Anti-Cancer Therapy Heats Up

Never underestimate the power of heat. The residents of south Louisiana will tell you that summer temperatures upwards of 105°F and extreme humidity drive their entire daily schedules, where residents will avoid the outdoors and schedule their activities around the hottest part of the day in order to avoid devastating heat strokes and other heat-related illnesses. But we are talking about heat in an entirely different context: using heat to image, target, and kill cancer cells in the human body. While researchers and clinicians are greatly interested in anti-cancer agents that can convert electromagnetic energy, in the form of light or radiofrequency waves, to tumor-damaging heat, a big hurdle remains heating efficiency. Biomedical researchers and material scientists, including Jae-Hyun Lee and coworkers whose work appeared this month in Nature Nanotechnology, are creating tiny ‘nano’-particles that more efficiently convert radiofrequency waves to cancer killing heat. The heat-generating nanoparticles’ super efficiency will translate into lower doses required for an effective fight against cancer. Lower required doses promise to reduce potentially harmful side effects of the tiny anti-cancer particles and their drug payloads on healthy tissues, and to increase the therapeutic potential of these ‘nano’-thermal agents. Tweet

Various agents of heat-induced cancer therapy are seeing real-life application. Most of these agents classify as nanomaterials, objects that exist on a scale 1000x smaller than the width of an average human hair. On this scale, even the smallest ant would seem like a giant (where 16,000 nanoparticles of the typical size used in biomedical applications would fit side by side from head-to-tail of the tiny thief ant), and direct interaction with individual human cells and component molecules allows for strong biological activity. One type of nanomaterial, the noble metal nanoparticle, is famous for its use in thermal therapy applications. Metallic nanoparticles, including those composed of silver and gold, have the unique capability to convert light to heat, making these materials appropriate for therapies that use heat to treat tumors and weed cancer cells out of the human body. Tiny metallic light-activated ‘heat-boxes’ can be used to damage cancer cells. This damage can be effected either indirectly through heat-triggered drug release (Cobley 2010), where drugs are stored inside the nanoparticle, or directly through photothermal therapy (Chen 2010). Photothermal therapy entails using light to heat up specific nanomaterials, for example gold nanoparticles, to temperatures that cause localized hyperthermia, or heat-damage to cells and tissues containing the nanoparticles.

While noble metal nanoparticles have been widely investigated with clinical potential as agents of thermal therapy, the fact that these materials require light for heat generation limits their use to some extent. Despite improvements made by pushing light activation from the visible into the near-infrared spectrum (there exists a ‘window of transparency’ for human tissues in the far-red spectrum – note 1), light is still limited in its penetration depth, or how far in can penetrate into the human body. Particles of light, or photons, interact with tissues and surrounding media in the human body as light travels from the skin surface to the location of a tumor within the body. Losses of photon energy during interaction with intermediary tissues, as well as light-to-heat conversion at the nanoparticle surface which is never 100%, lead to inefficient therapy systems that require high concentrations of nanoparticles at the site of tumor and involve potentially detrimental effects to surrounding healthy tissues.

Jae-Hyun Lee and coworkers have come up with a solution to current limitations associated with photothermal therapy and other forms of heat-based therapy by creating super-efficient core-shell magnetic nanoparticles. Tiny magnetic particles, also called nano-magnets, are not new to the field of magnetically-activated thermal therapy. It has been known for some time that under an alternating current (a.c.) magnetic field, magnetic nanoparticles undergo fluctuations in their magnetic properties that result in heat. Benefits of magnetic vs. light energy to generate heat include the use of radiofrequency waves to produce the fluctuations in the magnetic nanoparticles. Radiofrequency waves, unlike light waves, are not limited in their penetration depth into tissue (Lee 2011), meaning that thermal therapies with magnetic nanoparticles can non-invasively reach deeper tumors inside the human body. Magnetic nanoparticles can also be ‘seen’ using magnetic resonance imaging (MRI), allowing researchers and clinicians to monitor the movement of magnetically-activated thermal agents inside the human body during therapy.

Conventional magnetic nanoparticles, composed on iron oxide materials that are also classic contrast agents in magnetic resonance imaging (MRI), have undergone clinical trials in thermal therapies of brain and prostate cancer (Maier-Hauff 2007). While these conventional magnetic nanoparticles are typically composed of a single solid material, Lee and coworkers’ improved magnetic nanoparticles possess some very unique multi-faceted features that make them an order of magnitude more efficient than conventional metallic nanoparticles in converting magnetic energy to heat. By creating nanoparticles that have a ‘core’ of one type of magnetic material surrounded by a ‘shell’ of another type of material, Lee and coworkers’ were able to fine tune a magnetic property of the nanomaterial known as magnetocrystalline anisotropy, a measure of how much the internal energy of the nano-magnet depends on the direction of its magnetization (note 2). By controlling this property and varying the ‘core’ and ‘shell’ components with combinations of cobalt, iron, and manganese, the researchers were able to hone in on core-shell nanoparticle types that were most efficient in converting magnetic energy to heat. Indeed, Jae-Hyun Lee and coworkers’ multi-layer nanoparticles were found to be up to 34x more efficient in producing heat from incident radiofrequency waves than conventional iron-oxide magnetic nanoparticles used in MRI studies.

Not only were the ‘core’ and ‘shell’ nanoparticles found to be better at generating heat than traditional thermal agent magnetic nanoparticles, they were also found superior in their cancer-fighting properties (against tumors in mice) to the common anticancer drug doxorubicin. A regular one-two punch in thermal cancer therapy, fine-tuned core-shell nanoparticles may be a very useful tool for future heat-based disease therapies and heat-triggered drug release systems.

Notes:
(1) You can test yourself the fact that red light travels further through tissue than blue or green light. Place a blue or green laser pointer on the underside of your thumb (the thumb-print side), and observe any light that shows up on the opposite side (the nail of your thumb). Do the same with a red laser pointer. Which light is brightest on the other side?

(2) measure of how a material responds when a magnetic field is applied to it

References:
(1) Zeng et al. Exchange-coupled nanocomposite magnets by nanoparticle self-assembly. Nature 420, 395-398 (28 November 2002)
(2) Lee et al. Exchange-coupled magnetic nanoparticles for efficient heat induction. Nature Nanotechnology 6, 418-422 (2011)
(3) Jiang et al. A new approach for improving exchange-spring magnets. JOURNAL OF APPLIED PHYSICS 97, 10K311 (2005)
(4) Chen et al. Gold Nanocages as Photothermal Transducers for Cancer Treatment. Small 6, 811-817 (2010)

Zeng, H., Li, J., Liu, J., Wang, Z., & Sun, S. (2002). Exchange-coupled nanocomposite magnets by nanoparticle self-assembly Nature, 420 (6914), 395-398 DOI: 10.1038/nature01208