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Thứ Năm, 14 tháng 9, 2017

US Guided Drug Delivery in Cancer: Sonoporation Effects

In addition to diagnostic purposes, ultrasound is increasingly being used for therapeutic applications including imaging-guided drug and gene delivery to various tissue types [1-3]. Ultrasound-guided delivery of therapeutics has gained special attention since it allows spatially confined delivery of drugs into a target areas, such as a tumor, while minimizing systemic dose and toxicity [4,5]. Since ultrasound is widely available, relatively inexpensive and portable, along with the ability to focus it onto a target area non-invasively with high precision, ultrasound-guided drug delivery is a promising approach to efficiently treat certain cancer types that are anatomically accessible for ultrasound (for example liver tumors) [4,5].
Through a process called sonoporation, ultrasound and microbubble (USMB) mediated cavitation generates transient or permanent pores in the walls of blood vessels and can significantly enhance extravascular delivery of therapeutics in the region of interest (Fig. 1) [6]. USMB mediated drug delivery can be triggered through both stable and inertial cavitation of microbubbles. Cavitation is defined as the growing and shrinking response of microbubbles when subjected to the alternating low and high-pressure portions of the ultrasound wave [7]. Stable cavitation occurs when microbubbles stably oscillate without collapsing in an acoustic field (Fig. 2). In contrast, when microbubbles violently grow and collapse, this process is called inertial cavitation (Fig. 2). While both stable and inertial cavitation exert mechanical forces on adjacent tissues, microbubble collapse (inertial cavitation) can result in additional secondary mechanical effects such as shockwaves and liquid jetting that further enhance the effects of sonoporation.

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. 

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. 

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].

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