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Focused ultrasound-mediated drug delivery to pancreatic cancer in a mouse model.

Rapoport N, Payne A, Dillon C, Shea J, Scaife C, Gupta R - J Ther Ultrasound (2013)

Bottom Line: Paclitaxel (PTX) was used as a chemotherapeutic agent because it manifests high potency in the treatment of gemcitabine-resistant PDA.Positive treatment effects and even complete tumor resolution were achieved by treating the tumor with MRgFUS after injection of nanodroplet encapsulated drug.The effect of the pulsed MRgFUS treatment with PTX-loaded nanodroplets was clearly smaller than that of continuous wave MRgFUS treatment, supposedly due to significantly lower temperature increase as measured with MR thermometry and decreased extravasation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Bioengineering, University of Utah, 36 S. Wasatch Dr., Room 3100, Salt Lake City, UT 84112, USA.

ABSTRACT

Background: Many aspects of the mechanisms involved in ultrasound-mediated therapy remain obscure. In particular, the relative roles of drug and ultrasound, the effect of the time of ultrasound application, and the effect of tissue heating are not yet clear. The current study was undertaken with the goal to clarify these aspects of the ultrasound-mediated drug delivery mechanism.

Methods: Focused ultrasound-mediated drug delivery was performed under magnetic resonance imaging guidance (MRgFUS) in a pancreatic ductal adenocarcinoma (PDA) model grown subcutaneously in nu/nu mice. Paclitaxel (PTX) was used as a chemotherapeutic agent because it manifests high potency in the treatment of gemcitabine-resistant PDA. Poly(ethylene oxide)-co-poly(d,l-lactide) block copolymer stabilized perfluoro-15-crown-5-ether nanoemulsions were used as drug carriers. MRgFUS was applied at sub-ablative pressure levels in both continuous wave and pulsed modes, and only a fraction of the tumor was treated.

Results: Positive treatment effects and even complete tumor resolution were achieved by treating the tumor with MRgFUS after injection of nanodroplet encapsulated drug. The MRgFUS treatment enhanced the action of the drug presumably through enhanced tumor perfusion and blood vessel and cell membrane permeability that increased the drug supply to tumor cells. The effect of the pulsed MRgFUS treatment with PTX-loaded nanodroplets was clearly smaller than that of continuous wave MRgFUS treatment, supposedly due to significantly lower temperature increase as measured with MR thermometry and decreased extravasation. The time of the MRgFUS application after drug injection also proved to be an important factor with the best results observed when ultrasound was applied at least 6 h after the injection of drug-loaded nanodroplets. Some collateral damage was observed with particular ultrasound protocols supposedly associated with enhanced inflammation.

Conclusion: This presented data suggest that there exists an optimal range of ultrasound application parameters and drug injection time. Decreased tumor growth, or complete resolution, was achieved with continuous wave ultrasound pressures below or equal to 3.1 MPa and drug injection times of at least 6 h prior to treatment. Increased acoustic pressure or ultrasound application before or shortly after drug injection gave increased tumor growth when compared to other protocols.

No MeSH data available.


Related in: MedlinePlus

Mouse photographs and whole-body fluorescence images before and after combined PTX-loaded nanodroplet and MRgFUS treatment. Photographs (A, C) and whole-body fluorescence images (B, D) of a mouse before (A, B) and after (C, D) combined treatment with PTX-loaded nanodroplets and MRgFUS. The dashed circles in (B,D) indicate the tumor location. Treatment parameters: MRgFUS was applied 8 h after drug injection; spiral beam pattern (5-mm diameter) shown in Figure 3A; FUS at 3.1 MPa; sonication time of 3 min. The tumor did not recur during a 5-month observation. The former location of the tumor is still slightly visible in D, indicated by the dashed white circle.
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Figure 4: Mouse photographs and whole-body fluorescence images before and after combined PTX-loaded nanodroplet and MRgFUS treatment. Photographs (A, C) and whole-body fluorescence images (B, D) of a mouse before (A, B) and after (C, D) combined treatment with PTX-loaded nanodroplets and MRgFUS. The dashed circles in (B,D) indicate the tumor location. Treatment parameters: MRgFUS was applied 8 h after drug injection; spiral beam pattern (5-mm diameter) shown in Figure 3A; FUS at 3.1 MPa; sonication time of 3 min. The tumor did not recur during a 5-month observation. The former location of the tumor is still slightly visible in D, indicated by the dashed white circle.

Mentions: Two different scenarios of the tumor response to treatment were observed: the first involved a complete tumor resolution without recurrence. This was observed in four mice after a single treatment with PTX-loaded nanodroplets and CW MRgFUS at an acoustic peak pressure of 2.4 or 3.4 MPa for either a spiral or grid beam trajectory. An example of a complete tumor resolution with both photograph and fluorescence images is presented in Figure 4.


Focused ultrasound-mediated drug delivery to pancreatic cancer in a mouse model.

Rapoport N, Payne A, Dillon C, Shea J, Scaife C, Gupta R - J Ther Ultrasound (2013)

Mouse photographs and whole-body fluorescence images before and after combined PTX-loaded nanodroplet and MRgFUS treatment. Photographs (A, C) and whole-body fluorescence images (B, D) of a mouse before (A, B) and after (C, D) combined treatment with PTX-loaded nanodroplets and MRgFUS. The dashed circles in (B,D) indicate the tumor location. Treatment parameters: MRgFUS was applied 8 h after drug injection; spiral beam pattern (5-mm diameter) shown in Figure 3A; FUS at 3.1 MPa; sonication time of 3 min. The tumor did not recur during a 5-month observation. The former location of the tumor is still slightly visible in D, indicated by the dashed white circle.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4265944&req=5

Figure 4: Mouse photographs and whole-body fluorescence images before and after combined PTX-loaded nanodroplet and MRgFUS treatment. Photographs (A, C) and whole-body fluorescence images (B, D) of a mouse before (A, B) and after (C, D) combined treatment with PTX-loaded nanodroplets and MRgFUS. The dashed circles in (B,D) indicate the tumor location. Treatment parameters: MRgFUS was applied 8 h after drug injection; spiral beam pattern (5-mm diameter) shown in Figure 3A; FUS at 3.1 MPa; sonication time of 3 min. The tumor did not recur during a 5-month observation. The former location of the tumor is still slightly visible in D, indicated by the dashed white circle.
Mentions: Two different scenarios of the tumor response to treatment were observed: the first involved a complete tumor resolution without recurrence. This was observed in four mice after a single treatment with PTX-loaded nanodroplets and CW MRgFUS at an acoustic peak pressure of 2.4 or 3.4 MPa for either a spiral or grid beam trajectory. An example of a complete tumor resolution with both photograph and fluorescence images is presented in Figure 4.

Bottom Line: Paclitaxel (PTX) was used as a chemotherapeutic agent because it manifests high potency in the treatment of gemcitabine-resistant PDA.Positive treatment effects and even complete tumor resolution were achieved by treating the tumor with MRgFUS after injection of nanodroplet encapsulated drug.The effect of the pulsed MRgFUS treatment with PTX-loaded nanodroplets was clearly smaller than that of continuous wave MRgFUS treatment, supposedly due to significantly lower temperature increase as measured with MR thermometry and decreased extravasation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Bioengineering, University of Utah, 36 S. Wasatch Dr., Room 3100, Salt Lake City, UT 84112, USA.

ABSTRACT

Background: Many aspects of the mechanisms involved in ultrasound-mediated therapy remain obscure. In particular, the relative roles of drug and ultrasound, the effect of the time of ultrasound application, and the effect of tissue heating are not yet clear. The current study was undertaken with the goal to clarify these aspects of the ultrasound-mediated drug delivery mechanism.

Methods: Focused ultrasound-mediated drug delivery was performed under magnetic resonance imaging guidance (MRgFUS) in a pancreatic ductal adenocarcinoma (PDA) model grown subcutaneously in nu/nu mice. Paclitaxel (PTX) was used as a chemotherapeutic agent because it manifests high potency in the treatment of gemcitabine-resistant PDA. Poly(ethylene oxide)-co-poly(d,l-lactide) block copolymer stabilized perfluoro-15-crown-5-ether nanoemulsions were used as drug carriers. MRgFUS was applied at sub-ablative pressure levels in both continuous wave and pulsed modes, and only a fraction of the tumor was treated.

Results: Positive treatment effects and even complete tumor resolution were achieved by treating the tumor with MRgFUS after injection of nanodroplet encapsulated drug. The MRgFUS treatment enhanced the action of the drug presumably through enhanced tumor perfusion and blood vessel and cell membrane permeability that increased the drug supply to tumor cells. The effect of the pulsed MRgFUS treatment with PTX-loaded nanodroplets was clearly smaller than that of continuous wave MRgFUS treatment, supposedly due to significantly lower temperature increase as measured with MR thermometry and decreased extravasation. The time of the MRgFUS application after drug injection also proved to be an important factor with the best results observed when ultrasound was applied at least 6 h after the injection of drug-loaded nanodroplets. Some collateral damage was observed with particular ultrasound protocols supposedly associated with enhanced inflammation.

Conclusion: This presented data suggest that there exists an optimal range of ultrasound application parameters and drug injection time. Decreased tumor growth, or complete resolution, was achieved with continuous wave ultrasound pressures below or equal to 3.1 MPa and drug injection times of at least 6 h prior to treatment. Increased acoustic pressure or ultrasound application before or shortly after drug injection gave increased tumor growth when compared to other protocols.

No MeSH data available.


Related in: MedlinePlus