Liposome-Encapsulated Hemoglobin Improves Tumor Oxygenation as Detected by Near-Infrared Spectroscopy in Colon Carcinoma in Mice

Artif Organs. 2017 Apr;41(4):327-335. doi: 10.1111/aor.12825. Epub 2016 Nov 22.

Abstract

Liposome-encapsulated hemoglobin (LEH) with high (h-LEH, P50 O2 = 10 mm Hg) or low O2 affinity (l-LEH, P50 O2 = 40 mm Hg) may improve O2 delivery to sensitize tumor tissues for radiotherapy. A total of 10 mL/kg of h-LEH, l-LEH, red blood cells (RBCs), or saline was infused in mice transplanted with murine colon carcinoma with near-infrared spectroscopy (NIRS) detectors set at the tumor (right leg) and intact muscle (left leg). NIRS recorded changes in the amount of oxyhemoglobin (oxyHb), deoxyhemoglobin (deoxyHb), and their sum (tHb) with the animals spontaneously breathing room air (10 min), pure O2 (5 min), and then back to room air. The tumor was finally excised for histological examination. In mice treated with h-LEH, tHb significantly increased compared to mice receiving other solutions. The magnitude was significantly attenuated in the tumor compared to the intact muscle under room air. Reciprocal changes in oxyHb and deoxyHb between intact muscle and tumor in response to infused solutions allowed assumption of average tissue PO2 between 30 and 40 mm Hg in muscle and at around 10 mm Hg in tumor. While O2 respiration increased oxyHb and decreased deoxyHb both in muscle and tumor, their sum or tHb consistently decreased in muscle and increased in tumor regardless of preceding infusion. Such responses were totally reversed when mice were placed under hypoxia (10% O2 ), suggesting that a lack of physiological circulatory regulation in tumor may account for heavier immunohistochemical staining for human hemoglobin in tumors of mice treated with h-LEH than with l-LEH. The results suggest that h-LEH may cause significant tumor oxygenation compared to RBC, l-LEH, or saline probably due to its nanometer size (vs. RBC) and high O2 affinity (vs. l-LEH) without increasing O2 content in the intact tissue (vs. O2 respiration) probably due to a lack of physiological circulatory regulation.

Keywords: -Artificial oxygen carrier; -Hypoxic fraction; -Liposome-encapsulated hemoglobin; -Near-infrared spectroscopy; -Oxygen affinity; -Radiosensitization; Tumor hypoxia.

MeSH terms

  • Animals
  • Blood Substitutes / administration & dosage
  • Blood Substitutes / pharmacology*
  • Carcinoma / metabolism*
  • Carcinoma / pathology
  • Colonic Neoplasms / metabolism*
  • Colonic Neoplasms / pathology
  • Hemoglobins / administration & dosage
  • Hemoglobins / pharmacology*
  • Humans
  • Immunohistochemistry
  • Infusions, Intravenous
  • Liposomes
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Neoplasms, Experimental / metabolism*
  • Neoplasms, Experimental / pathology
  • Oxygen Consumption / drug effects*
  • Particle Size
  • Spectroscopy, Near-Infrared

Substances

  • Blood Substitutes
  • Hemoglobins
  • Liposomes