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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

A nanoparticle size distribution for 5% PEG-PDLA/1% PFCE formulation. Fifty-nanometer particles are residual micelles; two-hundred sixty-two-nanometer particles are nanodroplets. Nanodroplet size may be decreased by increasing sonication pressure during emulsification. Micelle fraction can be decreased by decreasing copolymer concentration and/or increasing PFCE concentration [46]. PTX loading slightly increases nanodroplet sizes (e.g., from 260 to 280 nm).
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Figure 1: A nanoparticle size distribution for 5% PEG-PDLA/1% PFCE formulation. Fifty-nanometer particles are residual micelles; two-hundred sixty-two-nanometer particles are nanodroplets. Nanodroplet size may be decreased by increasing sonication pressure during emulsification. Micelle fraction can be decreased by decreasing copolymer concentration and/or increasing PFCE concentration [46]. PTX loading slightly increases nanodroplet sizes (e.g., from 260 to 280 nm).

Mentions: PTX-loaded perfluorocarbon nanodroplets were manufactured from PTX-loaded micelles formed by the water-soluble, biodegradable block copolymer PEG-PDLA with a molecular weight of either block of 2,000 Da (Akina, Inc., West Lafayette, IN, USA). PTX-containing PEG-PLA micellar solutions were prepared by a solid dispersion technique [20]. Typically, 20 or 50 mg PEG-PDLA and 5 mg PTX were co-dissolved in 1 ml tetrahydrofuran (THF). The THF was then evaporated under gentle nitrogen stream at 60°C or pumped out at room temperature. PTX-loaded micelles were reconstituted by dissolving residual gel matrix in 1 ml phosphate buffered saline (PBS; pH 7.4). Then 10 μl PFCE (MW 580.01, Oakwoods Products, Inc., West Columbia, SC, USA) was introduced into micellar solution and emulsified by sonication on ice (VCX500, Sonics and Materials, Inc., CT, USA) to obtain paclitaxel-loaded droplets of the composition 2% or 5% PEG-PDLA/0.5% PTX/1% PFCE. The components of micellar or nanodroplet formulations were obtained from commercial sources and used without further purification. Micellar solutions and perfluorocarbon compounds were sterilized by filtration and mixed in a sterile test tube before being sonicated on ice for the generation of the nanoemulsion. The size of PFCE nanodroplets (both empty and drug loaded) was in the range 250 to 300 nm (Figure 1).


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)

A nanoparticle size distribution for 5% PEG-PDLA/1% PFCE formulation. Fifty-nanometer particles are residual micelles; two-hundred sixty-two-nanometer particles are nanodroplets. Nanodroplet size may be decreased by increasing sonication pressure during emulsification. Micelle fraction can be decreased by decreasing copolymer concentration and/or increasing PFCE concentration [46]. PTX loading slightly increases nanodroplet sizes (e.g., from 260 to 280 nm).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: A nanoparticle size distribution for 5% PEG-PDLA/1% PFCE formulation. Fifty-nanometer particles are residual micelles; two-hundred sixty-two-nanometer particles are nanodroplets. Nanodroplet size may be decreased by increasing sonication pressure during emulsification. Micelle fraction can be decreased by decreasing copolymer concentration and/or increasing PFCE concentration [46]. PTX loading slightly increases nanodroplet sizes (e.g., from 260 to 280 nm).
Mentions: PTX-loaded perfluorocarbon nanodroplets were manufactured from PTX-loaded micelles formed by the water-soluble, biodegradable block copolymer PEG-PDLA with a molecular weight of either block of 2,000 Da (Akina, Inc., West Lafayette, IN, USA). PTX-containing PEG-PLA micellar solutions were prepared by a solid dispersion technique [20]. Typically, 20 or 50 mg PEG-PDLA and 5 mg PTX were co-dissolved in 1 ml tetrahydrofuran (THF). The THF was then evaporated under gentle nitrogen stream at 60°C or pumped out at room temperature. PTX-loaded micelles were reconstituted by dissolving residual gel matrix in 1 ml phosphate buffered saline (PBS; pH 7.4). Then 10 μl PFCE (MW 580.01, Oakwoods Products, Inc., West Columbia, SC, USA) was introduced into micellar solution and emulsified by sonication on ice (VCX500, Sonics and Materials, Inc., CT, USA) to obtain paclitaxel-loaded droplets of the composition 2% or 5% PEG-PDLA/0.5% PTX/1% PFCE. The components of micellar or nanodroplet formulations were obtained from commercial sources and used without further purification. Micellar solutions and perfluorocarbon compounds were sterilized by filtration and mixed in a sterile test tube before being sonicated on ice for the generation of the nanoemulsion. The size of PFCE nanodroplets (both empty and drug loaded) was in the range 250 to 300 nm (Figure 1).

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