Enhancing chemotherapeutic drug inhibition on tumor growth by ultrasound: an<i>in vivo</i>experiment

Zhao, Ying‐Zheng; Lu, Cui-Tao; Zhou, Zhi-Cai; Jin, Zhuo; Zhang, Lu; Sun, Changzheng; Xu, Yujuan; Gao, Hui-Sheng; Tian, Jilai; Gao, Feng‐Hou; Tang, Qinqin; Li, Wei; Xiang, Qi; Li, Xiaokun; Li, Wenfeng

doi:10.3109/10611861003801834

Cited by 34 publications

(20 citation statements)

References 19 publications

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“…, increased apoptotic activity and cell death) when comparing tumors treated with US-stimulated drug delivery compared to drug alone. When exploring other in vivo applications of US-stimulated drug delivery, previously reported methods analyzed secondary indicators of tumor response to treatment by measuring size and evaluating histological results post-mortem (Zhao, Lu 2011). MRI-based measures have also shown to be effective in confirming US-stimulated drug delivery through the blood-brain barrier (Kinoshita, McDannold 2006, McDannold, Arvanitis 2012, O'Reilly, Waspe 2012, Treat, McDannold 2012).…”

Section: Discussionmentioning

confidence: 99%

Ultrasound-Stimulated Drug Delivery for Treatment of Residual Disease after Incomplete Resection of Head and Neck Cancer

Sorace

Korb

Warram

et al. 2014

Ultrasound in Medicine & Biology

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Microbubbles triggered with localized ultrasound (US) can improve tumor drug delivery and retention. Termed US-stimulated drug delivery, this strategy was applied to head and neck cancer (HNC) in a post-surgical tumor resection model. Nude athymic mice (N = 24) were implanted in the flank with luciferase-positive HNC squamous cell carcinoma (SCC) and underwent various degrees of surgical tumor resection (0%, 50% or 100%). Following surgery, animals received adjuvant therapy with cetuximab-IRDye alone, cetuximab-IRDye in combination with US-stimulated drug delivery, or saline injections (control) on days 4, 7, and 10. Tumor drug delivery was assessed on days 0, 4, 7, 10, 14, and 17 with an in vivo fluorescence imaging system, while tumor viability was evaluated at the same time points with in vivo bioluminescence imaging. Tumor caliper measurements occurred two times per week for days. Optical imaging demonstrated that in the 50% tumor resection group, US-stimulated drug delivery resulted in a significant increase in cetuximab delivery compared to drug alone on day 10 (day of peak fluorescence) (p = 0.03). Tumor viability decreased in all groups receiving US-stimulated drug delivery plus drug compared to the drug alone group. After various degrees of surgical resection, this novel study demonstrates positive improvements in drug uptake in the residual cancer cells when combined with US-stimulated drug delivery.

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Section: Discussionmentioning

confidence: 99%

Ultrasound-Stimulated Drug Delivery for Treatment of Residual Disease after Incomplete Resection of Head and Neck Cancer

Sorace

Korb

Warram

et al. 2014

Ultrasound in Medicine & Biology

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“…The most relevant in vivo analogue of this in vitro approach requires the direct injection of MBs into tumor tissue. With this approach, it has been reported that combined USMB-drug treatments can result in growth inhibition, though significantly enhanced antitumor effects relative to drug only or USMB-only groups were not found [11], [12]. Studies using systemically (intravenously) injected MBs, the current clinically approved method for introducing agents into the body, have also been conducted with rationale of enhancing drug delivery into tumor tissue by increasing extravasation.…”

Section: Discussionmentioning

confidence: 99%

“…In brain tumors, results have begun to emerge showing improved therapeutic effects by employing ultrasound stimulated microbubbles (USMB) with liposomal drug formulations under conditions that produce enhanced drug extravasation [6]–[8]. Outside the brain, results have recently been obtained indicating that the use of USMBs with anticancer agents can result in improved delivery and therapeutic effects relative to the drug only case [9]–[12]. With the exception of brain tumors, where the blood-brain-barrier presents a significant drug delivery obstacle, it must also be considered that in many circumstances the penetration of antitumor agents into tumor tissue is not inhibited by their inability to extravasate from the bloodstream.…”

Section: Introductionmentioning

confidence: 99%

Antitumor Effects of Combining Docetaxel (Taxotere) with the Antivascular Action of Ultrasound Stimulated Microbubbles

et al. 2012

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Ultrasound stimulated microbubbles (USMB) are being investigated for their potential to promote the uptake of anticancer agents into tumor tissue by exploiting their ability to enhance microvascular permeability. At sufficiently high ultrasound transmit amplitudes it has also recently been shown that USMB treatments can, on their own, induce vascular damage, shutdown blood flow, and inhibit tumor growth. The objective of this study is to examine the antitumor effects of ‘antivascular’ USMB treatments in conjunction with chemotherapy, which differs from previous work which has sought to enhance drug uptake with USMBs by increasing vascular permeability. Conceptually this is a strategy similar to combining vascular disrupting agents with a chemotherapy, and we have selected the taxane docetaxel (Taxotere) for evaluating this approach as it has previously been shown to have potent antitumor effects when combined with small molecule vascular disrupting agents. Experiments were conducted on PC3 tumors implanted in athymic mice. USMB treatments were performed at a frequency of 1 MHz employing sequences of 50 ms bursts (0.00024 duty cycle) at 1.65 MPa. USMB treatments were administered on a weekly basis for 4 weeks with docetaxel (DTX) being given intravenously at a dose level of 5 mg/kg. The USMB treatments, either alone or in combination with DTX, induced an acute reduction in tumor perfusion which was accompanied at the 24 hour point by significantly enhanced necrosis and apoptosis. Longitudinal experiments showed a modest prolongation in survival but no significant growth inhibition occurred in DTX–only and USMB-only treatment groups relative to control tumors. The combined USMB-DTX treatment group produced tumor shrinkage in weeks 4–6, and significant growth inhibition and survival prolongation relative to the control (p<0.001), USMB-only (p<0.01) and DTX-only treatment groups (p<0.01). These results suggest the potential of enhancing the antitumor activity of docetaxel by combining it with antivascular USMB effects.

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“…The interaction of ultrasound waves with MBs may cause oscillation and cavitation of the bubbles and lead to the rupture of vascular walls. [14][15][16] For overcoming the difficulties of drug delivery posed by vascular walls, US sonication in the presence of MBs can produce ruptured openings to increase vascular permeability of sonicated tissues and permit a specific and effective cellular uptake. [17][18][19][20] Studies have recently demonstrated that ultrasoundmediated chemotherapeutics with MBs showed promising potential for animal tumor treatment.…”

Section: Introductionmentioning

confidence: 99%

Ultrasound sonication with microbubbles disrupts blood vessels and enhances tumor treatments of anticancer nanodrug

Lin¹,

Lin²,

Tseng³

et al. 2012

IJN

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Ultrasound (US) sonication with microbubbles (MBs) has the potential to disrupt blood vessels and enhance the delivery of drugs into the sonicated tissues. In this study, mouse ear tumors were employed to investigate the therapeutic effects of US, MBs, and pegylated liposomal doxorubicin (PLD) on tumors. Tumors started to receive treatments when they grew up to about 15 mm 3 (early stage) with injection of PLD 10 mg/kg, or up to 50 mm 3 (medium stage) with PLD 6 (or 4) mg/kg. Experiments included the control, PLD alone, PLD + MBs + US, US alone, and MBs + US groups. The procedure for the PLD + MBs + US group was that PLD was injected first, MB (SonoVue) injection followed, and then US was immediately sonicated on the tumor. The results showed that: (1) US sonication with MBs was always able to produce a further hindrance to tumor growth for both early and medium-stage tumors; (2) for the medium-stage tumors, 6 mg/kg PLD alone was able to inhibit their growth, while it did not work for 4 mg/kg PLD alone; (3) with the application of MBs + US, 4 mg/kg PLD was able to inhibit the growth of medium-stage tumors; (4) for early stage tumors after the first treatment with a high dose of PLD alone (10 mg/kg), the tumor size still increased for several days and then decreased (a biphasic pattern); (5) MBs + US alone was able to hinder the growth of early stage tumors, but unable to hinder that of medium stage tumors. The results of histological examinations and blood perfusion measurements indicated that the application of MBs + US disrupts the tumor blood vessels and enhances the delivery of PLD into tumors to significantly inhibit tumor growth.

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Enhancing chemotherapeutic drug inhibition on tumor growth by ultrasound: anin vivoexperiment

Cited by 34 publications

References 19 publications

Ultrasound-Stimulated Drug Delivery for Treatment of Residual Disease after Incomplete Resection of Head and Neck Cancer

Ultrasound-Stimulated Drug Delivery for Treatment of Residual Disease after Incomplete Resection of Head and Neck Cancer

Antitumor Effects of Combining Docetaxel (Taxotere) with the Antivascular Action of Ultrasound Stimulated Microbubbles

Ultrasound sonication with microbubbles disrupts blood vessels and enhances tumor treatments of anticancer nanodrug

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