Liong Celine, Ortiz Daniel, Ao-ieong Eilleen, Navati Mahantesh S, Friedman Joel M, Cabrales Pedro
Department of Bioengineering University of California, San Diego La Jolla, CA 92093 USA.
Nanotechnology. 2014 Jul 4;25(26):265102. doi: 10.1088/0957-4484/25/26/265102. Epub 2014 Jun 12.
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 O2 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.
缺氧是肿瘤放射治疗成功的主要障碍。通过输送更多氧气来提高组织氧分压（PO2）的尝试在临床上并不理想，这主要是由于红细胞（RBC）内血红蛋白（Hb）运输和释放氧气的方式所致。由于血流的代谢自动调节以防止过度氧合，对氧气运输进行全身调控会增加血管阻力。本研究调查了一种新技术，即通过降低靶向组织内循环血液中血红蛋白与氧气的亲和力来增加氧气输送到目标组织。随着血红蛋白与氧气亲和力的降低，满足组织氧代谢需求的组织PO2增加，而无需增加氧气输送或摄取。使用氧化钆合成的顺磁性纳米颗粒（PMNPs）用可渗透细胞的血红蛋白变构效应剂L35（3,5-三氯苯脲基-苯氧基-甲基丙酸）进行包被。L35降低血红蛋白对氧气的亲和力并促进氧气释放。将L35包被的PMNPs（L35-PMNPs）静脉注射（10 mg kg(-1)）给配备背窗室模型的仓鼠。施加3 mT的磁场将L35-PMNPs的作用定位到窗室。在有或没有磁场的情况下给予L35-PMNPs后，测量全身氧气运输特征和微血管组织氧合情况。未治疗的对照动物的组织PO2为25.2 mmHg。没有磁场的L35-PMNPs将组织PO2降低至23.4 mmHg，增加血压并减少血流，这主要是由于血红蛋白与氧气亲和力的全身改变所致。有磁场的L35-PMNPs将组织PO2增加至27.9 mmHg，而没有全身或微循环动力学变化。这些结果表明，局部改变血红蛋白与氧气的亲和力可以增加目标组织的PO2，而不影响全身氧气输送或触发氧气自动调节机制。该技术可用于治疗局部缺氧并增加肿瘤中的氧气，提高放射治疗的疗效。
