A new kind of PEARL
TORONTO—Nanoparticles have been in use for years as vehicles for drugs and therapeutics, particularly in cancer, where they offer versatility and the ability to deliver drug payloads directly to tumors and thereby avoid—or at least reduce—the risk of off-target effects. And now there's a new contender out of the Princess Margaret Cancer Centre: an organic, biodegradable nanoparticle that utilizes heat and light in a way that could target and destroy tumors with greater precision.
This work was conducted by Dr. Gang Zheng—senior scientist at the Princess Margaret, professor of medical biophysics at the University of Toronto and the Joey and Toby Tanenbaum/Brazilian Ball Chair in Prostate Cancer Research—and a team of biomedical researchers. The proof-of-concept findings were detailed in the paper “Controlling Spatial Heat and Light Distribution by Using Photothermal Enhancing Auto-Regulated Liposomes (PEARLs),” which appeared online in Angewandte Chemie.
"Our smart nanoparticle is super cool,” said Zheng in describing the new nanoparticle. “It can absorb light, generate heat and ablate the tumor. It's a thermal sensor, and once it reaches the desired ablation temperature of 55C, it becomes invisible, allowing the light to move deeper into more areas of tumor and repeat the treatment process. The result is a promising new way to heat and ablate larger volumes of tumor with minimal damage to surrounding tissues in a controlled and precise way. The next step is to conduct preclinical studies to test the concept further."
The two primary bottlenecks that currently limit more effective use of photo-thermal therapy in patients are overheating of tissue (which can cause collateral damage during treatment) and the inability to ablate greater volumes of tumors due to the fact that light stops traveling when it's absorbed. As noted in the paper's abstract, “Photo-thermal therapy (PTT) is enhanced by the use of nanoparticles with a large optical absorption at the treatment wavelength. However, this comes at the cost of higher light attenuation that results in reduced depth of heating as well as larger thermal gradients, leading to potential over- and under-treatment in the target tissue.”
“Specifically in the design of nanoparticles for photo-thermal therapy (PTT) of cancer, strong absorption at near-infrared (NIR) wavelengths is desired, since this minimizes light absorption by endogenous absorbers in tissue, while maximizing temperature generation mediated by the tumor-specific accumulation of nanoparticles,” the paper explains. “However, NPs that are dispersed homogenously throughout the target tissue volume will also increase the light attenuation (which is a combination of absorption and elastic scattering), so that the deeper lying tissues will be exposed to lower light intensity and either take longer or fail to reach the desired temperature sufficient for hyperthermia or coagulative necrosis. This effect then imposes limits on the treatment volume.”
Given these issues, there is “a significant trade-off required between the nanoparticle concentration, treatment time and light irradiance to ensure that effective treatment is delivered to the full target tissue thickness in a clinically practical time and using affordable light sources, while avoiding overheating nearer the surface that can be hazardous to the patient and further limits the light penetration if charring occurs.”
At present, the authors report, the options for getting around these roadblocks consist largely of modifying the method of light delivery through tactics such as “water-cooled fiber-optic sheaths for interstitial PTT, the use of image guidance and/or feed-back control through on-line thermometry.”
The researchers used phantom models in the lab to show how PEARLs can address and overcome these obstacles. The nanoparticles are “based on thermochromic J-aggregate forming dye–lipid conjugates that reversibly alter their absorption above a predefined lipid phase-transition temperature. Under irradiation by near-infrared light, deeper layers of the target tissue revert to the intrinsic optical absorption, halting the temperature rise and enabling greater light penetration and heat generation at depth. This effect is demonstrated in both nanoparticle solutions and in gel phantoms containing the nanoparticles,” the paper explains.
Zheng's work at the Princess Margaret for the past decade has been focused on the advancement of nanoparticle technology, specifically through the use of light, heat and sound to further imaging and targeted treatment of tumors. For example, last year in March, Zheng and his team reported that they had converted microbubbles into nanoparticles that remain trapped in tumors to deliver payloads. The microbubbles were created using porphyrin, a naturally occurring pigment that harvests light. When exposed to low-frequency ultrasound, the bubbles burst and fragmented into nanoparticles, which stayed in the tumors and could also be tracked via imaging. This is a step up from conventional microbubbles, which burst soon after entering the bloodstream and lose their therapeutic and imaging properties, Zheng explained at the time.
This work was funded by several organizations, including the Terry Fox Research Institute, Prostate Cancer Canada, the Canadian Institutes of Health Research, Ontario Institute for Cancer Research, the Natural Sciences and Engineering Research Council of Canada, the Canada Foundation for Innovation, the Tanenbaum Chair in Prostate Cancer Research and The Princess Margaret Cancer Foundation.