Localized increase of tissue oxygen tension by magnetic targeted drug delivery

摘要

Hypoxia is the major hindrance to successful radiation therapy of tumors. Attempts to increase the oxygen (O_2) tension (PO_2) of tissue by delivering more O_2 have been clinically disappointing, largely due to the way O_2 is transported and released by the hemoglobin (Hb) within the red blood cells (RBCs). Systemic manipulation of O_2 transport increases vascular resistance due to metabolic autoregulation of blood flow to prevent over oxygenation. This study investigates a new technology to increase O_2 delivery to a target tissue by decreasing the Hb-O_2 affinity of the blood circulating within the targeted tissue. As the Hb-O_2 affinity decreases, the tissue PO_2 to satisfy tissue O_2 metabolic needs increases without increasing O_2 delivery or extraction. Paramagnetic nanoparticles (PMNPs), synthetized using gadolinium oxide, were coated with the cell permeable Hb allosteric effector L35 (3,5-trichlorophenylureido-phenoxymethylpropionic acid). L35 decreases Hb affinity for O_2 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 O_2 transport characteristics and microvascular tissue oxygenation were measured after administration of L35-PMNPs with and without magnetic field. The tissue PO_2 in untreated control animals was 25.2 mmHg. L35- PMNPs without magnetic field decreased tissue PO_2 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 PO_2 to 27.9 mmHg, without systemic or microhemodynamic changes. These results indicate that localized modification of Hb-O_2 affinity can increase PO2 of target tissue without affecting systemic O_2 delivery or triggering O_2 autoregulation mechanisms. This technology can be used to treat local hypoxia and to increase O_2 in tumors, enhancing the efficacy of radiation therapies.