Ultrasound-guided drug delivery in cancer

Abstract

Recent advancements in ultrasound and microbubble (USMB) mediated drug delivery technology has shown that this approach can improve spatially confined delivery of drugs and genes to target tissues while reducing systemic dose and toxicity. The mechanism behind enhanced delivery of therapeutics is sonoporation, the formation of openings in the vasculature, induced by ultrasound-triggered oscillations and destruction of microbubbles. In this review, progress and challenges of USMB mediated drug delivery are summarized, with special focus on cancer therapy.

Keywords: Cancer therapy; Drug delivery systems; Genetic therapy; Microbubbles; Ultrasonography.

Fig. 1.. Principle of ultrasound and microbubble mediated nanoparticle delivery in vivo.

Microbubbles and nanoparticles are injected intravenously (IV) and therapeutic ultrasound is focused at the region of interest to induce microbubble cavitation and subsequent opening of the vasculature to allow penetration of therapeutic payload in nanoparticles into the extravascular space. Modified from Delalande et al. Gene 2013;525:191-199, with permission from Elsevier through RightsLink [6].

Fig. 2.. Schematic drawing of the principles of stable and inertial cavitation.

The type of cavitation strongly depends on pressure intensity. When relatively low pressure intensities are applied, the negative and positive pressure phases of the ultrasound (US) waves cause respective growth and shrinkage of microbubbles, which can repeat stably for many cycles. Such stable oscillation of microbubbles which depends on their resonance frequency, is known as stable cavitation. In contrast, when relatively high pressure intensities are applied, microbubbles violently grow to a much larger size followed by energetic collapse, a phenomenon known as inertial cavitation.

Fig. 3.. Visualizing inertial cavitation.

Optical frame images (A-G) and corresponding streak image (H) shows oscillation and inertial cavitation of a microbubble over a 5-microsecond period in response to ultrasound. Initially, the microbubble had a diameter of ~3 μm. The microbubble then underwent expansion and contraction and finally fragmentation due to inertial cavitation. Optical data was captured with a combined frame and streak camera (Imacon 468, DRS Hadland). Modified from Chomas et al. Appl Phys Lett 2000;77:1056-1058, with permission from AIP Publishing through RightsLink [21].

Fig. 4.. Ultrasound and microbubble (USMB) mediated sonoporation and drug delivery.

A. Representative contrast-enhanced ultrasound (US) images of a subcutaneous cancer xenograft during a 2-minute USMB treatment cycle. Image signal increased as microbubbles entered into the tumor (up to 60 seconds), and then substantially decreased during sonoporation (70-120 seconds), indicating inertial cavitation of the microbubbles. B, C. Quantitative reverse transcription polymerase chain reaction shows that USMB mediated delivery substantially enhances intratumoral delivery of therapeutics such as microRNAs (miRNA) compared to untreated and no-US controls. ^a)P=0.005, ^b)P=0.002, ^c)P=0.001, all compared to untreated control tumors. Adapted from Mullick Chowdhury et al. J Control Release 2016;238:272-280, with permission from Elsevier through RightsLink [5] and Wang et al. J Control Release 2015;203:99-108, with permission from Elsevier through RightsLink [22].

Fig. 5.. Therapeutic effects of ultrasound and microbubble (USMB) mediated drug delivery.

A. Summary of terminal deoxynucleotidyl transferase dUTP nick end labeling assay data for quantification of apoptosis shows USMB mediated delivery of miRNAs resulted in increased therapeutic effects compared to control conditions in both doxorubicin (DOX)-resistant and non-resistant human hepatocellular carcinoma (HCC) xenografts in mice. US, ultrasound; miRNA, miRNA122+antimiRNA-21. ^a),b)P<0.05 compared to untreated control tumors. B, C. Transmission electron microscopy image shows that USMB mediated therapeutic delivery can result in entry of therapeutic miRNA loaded poly lactic-co-glycolic acid nanoparticles into tumor cells ultimately resulting in apoptosis of the cells. Red arrows show internalized nanoparticles, yellow arrows show double layered vacuolar structures in the cytoplasm, and black arrow demonstrates evidence of detachment from surrounding HCC cells, indicating apoptosis. Adapted from Mullick Chowdhury et al. J Control Release 2016;238:272-280, with permission from Elsevier through RightsLink [5].

Fig. 6.. First clinical ultrasound (US) and microbubble (MB) mediated drug delivery study.

Comparison of patients treated with US, MB, and gemcitabine versus gemcitabine alone indicates that survival improved in the combined treatment group compared to treatment with gemcitabine alone. Median survival was found to improve from 8.9 to 17.6 months (P=0.011, log-rank test) with the use of sonoporation. Patients treated with sonoporation also showed a statistically significant increase in number of treatment cycles (P=0.082, unpaired t test) indicating less toxicity to the patients. CI, confidence interval. Adapted from Dimsevski et al. J Control Release 2016;243:172-181, according to Creative Common license [9].