SPMNPs in Hyperthermia Treatment for Cancer

Hyperthermia is when temperatures of certain organs or tissues are raised to 41-46°C. If the temperature is raised to above 47°C, tissue destruction occurs and this process is called thermoablation (Jordan et al. 1999). Thermoablation is characterized by acute necrosis, coagulation, or carbonization of tissue. It is clearly undesirable in a clinical situation due to systemic side effects and further clinical complications (Moroz et al. 2002). Modern hyperthermia trials focus mainly on the optimization of thermal homogeneity at moderate temperatures (42-43°C) in the target volume. SPMNPs have the potential to solve this optimizing problem.

As it is well known, tumor cells are more susceptible to heat increases than healthy, normal cells (Chen et al. 2007). Clinical experiments have been taking advantage of the higher sensitivity of tumor cells to temperatures in the range of 42-45°C than normal tissue cells (Overgaard and Overgaard 1972; Moroz et al. 2001). Hyperthermia treatment for cancer works by raising the tumor temperature resulting in damage in the plasma membrane, the cytoskeleton, and the cell nucleus (Shellman et al. 2008). In addition, certain regulatory proteins, cytokines, or kinases are influenced by hyperthermia, which leads to changes in the cell cycle and can even induce apoptosis (i.e., cell death driven by the cell regulatory system itself) (Fairbairn et al. 1995; Sellins and Cohen 1991). Cancer cells are more vulnerable to elevated temperatures compared to normal, healthy cells because (Chen et al. 2007):

1. Normal cells reside close to normal blood streams which can dissipate heat more effectively compared to cancerous cells which have abnormal blood flow and

2. Cancerous cells have a more acidic surrounding environment, therefore they are more susceptible to hyperthermia

There are several different methods for creating local heat elevation (such as using microwave radiation, capacitive or inductive coupling of radiofrequency fields) by implanting electrodes, by ultrasound, or by lasers. Magnetic hyper-thermia utilizes losses during the magnetization reversal process of the particles when exposed to alternating magnetic fields to convert such losses to heat. In magnetic hyperthermia, superparamagnetic particles are directed and concentrated at the desired location. An alternating magnetic field will be applied and this application results in the magnetization reversal process of the particles. Energy lost in this process is converted to heat.

The advantages of using SPMNPs in hyperthermia are as followed. First, they can be effectively directed to tumor tissues using magnetic fields and hence can avoid heating up normal tissues. For example, in one study, superparamagnetic magnetite (Fe2O3/Fe3O4) particles (core size 3.1 ± 0.7 nm) coated with modified dextran were targeted to C3H mammary carcinoma in the right hind leg of mice using magnets after intratumoral injection of the particles. With an applied 50 mT magnetic field, the iron concentration at the tumor site was shown to increase 2.5-fold compared to the control in which no magnets were used for targeting (Jordan et al. 1996).

Second, SPMNPs can be readily conjugated with therapeutic agents and delivered to tumors. Upon reaching the tumor site, an alternating magnetic field will be applied causing the particles to be heated, melting the thermosensitive surface, leaking the drug at the tumor site and, at the same time, heating the tumor. This strategy has a dual effect on cancer treatment as researchers have shown increased chemotherapy efficacy when combined with hyperthermia (Wust et al. 2002; Falk and Issels 2001; Kapp et al. 2000; Gerner et al. 2000).

Another advantage of SPMNPs in hyperthermia is that they possess an appropriate and specific Curie temperature (TC) (i.e., the temperature above which SPMNPs lose their magnetic properties and, in turn, their coupling with the external magnetic field) that limits the hyperthermia at the predetermined temperature. For example, copper nickel (Cu/Ni) alloy magnetic nanoparticles were synthesized and coated with PEG and these particles have a Curie temperature in the range of 43-46°C (Chatterjee et al. 2005). This low range of Curie temperature of the Cu/Ni magnetic nanoparticles is very desirable in hyperthermia applications. Once the temperature of the magnetic nanoparticles increases to above TC (from 43 to 46°C in this case), the external magnetic field will stop interacting with the nanoparticles; hence, further tissue heating will not occur.

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