Targeted Delivery of Radioprotective Agents to Mitochondria

Abstract

Adverse effects of ionizing radiation are mediated through reactive oxygen and nitrogen species. Mitochondria are the principal source of these species in the cell and play an important role in irradiation-induced apoptosis. The use of free radical scavengers and nitric oxide synthase inhibitors has proven to protect normal tissues and, in some cases, to sensitize tumor tissues to radiation damage. Dual molecules that combine radical-scavenging and NOS-inhibitory functions may be particularly effective. Drugging strategies that target mitochondria can enhance the effectiveness of such agents, in comparison to systemic administration, and circumvent side effects.

Association between Mitochondrial Bioenergetics and Radiation- Related Fatigue: A Possible Mechanism and Novel Target

“…It is known that radiation-induced damage alters mitochondrial metabolism, inhibits the mitochondrial respiratory chain, and forms highly reactive peroxynitrite (ONO 2 -) [36]. Once mitochondrial proteins are damaged, the affinity of substrates or enzymes is decreased resulting in mitochondrial dysfunction [20].…”

Nutritional Supplements for Cancer-Associated

“…However, genetic damage is also mediated by excess ROS/RNS (Epperly et al, 2003;Feinendegen et al, 2007). Recently the principal source of excess ROS/RNS during radiotherapy has been shown to be the mitochondria (Epperly et al, 2003;Sabbarova & Kanai, 2007). The initial cytotoxicity of radiation is now thought to be due to excess ROS/RNS triggering of apoptosis via alteration of mitochondrial metabolism.…”

“…In addition to chemotherapy, radiotherapy also produces damage to tissues other than cancerous tissues. Agents that protect tissues against radiation effects have been used to reduce unwanted damage (Brizel, 2007;Sabbarova & Kanai, 2007). Radioprotective agents that have been used to decrease the adverse effects of radiotherapy are: antioxidants, free radical scavengers, inhibitors of nitric oxide synthase and antiinflammatory and immunomodulatory agents (Brizel, 2007;Sabbarova & Kanai, 2007).…”

“…This causes transiently opening of mitochondrial permeability transition pores, which increases the influx of calcium ions into the matrix. The influx of calcium ions stimulates mitochondrial nitric oxide synthase and generation of nitric oxide, which inhibits the respiratory chain and eventually stimulates excess ROS/RNS free radicals that initiate apoptosis (Leach et al, 2002;Sabbarova & Kanai, 2007).…”

“…Agents that protect tissues against radiation effects have been used to reduce unwanted damage (Brizel, 2007;Sabbarova & Kanai, 2007). Radioprotective agents that have been used to decrease the adverse effects of radiotherapy are: antioxidants, free radical scavengers, inhibitors of nitric oxide synthase and antiinflammatory and immunomodulatory agents (Brizel, 2007;Sabbarova & Kanai, 2007). The most effective of these under development target mitochondria, such as proteins and peptides that can be transported into mitochondria and plasmids or nucleotide sequences, for example, agents that target and stimulate mitochondrial manganese superoxide dismutase genes to produce this important dismutase have been used as radioprotective agents (Sabbarova & Kanai, 2007).…”