Preparation of artificial red cell and its application on alleviation of tumor hypoxia.

Abstract

Hemoglobin-based oxygen carriers were developed as an alternative for blood transfusion. However, the research progress for their further clinic applications was slow in recent several years. Hypoxia is found in most solid tumors, which is responsible for the tumor formation, increased metastasis, drug resistance during therapeutic process as well as poor patient survival. In this work, novel hemoglobin (Hb) loaded nanoliposomes, as artificial red cells for oxygen delivery, were optimized by screening various types of phospholipids and analyzing different mole ratio of phospholipid to cholesterol. The nanoliposomes presented a high encapsulating efficiency to hemoglobin and also significantly enhanced its stability. The obtained hemoglobin loaded nanoliposome (HLL) could be lyophilized for long term storage. HLL did not cause significant cell death in the concentration range of 0-100μg equivalent Hb/mL under normoxia and hypoxia incubation conditions, suggesting the low cytotoxicity and high biocompatibility of HLL. Importantly, HLL could efficiently accumulate into subcutaneous and deep orthotopic tumors, inducing a significant decrease of hypoxia-inducible factors 1α subunits (HIF-1α) in the tumors and remarkably reduced expression of vascular endothelial growth factor (VEGF). The study of acute and chronic toxicity indicated that HLL did not induce obvious damage to main organs of mice after intravenous injections with total Hb dose of 120mg/kg. We presented a promising method for relieving the hypoxia degree in solid tumors and down-regulating HIF-1α protein by directly delivering oxygen into tumors, which will be very helpful for subsequent cancer therapy.

• Authors: Jiaxin Qu, Xiaomeng Guo, Wei Li, Wanqing Hou, Hanbo Zhang, Lihua Luo, Chunqi Zhu, Jie Yang, Xiaoyi Yin, Yuan Tao, Yongzhong Du, Yan Lou, Dawei Chen, Jian You
• Journal: Colloids and surfaces. B, Biointerfaces (Colloids Surf B Biointerfaces) Vol. 160 Pg. 446-454 (Dec 01 2017) ISSN: 1873-4367 [Electronic] Netherlands
• PMID: 28985606 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Hemoglobins
• Hypoxia-Inducible Factor 1, alpha Subunit
• Liposomes
• Vascular Endothelial Growth Factor A

Topics

• Animals
• Cell Line, Tumor
• Cell Survival (drug effects)
• Hemoglobins (chemistry, pharmacokinetics, pharmacology)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Liposomes (chemistry, pharmacokinetics, pharmacology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred ICR
• Microscopy, Electron, Transmission
• Nanoparticles (chemistry, ultrastructure)
• Neoplasms, Experimental (drug therapy, metabolism, pathology)
• Tissue Distribution
• Tumor Hypoxia
• Vascular Endothelial Growth Factor A (metabolism)