Mixtures of tense and relaxed state polymerized human hemoglobin regulate oxygen affinity and tissue construct oxygenation

Belcher, Donald; Banerjee, Uddyalok; Baehr, Christopher Michael; Richardson, Kristopher Emil; Cabrales, Pedro; Berthiaume, François; Palmer, Andre F.

doi:10.1371/journal.pone.0185988

Cited by 21 publications

(44 citation statements)

References 46 publications

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“…PolyhHbs were synthesized from human Hb and glutaraldehyde using our previously reported procedure [ 40 ]. Expired human plasma for viscosity analysis was generously donated by Transfusion Services, Wexner Medical Center, The Ohio State University, Columbus, Ohio.…”

Section: Methodsmentioning

confidence: 99%

“…We have recently explored the biophysical properties of both high and low O 2 affinity HBOCs via the production of polymerized Hbs locked in either the relaxed (R) or tense (T) quaternary state [ 36 – 38 ]. We have used information from prior studies and a recent down selection study to better engineer polymerized Hbs with decreased in vivo oxidation and increased circulatory half-life [ 39 , 40 ].…”

Section: Introductionmentioning

confidence: 99%

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The quaternary state of polymerized human hemoglobin regulates oxygenation of breast cancer solid tumors: A theoretical and experimental study

Belcher

Baek

et al. 2018

PLoS ONE

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A major constraint in the treatment of cancer is inadequate oxygenation of the tumor mass, which can reduce chemotherapeutic efficacy. We hypothesize that polymerized human hemoglobin (PolyhHb) can be transfused into the systemic circulation to increase solid tumor oxygenation, and improve chemotherapeutic outcomes. By locking PolyhHb in the relaxed (R) quaternary state, oxygen (O2) offloading at low O2 tensions (<20 mm Hg) may be increased, while O2 offloading at high O2 tensions (>20 mm Hg) is facilitated with tense (T) state PolyhHb. Therefore, R-state PolyhHb may deliver significantly more O2 to hypoxic tissues. Biophysical parameters of T and R-state PolyhHb were used to populate a modified Krogh tissue cylinder model to assess O2 transport in a tumor. In general, we found that increasing the volume of transfused PolyhHb decreased the apparent viscosity of blood in the arteriole. In addition, we found that PolyhHb transfusion decreased the wall shear stress at large arteriole diameters (>20 μm), but increased wall shear stress for small arteriole diameters (<10 μm). Therefore, transfusion of PolyhHb may lead to elevated O2 delivery at low pO2. In addition, transfusion of R-state PolyhHb may be more effective than T-state PolyhHb for O2 delivery at similar transfusion volumes. Reduction in the apparent viscosity resulting from PolyhHb transfusion may result in significant changes in flow distributions throughout the tumor microcirculatory network. The difference in wall shear stress implies that PolyhHb may have a more significant effect in capillary beds through mechano-transduction. Periodic top-load transfusions of PolyhHb into mice bearing breast tumors confirmed the oxygenation potential of both PolyhHbs via reduced hypoxic volume, vascular density, tumor growth, and increased expression of hypoxia inducible genes. Tissue section analysis demonstrated primary PolyhHb clearance occurred in the liver and spleen indicating a minimal risk for renal damage.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The quaternary state of polymerized human hemoglobin regulates oxygenation of breast cancer solid tumors: A theoretical and experimental study

Belcher

Baek

et al. 2018

PLoS ONE

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“…Prior research has demonstrated that polymerized human Hb (PolyhHb) frozen in the tense quaternary state (T-state) can regulate O 2 transport to cells housed in the ECS. 17 This can prevent the development of hypoxia and hyperoxia, allowing the hepatocytes to function more effectively.…”

Section: Introductionmentioning

confidence: 99%

Next‐generation polymerized human hemoglobins in hepatic bioreactor simulations

Cuddington

Moses

Belcher

et al. 2020

Biotechnology Progress

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Hepatic hollow fiber (HF) bioreactors can be used to provide temporary support to patients experiencing liver failure. Before being connected to the patient's circulation, cells in the bioreactor must be exposed to a range of physiological O 2 concentrations as observed in the liver sinusoid to ensure proper performance. This zonation in cellular oxygenation promotes differences in hepatocyte phenotype and may better approximate the performance of a real liver within the bioreactor. Polymerized human hemoglobin (PolyhHb) locked in the tense quaternary state (T-state) has the potential to both supply and regulate O 2 transport to cultured hepatocytes in the bioreactor due to its low O 2 affinity. In this study, T-state PolyhHb production and purification processes were optimized to minimize the concentration of low-molecularweight PolyhHb species in solution. Deconvolution of size-exclusion chromatography spectra was performed to calculate the distribution of polymeric Hb species in the final product. Fluid flow and mass transport within a single fiber of a hepatic HF bioreactor was computationally modeled with finite element methods to simulate the effects of employing T-state PolyhHb to facilitate O 2 transport in a hepatic bioreactor system. Optimal bioreactor performance was defined as having a combined hypoxic and hyperoxic volume fraction in the extracapillary space of less than 0.05 where multiple zones were observed. The Damköhler number and Sherwood number had strong inverse relationships at each cell density and fiber thickness combination. These results suggest that targeting a specific Damköhler number may be beneficial for optimal hepatic HF bioreactor operation. K E Y W O R D S fluid flow modeling, hemoglobin-based oxygen carrier, hollow fiber bioreactor, polymerized human hemoglobin, red blood cell substitute

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“…Weekly treatment with low MW PolyHb at low doses insufficient to increase blood O 2 carrying capacity with short circulatory half-life (10 hours intravascular half-life) limits the oxygenation potential of PolyHb as a cisplatin sensitizing mechanism in NSCLC. In our previous study, we dosed every two days with higher concentrations of large MW PolyHb (24 hours intravascular half-life) to significantly increase oxygenation in breast tumors and directly induce O 2 dependent antitumor activity [ 26 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

“…R-state PolyHb was prepared from human Hb (hHb) extracted from human RBCs as described previously [ 48 ]. After purifying the material, we measured the biophysical properties of the PolyHb [ 31 ]. The cyanomethemoglobin method was used to measure the Hb concentration and the methemoglobin (metHb) level of hHb/PolyHb solutions [ 49 , 50 ].…”

Section: Methodsmentioning

confidence: 99%

Polymerized human hemoglobin increases the effectiveness of cisplatin-based chemotherapy in non-small cell lung cancer

et al. 2020

Self Cite

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Cisplatin is a promising therapeutic for the treatment of non-small cell lung cancer (NSCLC). Unfortunately, a significant portion of NSCLC patients relapse due to cisplatin chemoresistance. This chemoresistance is thought to be primarily associated with hypoxia in the tumor microenvironment. Administration of hemoglobin (Hb)-based oxygen (O 2 ) carriers (HBOCs) is a promising strategy to alleviate hypoxia in the tumor, which may make cisplatin more effective. In this study, we administered a high O 2 affinity, relaxed state (R-state) polymerized hemoglobin (PolyHb) to three different NSCLC cell lines cultured in vitro and implanted in vivo into healthy mice. The R-state PolyHb administered in this study is unable to deliver O 2 unless under severe hypoxia which significantly limits its oxygenation potential. In vitro sensitivity studies indicate that the administration of PolyHb increases the effectiveness of cisplatin under hypoxic conditions. Additional animal studies revealed that co-administration of PolyHb with cisplatin attenuated tumor growth without alleviating hypoxia. Analysis of reactive O 2 species production in the presence of hypoxic culture indicates that exogenous ROS production by oxidized PolyHb may the mechanism of chemosensitization. This ROS mechanism, coupled with oxygenation, may be a potential chemosensitizing strategy for use in NSCLC treatment.

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Mixtures of tense and relaxed state polymerized human hemoglobin regulate oxygen affinity and tissue construct oxygenation

Cited by 21 publications

References 46 publications

The quaternary state of polymerized human hemoglobin regulates oxygenation of breast cancer solid tumors: A theoretical and experimental study

The quaternary state of polymerized human hemoglobin regulates oxygenation of breast cancer solid tumors: A theoretical and experimental study

Next‐generation polymerized human hemoglobins in hepatic bioreactor simulations

Polymerized human hemoglobin increases the effectiveness of cisplatin-based chemotherapy in non-small cell lung cancer

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