ACS Nano. 2016 Jan;10(2):2549-58.
Continuous Cavitation Designed for Enhancing Radiofrequency Ablation via a Special Radiofrequency Solidoid Vaporization Process
Zhang K, Li P, Chen HR, Bo XW, Li XL, Xu HX
Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, 301 Yan-chang-zhong Road, Shanghai 200072, P. R. China
This study focused on how to improve radiofrequency (RF) ablation outcomes, reduce RF time and times, and lower RF power, ultimately alleviating the side effects and improving life quality. In this study, we proposed a continuous cavitation principle and employed it to enhance RF ablation. To validate it, we engineered an intelligent theranostic agent featured of a continuous vaporization property, i.e., solid menthol-encapsulated poly lactide-glycolide acid (PLGA) nanocapsules. Experimental results demonstrated these nanocapsules could respond radio frequency to generate menthol bubbles via solid-liquid-gas (SLG) tri-phase transformation, thus could significantly enhance ultrasound-imaging performance for tumor-responsive imaging, and further facilitated RF ablation ex vivo and in vivo, consequently delayed the growth of tumor. Herein, such a RF-mediated triphase transformation can be called radiofrequency solidoid evaporation (RSV), which can overcome drawbacks and limitations of acoustic droplet vaporization (ADV) and optical droplet vaporization (ODV), e.g., ultrasound is easily and substantially scattered by gas or bone, limiting its precision and efficiency, and the penetration-depth of laser is very shallow, substantially hindering its further clinical translations. Such solid menthol-encapsulated nanocapsules based on the continuous cavitation principle for enhance RF ablation can truthfully lower the RF output power and therapeutic time, because it can maximally improve the efficiency of RF energy by incipiently storing heat and hindering free diffusion-induced loss, and afterwards releasing energy to enhance RF ablation by virtue of bubbles’ cavitation effect. More importantly, the excellent biosafety and biodegradability of such solid menthol-encapsulated nanocapsules can be expected to quickly promote the clinical translations of intelligent diagnostic/therapeutic modalities, especially on fighting against cancer. Thus, the present strategy and results will attract, as we believe, growing attentions among biologist, doctor, chemists and engineers, etc.
How to efficiently fight against tumor in a minimally or non-invasively approach is a challenging but urgent pursuit. Radiofrequency as a minimally invasive therapeutic method has been widely applied; however, the inevitable high output power and long irradiation time still threaten normal organs or tissues. In an attempt to lowering RF power and enhancing RF ablation, the principle, i.e., using magnetic metal-based nanoparticles to heat in an oscillating magnetic field component of RF field, has been employed. However, this principle still demanded high output power so as to acquire high oscillating magnetic field for highly-effective magnetic-heat transformation. More significantly, disputed biotoxicity and biodegradability of inorganic nanoparticles remain unresolved, disabling the clinical translation. Cavitation that is universal in ultrasound diagnostics is an ideal choice, since microjects, shock waves, local hyperpyrexia, etc., which can maximally improve the utilization efficiency of energy, decreasing the heat diffusion.(1) Conventional exogenous nuclei, i.e., microbubbles or droplets, have been tried to enhance RF ablation, and they failed in enhancing RF ablation. This result can be attributed that the violent and transient cavitation in conventional microbubbles or droplets is inappropriate for enhancing RF ablation, since the RF irradiation featured of progressive temperature rise determines the continuous cavitation is desirable. Thus, new strategies capable of solving the drawbacks of RF ablation are highly desiring but still challenging.
Figure 1. SEM image of DLM-encapsulated PLGA capsules
We constructed a solid DL-menthol-encapsulated PLGA capsules (Figure 1), and used them, as a concept of proof, to demonstrate the role of DLM-mediated continuous cavitation in enhancing RF ablation. We have demonstrated the employed DL-menthol was hydrophobic but miscible with most molecules and it also can vaporize into gas bubbles especially exposure to heating. (2) More significantly, the vaporation process was continuous, and enabled the continuous ultrasound imaging and multiple enhanced HIFU ablations under once injection.(2) Depending on these unique characteristic features, we observe the obtained PLGA capsules could generate bubbles via optical microscopy when RF heating, and in contrast no bubbles were found in DLM-free PLGA capsules. (Figure 2) Furthermore, we found these capsules could enhance in vitro and in vivo contrasts of ultrasonic images under B fundamental mode and contrast harmonic mode. (3) By comparing PBS control and DLM-free PLGA capsules, we validated that the evidently enhanced contrast was attributed to the RF-induced solidoid vaporation (RSV) process of encapsulated DLM.(3)
Figure 2. the optical microscopic images of DLM-free (left) and DLM-encapsulated (right) PLGA capsules after RF irradiation.
We hypothesized that the premise of enhanced RF ablation using this DLM-encapsulated PLGA capsule was continuous cavitation property. As it turns out, our hypothesis was correct to some extent, and 30 min later, such capsules remain equipped with high cavitation dose that was approximately to the initial one (3). We then investigated how such DLM-encapsulated capsules featured of continuous cavitation enhance RF ablation. Firstly, in ex vivo liver model, we found that no RF-induced necrosis was observed under 1 W for 30 s when only PBS was injected, whereas a large volume of necrotic zone was observed when injecting such DLM-encapsulated capsules (3). Moreover, the ablated volume using DLM-encapsulated PLGA capsules was above 2-fold larger than that using DLM-free PLGA capsules. Afterwards, nude mice subcutaneously bearing HeLa solid tumor were taken research models. In an intratumoral injection manner, we obtained that such capsules harvested over 6-fold increase in RF ablation volume of HeLa solid tumor on basis of DLM-free capsules. Even though using intravenous injection method, a 2-fold increase in ablation volume using this DLM-encapsulated PLGA capsules was observed. (3) However, despite largest ablation volume, residual tumor tissues remained existence, (3) and as incubation lasted, the tumor volume was found to growth again (Figure 3). Thus, the following chemotherapy was necessary.
Figure 3. Digital photo of HeLa solid tumor after RF ablation and subsequent 15 day incubation.
The importance of this study is two-fold. Firstly, we introduced cavitation effect in other non-ultrasound thermal ablation methods, and successfully demonstrated the feasibility of this caivtation in enhancing RF ablation. This introduction will benefit other treatment methods, e.g., laser, microwave, etc. Secondly, this special DLM-encapsulated PLGA capsules indeed lowered the RF power, reduce the treatment time and improve the treatment biosafety. Moreover, such capsules shared excellent biocompatibility, all of which determined such capsules will hold great potentials in RF ablation.
- Zhang K, Xu HX, Chen HR, Jia XQ, Zheng SG, Cai XJ, Wang RH, Mou J, Zheng YY, Shi JL 2015 CO2 bubbling-based ‘Nanobomb’ System for Targetedly Suppressing Panc-1 Pancreatic Tumor via Low Intensity Ultrasound-activated Inertial Cavitation. Theranostics 5:1291-1302.
- Zhang K, Chen HR, Li FQ, Wang Q, Zheng SG, Xu HX, Ma M, Jia X, Chen Y, Mou J 2014 A continuous tri-phase transition effect for HIFU-mediated intravenous drug delivery. Biomaterials 35:5875-5885.
- Zhang K, Li P, Chen HR, Bo XW, Li XL, Xu HX 2016 Continuous Cavitation Designed for Enhancing Radiofrequency Ablation via a Special Radiofrequency Solidoid Vaporization Process. ACS Nano 10:2549-2558.
Acknowledgements: This study was supported by National Natural Science Foundation of China (Grant No. 81501473, 81371570), Fostering and Action Planning of Tongji University for Young Excellences (Grant No. 2015KJ061).
Contact: Huixiong Xu, Ph.D. Professor and Director Department of Medical Ultrasound
301 Yang-chang-zhong Road
Shanghai Tenth People’s Hospital, Tongji University School of Medicine Shanghai, 200072