fashion, chapter 5 shows that liposomes surface modified with Hb can also target drug delivery into monocytes and macrophages.;Taken together, the knowledge gained from this work should be helpful in the design of polymerized Hbs as RBC substitutes and in targeted drug delivery toward monocytes and macrophages.