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

Belcher, Donald; Ju, Julia A.; Baek, Jin Hyen; Yalamanoglu, Ayla; Buehler, Paul W.; Gilkes, Daniele M.; Palmer, Andre F.

doi:10.1371/journal.pone.0191275

Cited by 27 publications

(33 citation statements)

References 68 publications

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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%

“…The O 2 -hHb/PolyHb equilibrium binding curves were generated using a Hemox Analyzer (TCS Scientific Corp., New Hope, PA). The rheology of PolyHb plasma mixtures was measured using a DV3T-CP cone and plate rheometer (Brookfield AMETEK, Middleboro, MA) with cone spindle CPA-40Z [ 26 ]. The MW distribution was estimated with an Acclaim SEC-1000 column (Thermo Scientific, Waltham, MA) connected to a Thermo Scientific Dionex Ultimate HPLC/UHPLC system [ 38 ].…”

Section: Methodsmentioning

confidence: 99%

“…HBOCs often involve chemically cross-linked acellular hemoglobin (Hb) and are capable of transporting oxygen (O 2 ). Alterations in the biophysical properties of HBOCs designed to reduce hypoxia may lead to targeted O 2 release in the tumor [ 26 ]. This targeted O 2 release may alleviate hypoxia-induced cisplatin resistance.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

et al. 2020

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“…The chemical modifications that are necessary to make HBOCs safe for infusion typically alter the HBOC O 2 affinity 16,17,[19][20][21] . For example, conjugating polyethylene glycol to the surface of hemoglobin (Hb) results in an increased O 2 affinity (P 50 : 5-6 mm Hg) compared to unmodified Hb 22,23 .…”

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confidence: 99%

“…Previously, we computationally determined that alterations in the O 2 affinity of the HBOC impact how much O 2 an HBOC will supply to the surrounding tumor tissue 20,27 . From the results of these studies, we anticipate that R-state PolyHb and T-state PolyHb should increase O 2 delivery to hypoxic tissue.…”

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confidence: 99%

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

Belcher

Lucas

Cabrales

et al. 2020

Sci Rep

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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.

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Comprehensive characterization of tense and relaxed quaternary state glutaraldehyde polymerized bovine hemoglobin as a function of cross‐link density

Bolden-Rush

Cuddington

et al. 2020

Biotech & Bioengineering

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Previously, our lab developed high molecular weight (MW) tense (T) quaternary state glutaraldehyde polymerized bovine hemoglobins (PolybHbs) that exhibited reduced vasoactivity in several small animal models. In this study, we prepared PolybHb in the T and relaxed (R) quaternary state with ultrahigh MW (>500 kDa) with varying cross‐link densities, and investigated the effect of MW on key biophysical properties (i.e., O2 affinity, cooperativity (Hill) coefficient, hydrodynamic diameter, polydispersity, polymer composition, viscosity, gaseous ligand‐binding kinetics, auto‐oxidation, and haptoglobin [Hp]‐binding kinetics). To further optimize current PolybHb synthesis and purification protocols, we performed a comprehensive meta‐data analysis to evaluate correlations between procedural parameters (i.e., cross‐linker:bovine hemoglobin (bHb) molar ratio, gas‐liquid exchange time, temperature during sodium dithionite addition, and number of diafiltration cycles) and the biophysical properties of both T‐ and R‐state PolybHbs. Our results showed that, the duration of the fast‐step auto‐oxidation phase of R‐state PolybHb increased with decreasing glutaraldehyde:bHb molar ratio. Additionally, T‐state PolybHbs exhibited significantly higher bimolecular rate constants for binding to Hp and unimolecular O2 offloading rate constants compared to R‐state PolybHbs. The methemoglobin (metHb) level in the final product was insensitive to the molar ratio of glutaraldehyde to bHb for all PolybHbs. During tangential flow filtration processing of the final product, 14 diafiltration cycles was found to yield the lowest metHb level.

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

Cited by 27 publications

References 68 publications

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

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

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

Comprehensive characterization of tense and relaxed quaternary state glutaraldehyde polymerized bovine hemoglobin as a function of cross‐link density

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