Nanobubble ultrasound contrast agents for enhanced delivery of thermal sensitizer to tumors undergoing radiofrequency ablation.
OBJECTIVE
Pluronic has been shown to sensitize various tumor cell lines to chemotherapy and hyperthermia by altering the membrane fluidity, depleting ATP, and modulating the heat shock protein 70 expression. In our prior work, Pluronic was also used to formulate nanosized ultrasound contrast agents. In the current study we evaluate the use of these contrast agents as vehicles for image-guided delivery of Pluronic to improve outcomes of tumor radiofrequency (RF) ablation.


METHODS
Lipid-shelled Pluronic nanobubbles were prepared and examined for size distribution, zeta potential, stability, biodistribution, accumulation of nanobubbles in the tumor, and treatment efficacy. LS174-T xenograft tumor-bearing mice were used to evaluate tumor growth suppression and measure treatment efficacy after RF ablation.


RESULTS
The average diameter of Pluronic bubbles was 230 nm, and initial bubble echogenicity was 16 dB. In vitro, cells exposed to Pluronic nanobubbles exhibited low cytotoxicity in the absence of ultrasound, even if heat (43 ºC) was applied. When the cells were exposed to Pluronic nanobubbles, heat, and ultrasound; viability was significantly reduced. In vivo, tumors treated with ultrasound-modulated nanobubbles prior to RF ablation showed a significant reduction in growth compared to the RF alone (P<0.05).


CONCLUSIONS
Lipid and Pluronic-shelled, echogenic nanobubbles combined with ultrasound modulation can serve as an effective theranostic method for sensitization of tumors to RF ablation.
Case Center for Imaging Research, Department of Radiology, Case Western Reserve University, 11100 Euclid Ave, Cleveland, Ohio, 44106-5056, USA.
Reshani H
RH
Perera
Luis
L
Solorio
Hanping
H
Wu
Mihika
M
Gangolli
Eric
E
Silverman
Christopher
C
Hernandez
Pubudu M
PM
Peiris
Ann-Marie
AM
Broome
Agata A
AA
Exner
D000818:Animals; D017115:Catheter Ablation / Q000379:methods*; D002470:Cell Survival / Q000187:drug effects; D003287:Contrast Media / Q000737:chemistry*; D016503:Drug Delivery Systems; D006801:Humans; D051379:Mice; D045423:Microbubbles; D053758:Nanoparticles; D009369:Neoplasms / Q000175:diagnosis* / Q000601:surgery*; D014018:Tissue Distribution; D014463:Ultrasonography / Q000379:methods*; D023041:Xenograft Model Antitumor Assays
D003287:Contrast Media