Polymerized human hemoglobin facilitated modulation of tumor oxygenation is dependent on tumor oxygenation status and oxygen affinity of the hemoglobin-based oxygen carrier

Abstract

Administration of hemoglobin-based oxygen carriers (HBocs) into the systemic circulation is a potential strategy to relieve solid tumor hypoxia in order to increase the effectiveness of chemotherapeutics. previous computational analysis indicated that the oxygen (o 2) status of the tumor and HBoc o 2 affinity may play a role in increased O 2 delivery to the tumor. However, no study has experimentally investigated how low-and high-affinity HBOCs would perform in normoxic and hypoxic tumors. In this study, we examined how the HBOC, polymerized human hemoglobin (PolyhHb), in the relaxed (R) or tense (T) quaternary state modulates O 2 delivery to hypoxic (FME) and normoxic (LOX) human melanoma xenografts in a murine window chamber model. We examined microcirculatory fluid flow via video shearing optical microscopy, and O 2 distributions via phosphorescence quenching microscopy. Additionally, we examined how weekly infusion of a 20% top-load dose of PolyhHb influences growth rate, vascularization, and regional blood flow in the FME and LOX tumor xenografts. Infusion of low-affinity T-state PolyhHb led to increased tissue oxygenation, decreased blood flow, decreased tumor growth, and decreased vascularization in hypoxic tumors. However, infusion of both T-state and R-state PolyhHbs led to worse outcomes in normoxic tumors. Of particular concern was the high-affinity R-state PolyhHb, which led to no improvement in hypoxic tumors and significantly worsened outcomes in normoxic tumors. Taken together, the results of this study indicate that the tumor O 2 status is a primary determinant of the potency and outcomes of infused polyhHb. Unregulated angiogenesis and rapid cell proliferation in the tumor microenvironment result in decreased blood flow and oxygen (O 2) delivery 1. Under these conditions, cancer cells adapt to the hypoxic environment via activation of hypoxia-inducible factors, HIF-1 and HIF-2 2. These adaptations to chronic hypoxia are associated with metabolic reprogramming, angiogenesis, epithelial-mesenchymal transition, metastasis, and resistance to radiation and chemotherapy 3,4. Furthermore, many forms of cancer therapy require reactive oxygen species (ROS) to promote tumor suppression 5. Thus, increasing O 2 delivery to solid tumors is a promising target for cancer therapy.

Low‐Cost, High‐Pressure‐Synthesized Oxygen‐Entrapping Materials to Improve Treatment of Solid Tumors

“…Gas chromatography with a thermal conductivity detector was used to quantify the amount of oxygen entrapped in the foam, solid, and hydrogel GeMs. The oxygen concentration was approximately the Polymerized human hemoglobin 0.0069 30 [25] Perfluorochemical nanoemulsions 0.43 x [26] O 2 microbubbles w/ultrasound 0.097 x…”

“…Water-splitting nanoparticles 0.0015 x [27] O 2 carrying hydrogels w/radiotherapy 0.095 x [28] O 2 -generating hydrogels 0.004 12 [29] pH sensitive O 2 nanobubbles 0.0049 27 [30] RBC O 2 delivering microvehicles 0.0013 x [31] O 2 encapsulating polydopamine nanoparticles 0.0069 19.7 [32] Cyanobacteria O 2 pump 0.0084 x [33] same in all three (Figure 2B), and each material entrapped twice as much oxygen as previously studied materials (Table 1). [8,[24][25][26][27][28][29][30][31][32][33] In addition, the density of the foam O 2 -GeMs was significantly lower than those of hydrogel and solid O 2 -GeMs (Figure S5, Supporting Information).…”

Pharmaceutical Technology Innovation Strategy Based on the Function of Blood Transport Proteins as DDS Carriers for the Treatment of Intractable Disorders and Cancer

“…Apart from Hb-V, attempts have been made to develop hemoglobin-based medical gas carriers for the treatment of intractable disorders. 36,37) Since the lack of biological active gases, such as oxygen and CO, is associated with the pathogenesis of several disorders, the delivery of these gas molecules by hemoglobin-based preparations holds great potential for advancing the field of medicine. In addition, a few attempts have been made to develop DDS carriers that use hemoglobin as a ligand for targeting macrophages, on the basis of the fact that free hemoglobin is scavenged by macrophages via CD163.…”

ZIF-8 Metal–Organic Framework Nanoparticles Loaded with Hemoglobin as a Potential Red Blood Cell Substitute

“…Hemoglobin (Hb)-based oxygen carriers (HBOCs) constitute one major class of artificial red blood cell (RBC) substitute, which has gained considerable attention in treating hemorrhagic shock, , ameliorating traumatic brain injury, − and suppressing tumor growth via oxygenation of hypoxic tissues. − Unfortunately, prior generations of HBOCs yielded disappointing clinical outcomes due to significant safety concerns . Extravasation of cell-free Hb initially present in the vascular space through the vascular endothelium into the tissue space is regarded as the primary underlying cause of those safety concerns, which manifests through vasoconstriction, systemic hypertension, and oxidative tissue injury. ,, Fortunately, various strategies have been developed to reduce/prevent extravasation of cell-free Hb, including Hb polymerization, , surface conjugation of Hb, , and liposome encapsulation of Hb. , All of these strategies increase the molecular radius of Hb so that it is unable to extravasate through the blood vessel wall.…”