Focused Ultrasound–Triggered Release of Tyrosine Kinase Inhibitor From Thermosensitive Liposomes for Treatment of Renal Cell Carcinoma

• Published in: Journal of pharmaceutical sciences 2017-05, Vol.106 (5), p.1355-1362
• Main Authors: Abshire, Caleb, Murad, Hakm Y., Arora, Jaspreet S., Liu, James, Mandava, Sree Harsha, John, Vijay T., Khismatullin, Damir B., Lee, Benjamin R.
• Format: Article
• Language: English
• Subjects: Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - metabolism; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - physiology; Drug Liberation; focused ultrasound; Hot Temperature; Humans; Kidney Neoplasms - drug therapy; Kidney Neoplasms - metabolism; Liposomes; nanoparticles; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - radiation effects; renal cell carcinoma; thermally triggered chemotherapy; Treatment Outcome; tyrosine kinase inhibitor; Ultrasonic Waves
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1016/j.xphs.2017.01.027

This study reports, for the first time, development of tyrosine kinase inhibitor–loaded, thermosensitive liposomes (TKI/TSLs) and their efficacy for treatment of renal cell carcinoma when triggered by focused ultrasound (FUS). Uptake of these nanoparticles into renal cancer cells was visualized with confocal and fluorescent imaging of rhodamine B–loaded liposomes. The combination of TKI/TSLs and FUS was tested in an in vitro tumor model of renal cell carcinoma. According to MTT cytotoxic assay and flow cytometric analysis, the combined treatment led to the least viability (23.4% ± 2.49%, p < 0.001), significantly lower than that observed from treatment with FUS (97.6% ± 0.67%, not significant) or TKI/TSL (71.0% ± 3.65%, p < 0.001) at 96 h compared to control. The importance of this unique, synergistic combination was demonstrated in viability experiments with non-thermosensitive liposomes (TKI/NTSL + FUS: 58.8% ± 1.5% vs. TKI/TSL + FUS: 36.2% ± 1.4%, p < 0.001) and heated water immersion (TKI/TSL + WB43°: 59.3% ± 2.91% vs. TKI/TSL + FUS: 36.4% ± 1.55%, p < 0.001). Our findings coupled with the existing use of FUS in clinical practice make the proposed combination of targeted chemotherapy, nanotechnology, and FUS a promising platform for enhanced drug delivery and cancer treatment.