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Photothermal Ablation: A Perspective on Technique
Abstract: Limitations in methodology and inaccessible location of tumors have prevented widespread implementation of hyperthermia as a therapeutic option. However, hyperthermia achieved with photothermal ablation (PTA) paired with nanoparticles as sensitizers has been shown to have tremendous therapeutic potential. Further, advances in plasmonic gold nanomaterial synthesis, fabrication of thin NIR laser fiber-optic probes and knowledge of tumor microenvironment have improved efficacy of PTA. Currently, there are three main delivery options for PTA. Superficial PTA is effective to treat surface tumors, whereas percutaneous or transarterial delivery of PTA are suitable for deep tissue or solid organ tumors. Although the outcomes in animal studies are very reliable, these methods need to be further refined before being translated into clinical practice.
Key words: hyperthermia, nanoparticles, fiber-optic laser, photothermal ablation
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Due to altered vascularity, tumors have an impaired ability to adapt to high temperatures and thus hyperthermia can reduce tumor blood flow.1 In addition, cancer cells are more sensitive to hyperthermia and undergo irreversible damage via apoptosis and necrosis at 42°C, where as normal cells can survive up to 47°C.2,3 Whole body or localized hyperthermia is effective in treating cancer and can markedly improve survival in patients with cancer both as an independent and adjuvant therapy.4 However, wide implementation of hyperthermia is limited due to dose-limiting toxicity, difficulty of site-selective thermal delivery, lack of verification of therapeutic efficacy in various cancers, and relatively limited size of ablation zones.4
Thermal ablation combined with nanotechnology has therefore become a powerful tool to treat cancer, because nanomaterials can be fabricated to have preferential accumulation in cancer cells via receptor--mediated recognition5 together with active6 and/or passive transport.7,8 Local deposition of nanoparticles can enhance thermal ablation zones as reported in a recent phase 1 trial combining radiofrequency ablation (RFA) with thermosensitive liposomal doxorubicin.9 An alternative technique to RFA is photothermal ablation (PTA). Photothermal ablation focuses a light source, typically lasers, on a tumor and the absorbed light energy is transformed into heat. The heat generated by the laser can be lethal to cancer cells in isolation. Killing however can be enhanced with the addition of plasmonic photothermal sensitizers, such as gold nanoparticles, which have very high optical cross-sections at illumination wavelengths. When gold nanoparticles are activated by the lasers, there is a rapid increase in temperatures. Because of their strong photon energy absorption cross section and ability to transduce light into heat, plasmonic gold nanomaterials have been extensively investigated as sensitizers for PTA. Similarly, due to their spectral and optical properties, lasers in near infrared region (NIR) are the optimal light source for PTA. Photothermal ablation may be noninvasive10 or minimally invasive11 depending on the location of the tumor and type of sensitizers employed in this technique.
Efficacy of PTA has been shown in vitro, as it has been shown to kill an array of cancer cell lines including breast,12,13 liver,14 prostate,15 brain,16 lung,17 and pancreatic cancers.11 The advantage of PTA therapy is that it is immune to de novo or acquired drug resistance by cancer cells.18 In vitro, PTA can also be enhanced with the use of photothermal sensitizers. In order to achieve this, cells are incubated with sensitizers for a defined period of time allowing cellular uptake. Photothermal ablation is then performed by treating the cells with laser light, and cell survival can then be analyzed.7
This same approach of PTA is feasible in vivo on surface tumors, including primary breast cancer and subcutaneous tumor models when sensitizers are injected directly into the tumors. Depending on the temperature tolerance and sensitizers employed, lasers can be pulsed7 or delivered in a continuous manner.10 Nonetheless, metastatic and deep organ tumors pose additional challenges to PTA. Sensitizers and lasers somehow need to be able to reach the tumors. The enhanced permeability and retention (EPR) effect in the tumor microenvironment,19 synthesis of hybrid nanomaterials, and receptor-driven tumor homing of nanostructures largely alleviate the in vivo issues. Yet, laser radiation reaching the tumor remains elusive because of the limited penetration due to scattering induced by rapid diffusion of light through the biological tissues and fluids.20 Slim laser fiberoptic probes have been developed that can be delivered to tissues through needles and catheters. In vivo PTA techniques can be broadly categorized into the general methods described below.
Superficial Photothermal Ablation
The apparent advantage of this approach is its minimally invasive nature and ease of monitoring outcomes. Plasmonic nanomaterials can be administered either locally (intratumoral injection) or intravenously (IV). When administered via the IV route, it can take anywhere from 4 hours to 24 hours for the nanomaterials to accumulate in tumors. Following tumor deposition, subjects can be treated with a diode laser (emitting 3 W/cm2 at a wavelength of 808 nm). The beam is expanded (~1.2 cm in diameter) to cover the tumor surface in its entirety, or overlapping ablation zones can be utilized. Nanomaterials can also be customized for imaging, and adding a fluorescent probe allows for monitoring (Figure 1).
Intraprocedural temperature monitoring can be obtained using a thermocouple probe inserted into the tumor. Alternatively, ablation zones can be monitored using an infrared thermal imaging camera (Figure 2).7 Following treatment, efficacy is determined by monitoring tumor size regularly. This technique has shown efficacy in eradication of bony breast cancer metastases in animal models.7 However, NIR lasers are limited and are unable to treat large tumors because of the scattering of the light by the tissues.
Ultrasound-Guided Photothermal Ablation
Real-time ultrasound-guided visualization of tumors can allow for a percutaneous approach to placement of a PTA probe directly into the tumor. Depending on tumor site and planned needle trajectory, any organ can be treated with a percutaneous approach. Initially, a predetermined dose of nanomaterial (photothermal sensitizer) can be infused through the needle that has been placed into the tumor via a percutaneous ultrasound-guided approach. Subcutaneous thermal probes can be positioned 3 mm to 4 mm away from the planned treatment site to monitor the changes in temperature, or temperature can be monitored with an infrared camera (Figure 2). Then, a 100 micron to 400 micron fiber-optic probe equipped with an integrated diffusing tip element and cooling catheter21 is inserted in a coaxial fashion through the indwelling needle into the tumor, and a calculated duration and dose of NIR laser (usually 808 nm) will be administered (1 watt to 3 watts for 3 minutes to 5 minutes) with constant monitoring of temperature. Then, the fiber-optic probe is retracted and the needle withdrawn. The treatment algorithm for laser power and duration of ablation varies based on size and location of the tumor. Overlapping ablations can also be performed on tumors >3 cm in size without retracting the needle and fiber to cover the entire area of the tumor.
Transarterial Photothermal Ablation
This procedure involves gaining percutaneous transarterial access to the arteries supplying the tumor, which in humans would be via a transfemoral approach.22 In liver tumors, the hepatic artery is accessed and nanoparticles are administered in a site-selective manner to the arteries that supply the tumor. Then, the fiber-optic probe is advanced through the catheter, with the tip extending beyond the catheter in the artery. Then, intra-arterial ablation is performed (Figure 3). An example is shown in an HCC rat model, where transarterial PTA of liver tumors can be accomplished by performing a laparotomy to access the gastroduodenal artery and advancing the catheter/ablation probe into the hepatic artery.23
The choice of PTA method varies vastly with the tumor type and feasibility of the procedure. Although PTA techniques have shown promise, a great detail of knowledge was acquired based only on in vitro studies on cell lines or in preclinical animal models. Furthermore, this knowledge cannot be directly translated to patients because of the physical, physiological, and anatomical differences between animal models and humans. In addition, safety and toxicity of nanomaterials used as sensitizers remain uninvestigated largely because of the lack of good manufacturing practices and batch-to-batch inconsistencies in synthesis. However, studies to optimize image guided PTA laser probe placement, and scaled-up synthesis of well-characterized plasmonic nanostructures are under way in multiple laboratories to address these concerns in future.
Editor’s note: Disclosure: Dr. White reports consultancy to Guerbet LLC, IO-RAD, and Cook Medical; institutional grants from Siemens and Guerbet, LLC; honoraria from WCIO; and reimbursements from ECIO and SIR Foundation. Dr. Gogineni reports research support from Guerbet. The remaining authors report no related disclosures.
Acknowledgements: Drs. Joshi, Parchur, and Sharma gratefully acknowledge the funding support provided by NIH-ROI 5R01 CA151962. Dr. White acknowledges the funding from NIH 5 R25 CA 132822-03, RSNA Seed Grant #RSD1342 and RSNA Scholar Grant #RD3510.
Manuscript received October 12, 2015; manuscript accepted November 10, 2015.
Address for correspondence: Sarah B. White, MD, 8701 W. Watertown Plank Road, Milwaukee, Wisconsin, 53226. Email: sbwhite@mcw.edu
Suggested citation: Gogineni VR, Jagtap JM, Parchur AK, Sharma G, Joshi A, White SB. Photothermal ablation: a perspective on technique. Intervent Oncol 360. 2015;3(12):E141-E147.
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