Blood substitute composition and method of use
The present disclosure provides oxygen-carrying nanoparticles, methods of making the nanoparticles, and methods of using the nanoparticles to carry oxygen in blood.
1. A method for providing oxygen to an organ ex vivo, the method comprising perfusing an organ with an effective amount of an oxygen-carrying nanoparticle, wherein the nanoparticle has a substantially bi-concaved disc shape and comprises an aqueous core, a bi-layered shell comprising an amphiphilic polymer, and a payload; and wherein
the bi-layered shell has a hydrophilic outer layer, a hydrophilic inner layer, and a hydrophobic region between the hydrophilic outer layer and the hydrophilic inner layer;
the amphiphilic polymer comprises a branched, amine-containing polymer linked to a lipid; and
the payload comprises an oxygen-carrying agent, an allosteric effector, and a reducing agent.
2. The method of claim 1 , wherein the amphiphilic polymer comprising the hydrophilic outer layer of the shell is derivatized with polyethylene glycol, such that the particle has a zeta potential of about −15 mV to about +15 mV.
3. The method of claim 1 , wherein the average diameter of the nanoparticle is from about 150 nm to about 300 nm, and the average height of the nanoparticle is from about 30 nm to about 80 nm.
4. The method of claim 1 , wherein the oxygen-carrying agent is synthetic hemoglobin or naturally occurring hemoglobin.
5. The method of claim 1 , wherein the allosteric effector is selected from the group consisting of 2,3-diphosphoglycerate (2,3-DPG), inositol hexaphosphate (IHP), pyridoxal-phosphate (PLP), and 2-[4-[[(3,5-dimethylanilino carbonyl]methyl]-phenoxy]-2-methylpropionic acid.
6. The method of claim 1 , wherein the reducing agent is selected from the group consisting of leucomethylene blue, glutathione and ascorbate.
7. The method of claim 1 , wherein the nanoparticle comprises about 3000 to about 10,000 hemoglobin molecules.
8. The method of claim 1 , wherein the nanoparticle comprises about 20% to about 60% (w/v) hemoglobin or about 30% to about 60% (w/v) hemoglobin.
9. The method of claim 1 , wherein the nanoparticle limits the oxidation of hemoglobin to about 10% or less of the total concentration of hemoglobin in the nanoparticle.
10. The method of claim 1 , wherein the branched, amine-containing polymer is selected from the group consisting of a polyethyleneimine branched polymer, a PAMAM dendrimer, a star polymer, and a graft polymer.