Radiation protection by MnSOD-plasmid liposome gene therapy

Abstract

Understanding the molecular mechanism of ionizing irradiation killing of normal tissues compared to tumor cells has uncovered potential therapeutic strategies for radiotherapeutic dose escalation in the treatment of solid tumors. One strategy exploits the difference in redox balance between normal tissues and solid tumors with organ-specific and systemic (intravenous) administration of plasmid liposomes containing the human manganese superoxide dismutase (MnSOD) transgene. When delivered, this transgene product produced significant protection against single fraction and fractionated radiation in organ-specific radioprotective gene therapy by each of several routes of administration (inhalation, swallowed, intravesicle, intra-intestinal), and this strategy was shown to avoid tumor tissue. Furthermore, systemic administration of MnSOD-PL also provides radioprotection with selective normal tissue reduction of apoptosis compared to tumor. The complex mechanism of selective normal tissue protection involves specific differences in redox balance, constitutive MnSOD expression, and compensatory metabolic changes, many of which can enhance the therapeutic effect.