Sickle erythrocytes target cytotoxics to hypoxic tumor microvessels and potentiate a tumoricidal response.

Terman, David S

Viglianti, Benjamin L

Zennadi, Rahima

Fels, Diane

Boruta, Richard J

Yuan, Hong

Dreher, Mathew R

Grant, Gerald

Rabbani, Zahid N

Moon, Ejung

Lan, Lan

Eble, Joseph

Cao, Yiting

Sorg, Brian

Ashcraft, Kathleen

Palmer, Greg

Telen, Marilyn J

Dewhirst, Mark W

Ulasov, Ilya

United States

2015-12-15T14:58:52Z

2013

Resistance of hypoxic solid tumor niches to chemotherapy and radiotherapy remains a major scientific challenge that calls for conceptually new approaches. Here we exploit a hitherto unrecognized ability of sickled erythrocytes (SSRBCs) but not normal RBCs (NLRBCs) to selectively target hypoxic tumor vascular microenviroment and induce diffuse vaso-occlusion. Within minutes after injection SSRBCs, but not NLRBCs, home and adhere to hypoxic 4T1 tumor vasculature with hemoglobin saturation levels at or below 10% that are distributed over 70% of the tumor space. The bound SSRBCs thereupon form microaggregates that obstruct/occlude up to 88% of tumor microvessels. Importantly, SSRBCs, but not normal RBCs, combined with exogenous prooxidant zinc protoporphyrin (ZnPP) induce a potent tumoricidal response via a mutual potentiating mechanism. In a clonogenic tumor cell survival assay, SSRBC surrogate hemin, along with H(2)O(2) and ZnPP demonstrate a similar mutual potentiation and tumoricidal effect. In contrast to existing treatments directed only to the hypoxic tumor cell, the present approach targets the hypoxic tumor vascular environment and induces injury to both tumor microvessels and tumor cells using intrinsic SSRBC-derived oxidants and locally generated ROS. Thus, the SSRBC appears to be a potent new tool for treatment of hypoxic solid tumors, which are notable for their resistance to existing cancer treatments.

http://www.ncbi.nlm.nih.gov/pubmed/23326340

PONE-D-12-18841

1932-6203

https://hdl.handle.net/10161/11164

eng

Public Library of Science (PLoS)

PLoS One

10.1371/journal.pone.0052543

Anemia, Sickle Cell

Animals

Blotting, Western

Cell Line, Tumor

Combined Modality Therapy

Cytotoxicity, Immunologic

Erythrocytes, Abnormal

Female

Heme Oxygenase-1

Hemin

Humans

Hydrogen Peroxide

Hypoxia

Immunotherapy, Adoptive

Membrane Proteins

Mice

Mice, Nude

Microscopy, Fluorescence

Neoplasms, Experimental

Neovascularization, Pathologic

Protoporphyrins

Reactive Oxygen Species

Tumor Microenvironment

Sickle erythrocytes target cytotoxics to hypoxic tumor microvessels and potentiate a tumoricidal response.

Journal article

Grant, Gerald|0000-0002-2651-4603

Palmer, Greg|0000-0003-2955-8297

Telen, Marilyn J|0000-0003-3809-1780

Dewhirst, Mark W|0000-0003-3459-6546

http://www.ncbi.nlm.nih.gov/pubmed/23326340

e52543

1

Biomedical Engineering

Clinical Science Departments

Duke

Duke Cancer Institute

Faculty

Institutes and Centers

Medicine

Medicine, Hematology

Pathology

Pediatrics

Pediatrics, Cardiology

Pratt School of Engineering

Radiation Oncology

School of Medicine

Published

8