Double-Effector Nanoparticles: A Synergistic Approach to Apoptotic Hyperthermia

Temperature control is an important method of self-defense in biological systems. For example, one response mounted by humans in an effort to fight injury, including viral and bacterial infections, involves an increase in body temperature, thus producing the well-recognized symptoms of fever.[1] Today, the idea of using artificial temperature control for disease removal is being realized with the aid of various techniques, such as ultrasound, near-infrared light, and magnetic field by increasing localized temperature in a targeted region.[2] Magnetic nanoparticles have attracted considerable attention for hyperthermia applications owing to their ability to generate heat effectively when exposed to an alternating magnetic field without a penetration depth limit.[3] Hyperthermia, the artificially induced heat treatment of a disease, uses temperatures ranging between 42 °C and 47°C. Generally, a temperature below 45 °C induces apoptotic cell death.[4] As compared to necrosis, apoptosis is a more benign form of “programmed” cell death.[5] Nonliving cells produced as the result of apoptotic process are cleaned by phagocytosis without affecting neighboring normal cells. In contrast, necrosis, typically generated by harsh and high-temperature hyperthermia, is considered relatively harmful because it can be correlated with inflammatory disease and metastasis.[6] However, achieving effective apoptotic hyperthermia is often difficult, as cells typically acquire resistance to induced thermal stress.[7] Repeated exposures to high temperatures with high concentration of magnetic nanoparticles are usually necessary to achieve a useful level of therapeutic efficacy even though the conditions could favor necrotic cell death rather than apoptosis. Because cancer cells are susceptible to heat at about 43 °C, while most normal tissues remain undamaged,[8] hyperthermia using this temperature defines a recognized but unmet goal.