Localized increase of tissue oxygen tension by magnetic targeted drug delivery

Celine Liong; Daniel Ortiz; Eilleen Ao-Ieong; Mahantesh S. Navati; Joel M. Friedman; Pedro Cabrales

doi:10.1088/0957-4484/25/26/265102

Localized increase of tissue oxygen tension by magnetic targeted drug delivery

Celine Liong, Daniel Ortiz, Eilleen Ao-Ieong, Mahantesh S. Navati, Joel M. Friedman, Pedro Cabrales

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Hypoxia is the major hindrance to successful radiation therapy of tumors. Attempts to increase the oxygen (O₂) tension (PO₂) of tissue by delivering more O₂ have been clinically disappointing, largely due to the way O₂ is transported and released by the hemoglobin (Hb) within the red blood cells (RBCs). Systemic manipulation of O₂ transport increases vascular resistance due to metabolic autoregulation of blood flow to prevent over oxygenation. This study investigates a new technology to increase O₂ delivery to a target tissue by decreasing the Hb-O₂ affinity of the blood circulating within the targeted tissue. As the Hb-O₂ affinity decreases, the tissue PO₂ to satisfy tissue O₂ metabolic needs increases without increasing O₂ delivery or extraction. Paramagnetic nanoparticles (PMNPs), synthetized using gadolinium oxide, were coated with the cell permeable Hb allosteric effector L35 (3,5-trichlorophenylureido-phenoxy- methylpropionic acid). L35 decreases Hb affinity for O₂ and favors the release of O₂. The L35-coated PMNPs (L35-PMNPs) were intravenously infused (10 mg kg^-1) to hamsters instrumented with the dorsal window chamber model. A magnetic field of 3 mT was applied to localize the effects of the L35-PMNPs to the window chamber. Systemic O₂ transport characteristics and microvascular tissue oxygenation were measured after administration of L35-PMNPs with and without magnetic field. The tissue PO₂ in untreated control animals was 25.2 mmHg. L35-PMNPs without magnetic field decreased tissue PO₂ to 23.4 mmHg, increased blood pressure, and reduced blood flow, largely due to systemic modification of Hb-O₂ affinity. L35-PMNPs with magnetic field increased tissue PO₂ to 27.9 mmHg, without systemic or microhemodynamic changes. These results indicate that localized modification of Hb-O₂ affinity can increase PO₂ of target tissue without affecting systemic O ₂ delivery or triggering O₂ autoregulation mechanisms. This technology can be used to treat local hypoxia and to increase O₂ in tumors, enhancing the efficacy of radiation therapies.

Original language	English (US)
Article number	265102
Journal	Nanotechnology
Volume	25
Issue number	26
DOIs	https://doi.org/10.1088/0957-4484/25/26/265102
State	Published - Jul 4 2014

Keywords

hemoglobin
microcirculation
oxygen delivery
paramagnets
tissue oxygen

ASJC Scopus subject areas

Bioengineering
General Chemistry
General Materials Science
Mechanics of Materials
Mechanical Engineering
Electrical and Electronic Engineering

Access to Document

10.1088/0957-4484/25/26/265102

Cite this

@article{68845c01c93947559738d9a0185d2a83,

title = "Localized increase of tissue oxygen tension by magnetic targeted drug delivery",

abstract = "Hypoxia is the major hindrance to successful radiation therapy of tumors. Attempts to increase the oxygen (O2) tension (PO2) of tissue by delivering more O2 have been clinically disappointing, largely due to the way O2 is transported and released by the hemoglobin (Hb) within the red blood cells (RBCs). Systemic manipulation of O2 transport increases vascular resistance due to metabolic autoregulation of blood flow to prevent over oxygenation. This study investigates a new technology to increase O2 delivery to a target tissue by decreasing the Hb-O2 affinity of the blood circulating within the targeted tissue. As the Hb-O2 affinity decreases, the tissue PO2 to satisfy tissue O2 metabolic needs increases without increasing O2 delivery or extraction. Paramagnetic nanoparticles (PMNPs), synthetized using gadolinium oxide, were coated with the cell permeable Hb allosteric effector L35 (3,5-trichlorophenylureido-phenoxy- methylpropionic acid). L35 decreases Hb affinity for O2 and favors the release of O2. The L35-coated PMNPs (L35-PMNPs) were intravenously infused (10 mg kg-1) to hamsters instrumented with the dorsal window chamber model. A magnetic field of 3 mT was applied to localize the effects of the L35-PMNPs to the window chamber. Systemic O2 transport characteristics and microvascular tissue oxygenation were measured after administration of L35-PMNPs with and without magnetic field. The tissue PO2 in untreated control animals was 25.2 mmHg. L35-PMNPs without magnetic field decreased tissue PO2 to 23.4 mmHg, increased blood pressure, and reduced blood flow, largely due to systemic modification of Hb-O2 affinity. L35-PMNPs with magnetic field increased tissue PO2 to 27.9 mmHg, without systemic or microhemodynamic changes. These results indicate that localized modification of Hb-O2 affinity can increase PO2 of target tissue without affecting systemic O 2 delivery or triggering O2 autoregulation mechanisms. This technology can be used to treat local hypoxia and to increase O2 in tumors, enhancing the efficacy of radiation therapies.",

keywords = "hemoglobin, microcirculation, oxygen delivery, paramagnets, tissue oxygen",

author = "Celine Liong and Daniel Ortiz and Eilleen Ao-Ieong and Navati, {Mahantesh S.} and Friedman, {Joel M.} and Pedro Cabrales",

year = "2014",

month = jul,

day = "4",

doi = "10.1088/0957-4484/25/26/265102",

language = "English (US)",

volume = "25",

journal = "Nanotechnology",

issn = "0957-4484",

publisher = "IOP Publishing Ltd.",

number = "26",

}

TY - JOUR

T1 - Localized increase of tissue oxygen tension by magnetic targeted drug delivery

AU - Liong, Celine

AU - Ortiz, Daniel

AU - Ao-Ieong, Eilleen

AU - Navati, Mahantesh S.

AU - Friedman, Joel M.

AU - Cabrales, Pedro

PY - 2014/7/4

Y1 - 2014/7/4

N2 - Hypoxia is the major hindrance to successful radiation therapy of tumors. Attempts to increase the oxygen (O2) tension (PO2) of tissue by delivering more O2 have been clinically disappointing, largely due to the way O2 is transported and released by the hemoglobin (Hb) within the red blood cells (RBCs). Systemic manipulation of O2 transport increases vascular resistance due to metabolic autoregulation of blood flow to prevent over oxygenation. This study investigates a new technology to increase O2 delivery to a target tissue by decreasing the Hb-O2 affinity of the blood circulating within the targeted tissue. As the Hb-O2 affinity decreases, the tissue PO2 to satisfy tissue O2 metabolic needs increases without increasing O2 delivery or extraction. Paramagnetic nanoparticles (PMNPs), synthetized using gadolinium oxide, were coated with the cell permeable Hb allosteric effector L35 (3,5-trichlorophenylureido-phenoxy- methylpropionic acid). L35 decreases Hb affinity for O2 and favors the release of O2. The L35-coated PMNPs (L35-PMNPs) were intravenously infused (10 mg kg-1) to hamsters instrumented with the dorsal window chamber model. A magnetic field of 3 mT was applied to localize the effects of the L35-PMNPs to the window chamber. Systemic O2 transport characteristics and microvascular tissue oxygenation were measured after administration of L35-PMNPs with and without magnetic field. The tissue PO2 in untreated control animals was 25.2 mmHg. L35-PMNPs without magnetic field decreased tissue PO2 to 23.4 mmHg, increased blood pressure, and reduced blood flow, largely due to systemic modification of Hb-O2 affinity. L35-PMNPs with magnetic field increased tissue PO2 to 27.9 mmHg, without systemic or microhemodynamic changes. These results indicate that localized modification of Hb-O2 affinity can increase PO2 of target tissue without affecting systemic O 2 delivery or triggering O2 autoregulation mechanisms. This technology can be used to treat local hypoxia and to increase O2 in tumors, enhancing the efficacy of radiation therapies.

AB - Hypoxia is the major hindrance to successful radiation therapy of tumors. Attempts to increase the oxygen (O2) tension (PO2) of tissue by delivering more O2 have been clinically disappointing, largely due to the way O2 is transported and released by the hemoglobin (Hb) within the red blood cells (RBCs). Systemic manipulation of O2 transport increases vascular resistance due to metabolic autoregulation of blood flow to prevent over oxygenation. This study investigates a new technology to increase O2 delivery to a target tissue by decreasing the Hb-O2 affinity of the blood circulating within the targeted tissue. As the Hb-O2 affinity decreases, the tissue PO2 to satisfy tissue O2 metabolic needs increases without increasing O2 delivery or extraction. Paramagnetic nanoparticles (PMNPs), synthetized using gadolinium oxide, were coated with the cell permeable Hb allosteric effector L35 (3,5-trichlorophenylureido-phenoxy- methylpropionic acid). L35 decreases Hb affinity for O2 and favors the release of O2. The L35-coated PMNPs (L35-PMNPs) were intravenously infused (10 mg kg-1) to hamsters instrumented with the dorsal window chamber model. A magnetic field of 3 mT was applied to localize the effects of the L35-PMNPs to the window chamber. Systemic O2 transport characteristics and microvascular tissue oxygenation were measured after administration of L35-PMNPs with and without magnetic field. The tissue PO2 in untreated control animals was 25.2 mmHg. L35-PMNPs without magnetic field decreased tissue PO2 to 23.4 mmHg, increased blood pressure, and reduced blood flow, largely due to systemic modification of Hb-O2 affinity. L35-PMNPs with magnetic field increased tissue PO2 to 27.9 mmHg, without systemic or microhemodynamic changes. These results indicate that localized modification of Hb-O2 affinity can increase PO2 of target tissue without affecting systemic O 2 delivery or triggering O2 autoregulation mechanisms. This technology can be used to treat local hypoxia and to increase O2 in tumors, enhancing the efficacy of radiation therapies.

KW - hemoglobin

KW - microcirculation

KW - oxygen delivery

KW - paramagnets

KW - tissue oxygen

UR - http://www.scopus.com/inward/record.url?scp=84902438074&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84902438074&partnerID=8YFLogxK

U2 - 10.1088/0957-4484/25/26/265102

DO - 10.1088/0957-4484/25/26/265102

M3 - Article

C2 - 24920392

AN - SCOPUS:84902438074

SN - 0957-4484

VL - 25

JO - Nanotechnology

JF - Nanotechnology

IS - 26

M1 - 265102

ER -

Localized increase of tissue oxygen tension by magnetic targeted drug delivery

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this