Therapeutic potential of ultrasound microbubbles in gastrointestinal oncology: recent advances and future prospects

Khokhlova, Tatiana D.; Haider, Yasser; Hwang, Joo Ha

doi:10.1177/1756283x15592584

Cited by 29 publications

(26 citation statements)

References 46 publications

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“…By providing evidence for the intracellular delivery and activation of folate receptor-targeted PCCAs in breast cancer cells in vitro , we hope to expand the scope of exploratory investigation and clinical potential of ultrasound theranostics for breast cancer. For the most part, ultrasound theranostic applications for cancer have remained limited to the vasculature [9, 10, 53, 54], yet the PCCA concept studied herein offers a platform toward extravascular imaging and therapy. Soon, we hope to expand our research to in vivo ultrasound imaging of breast cancer tumors in mice.…”

Section: Discussionmentioning

confidence: 99%

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Intracellular delivery and ultrasonic activation of folate receptor-targeted phase-change contrast agents in breast cancer cells in vitro

Marshalek

Sheeran

Ingram

et al. 2016

Journal of Controlled Release

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Breast cancer is a diverse and complex disease that remains one of the leading causes of death among women. Novel, outside-of-the-box imaging and treatment methods are needed to supplement currently available technologies. In this study, we present evidence for the intracellular delivery and ultrasound-stimulated activation of folate receptor (FR)-targeted phase-change contrast agents (PCCAs) in MDA-MB-231 and MCF-7 breast cancer cells in vitro. PCCAs are lipid-coated, perfluorocarbon-filled particles formulated as nanoscale liquid droplets capable of vaporization into gaseous microbubbles for imaging or therapy. Cells were incubated with 1:1 decafluorobutane (DFB) / octafluoropropane (OFP) PCCAs for 1 hour, imaged via confocal microscopy, exposed to ultrasound (9 MHz, MI = 1.0 or 1.5), and imaged again after insonation. FR-targeted PCCAs were observed intracellularly in both cell lines, but uptake was significantly greater (p < 0.001) in MDA-MB-231 cells (93.0% internalization at MI = 1.0, 79.5% at MI = 1.5) than MCF-7 cells (42.4% internalization at MI = 1.0, 35.7% at MI = 1.5). Folate incorporation increased the frequency of intracellular PCCA detection 45-fold for MDA-MB-231 cells and 7-fold for MCF-7 cells, relative to untargeted PCCAs. Intracellularly activated PCCAs ranged from 500 nm to 6 microns (IQR = 800 nm – 1.5 microns) with a mean diameter of 1.15 ± 0.59 (SD) microns. The work presented herein demonstrates the feasibility of PCCA intracellular delivery and activation using breast cancer cells, illuminating a new platform toward intracellular imaging or therapeutic delivery with ultrasound.

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Section: Discussionmentioning

confidence: 99%

“…Ultrasound (US) has been utilized for a broad range of applications in tumor imaging [3, 4, 5, 6, 7] as well as drug and gene delivery [8, 9, 10, 40, 41]. Compared to other imaging paradigms, ultrasound is particularly advantageous as a noninvasive and nonionizing modality.…”

Section: Introductionmentioning

confidence: 99%

Intracellular delivery and ultrasonic activation of folate receptor-targeted phase-change contrast agents in breast cancer cells in vitro

Marshalek

Sheeran

Ingram

et al. 2016

Journal of Controlled Release

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“…In brief, insonation of the vascular compartment containing microbubbles leads to a variety of biomechanical effects that increase the permeability of the endothelial barrier both paracellularly and transcellularly 4. The increased permeability leads to enhanced extravasation, distribution and uptake of drug molecules in the target tissue 5-7. This approach is currently being evaluated in two separate clinical trials (ClinicalTrials.gov identifier NCT02343991 8 and NCT02253212) 9, 10.…”

Section: Introductionmentioning

confidence: 99%

Efficient Enhancement of Blood-Brain Barrier Permeability Using Acoustic Cluster Therapy (ACT)

et al. 2017

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The blood-brain barrier (BBB) is a major obstacle in drug delivery for diseases of the brain, and today there is no standardized route to surpass it. One technique to locally and transiently disrupt the BBB, is focused ultrasound in combination with gas-filled microbubbles. However, the microbubbles used are typically developed for ultrasound imaging, not BBB disruption. Here we describe efficient opening of the BBB using the promising novel Acoustic Cluster Therapy (ACT), that recently has been used in combination with Abraxane® to successfully treat subcutaneous tumors of human prostate adenocarcinoma in mice. ACT is based on the conjugation of microbubbles to liquid oil microdroplets through electrostatic interactions. Upon activation in an ultrasound field, the microdroplet phase transfers to form a larger bubble that transiently lodges in the microvasculature. Further insonation induces volume oscillations of the activated bubble, which in turn induce biomechanical effects that increase the permeability of the BBB. ACT was able to safely and temporarily permeabilize the BBB, using an acoustic power 5-10 times lower than applied for conventional microbubbles, and successfully deliver small and large molecules into the brain.

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“…In recent years, several concepts for ultrasound (US) mediated, targeted drug delivery have been investigated, some with quite encouraging results [7][8][9][10][11][12]. Many of the these approaches explore the use of regular US contrast microbubbles such as Sonovue™ (Bracco Imaging S.p.A, Italy) or Optison™ (GE Healthcare AS, Norway) co-injected with various drug formulations.…”

Section: Introductionmentioning

confidence: 99%

Acoustic Cluster Therapy (ACT) enhances the therapeutic efficacy of paclitaxel and Abraxane® for treatment of human prostate adenocarcinoma in mice

Wamel

Sontum

Healey

et al. 2016

Journal of Controlled Release

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Acoustic cluster therapy (ACT) is a novel approach for ultrasound mediated, targeted drug delivery. In the current study, we have investigated ACT in combination with paclitaxel and Abraxane® for treatment of a subcutaneous human prostate adenocarcinoma (PC3) in mice. In combination with paclitaxel (12 mg/kg given i.p)., ACT induced a strong increase in therapeutic efficacy; 120 days after study start, 42% of the animals were in stable, complete remission vs. 0% for the paclitaxel only group and the median survival was increased by 86%. In combination with Abraxane® (12 mg paclitaxel/kg given i.v.), ACT induced a strong increase in the therapeutic efficacy; 60 days after study start 100% of the animals were in stable, remission vs. 0% for the Abraxane® only group, 120 days after study start 67% of the animals were in stable, complete remission vs. 0% for the Abraxane® only group. For the ACT + Abraxane group 100% of the animals were alive after 120 days vs. 0% for the Abraxane® only group. Proof of concept for Acoustic Cluster Therapy has been demonstrated; ACT markedly increases the therapeutic efficacy of both paclitaxel and Abraxane® for treatment of human prostate adenocarcinoma in mice.

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Therapeutic potential of ultrasound microbubbles in gastrointestinal oncology: recent advances and future prospects

Cited by 29 publications

References 46 publications

Intracellular delivery and ultrasonic activation of folate receptor-targeted phase-change contrast agents in breast cancer cells in vitro

Intracellular delivery and ultrasonic activation of folate receptor-targeted phase-change contrast agents in breast cancer cells in vitro

Efficient Enhancement of Blood-Brain Barrier Permeability Using Acoustic Cluster Therapy (ACT)

Acoustic Cluster Therapy (ACT) enhances the therapeutic efficacy of paclitaxel and Abraxane® for treatment of human prostate adenocarcinoma in mice

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