Effect of Acoustic Radiation Force on the Distribution of Nanoparticles in Solid Tumors.

Acoustic radiation force (ARF) might improve the distribution of nanoparticles (NPs) in tumors. To study this, tumors growing subcutaneously in mice were exposed to focused ultrasound (FUS) either 15 min or 4 h after the injection of NPs, to investigate the effect of ARF on the transport of NPs across the vessel wall and through the extracellular matrix. Quantitative analysis of confocal microscopy images from frozen tumor sections was performed to estimate the displacement of NPs from blood vessels. Using the same experimental exposure parameters, ARF was simulated and compared with the experimental data. Enhanced interstitial transport of NPs in tumor tissues was observed when FUS (10 MHz, acoustic power 234 W/cm2, 3.3% duty cycle) was given either 15 min or 4 h after NP administration. According to acoustic simulations, the FUS generated an ARF per unit volume of 2.0×106 N/m3. The displacement of NPs was larger when FUS was applied 4 h after NP injection compared with after 15 min. This study shows that ARF might contribute to a modest improved distribution of NPs into the tumor interstitium.

Image Quality Measured From Ultra-Low Dose Chest Computed Tomography Examination Protocols Using 6 Different Iterative Reconstructions From 4 Vendors, a Phantom Study.

PURPOSE: This study aimed to evaluate image quality of ultra-low dose chest computed tomography using 6 iterative reconstruction (IR) algorithms. METHOD: A lung phantom was scanned on 4 computed tomography scanners using fixed tube voltages and the lowest mAs available on each scanner, resulting in dose levels of 0.1 to 0.2 mGy (80 kVp) and 0.3 to 1 mGy (140 kVp) volume CT dose index (CTDIvol). Images were reconstructed with IR available on the scanners. Image noise, signal-to-noise ratios, contrast-to-noise ratios, uniformity, and noise power spectrum (NPS) were assessed for evaluation of image quality. RESULTS: Image quality parameters increased with increasing dose for all algorithms. At constant dose levels, model-based techniques improved the contrast-to-noise ratio of lesions more than the statistical algorithms. All algorithms tested at 0.1 mGy showed lower NPS peak frequencies compared with 0.39 mGy. In contrast to the statistical techniques, model-based algorithms showed lower NPS peak frequencies at the lowest doses, indicating a coarser and blotchier noise texture. CONCLUSION: This study shows the importance of evaluating IR when introduced clinically.

Ultra-low dose chest computed tomography: Effect of iterative reconstruction levels on image quality.

PURPOSE: To optimize image quality and radiation dose of chest CT with respect to various iterative reconstruction levels, detector collimations and body sizes. METHOD: A Kyoto Kagaku Lungman with and without extensions was scanned using fixed ultra-low doses of 0.25, 0.49 and 0.74 mGy CTDIvol, and collimations of 40 and 80 mm. Images were reconstructed with the lung kernel, filtered back projection (FBP) and different ASIR-V levels (10-100%). Contrast-to-noise ratios (CNR) were calculated for 12 mm simulated lesions of different densities in the lung. Image noise, signal-to-noise ratios (SNR), variations in Hounsfield units (HU), noise power spectrum (NPS) and noise texture deviations (NTD) were evaluated for all reconstructions. NTD was calculated as percentage of pixels outside 3 standard deviations to evaluate IR-specific artefacts. RESULTS: Compared to the FBP, image noise reduced (5-55%) with ASIR-V levels irrespective of dose or collimation. SNR correlated positively (r ≥ 0.925, p ≤ 0.001) with ASIR-V levels at all doses, collimations, and phantom sizes. ASIR-V enhanced the CNR of the lesion with the lowest contrast from 12.7-42.1 (0-100% ASIR-V) at 0.74 mGy with 40 mm collimation. As expected, higher SNR and CNR were measured in the smaller phantom than the bigger phantom. Uniform HU were observed between FBP and ASIR-V levels at all doses, collimations, and phantom sizes. NPS curves left-shifted towards lower frequencies at increasing levels of ASIR-V irrespective of collimation. A positive correlation (r ≥ 0.946, p ≥ 0.001) was observed between NTD and ASIR-V levels. NTD of the FBP was not significantly (p ≤ 0.087) different from NTD of ASIR-V ≤ 20%. The data from the NPS and NTD indicates a blotchier and coarser noise texture at higher levels of ASIR-V, especially at 100% ASIR-V. CONCLUSION: In comparison with the FBP technique, ASIR-V enhanced quantitative image quality parameters at all ultra-low doses tested. Moreover, the use of ASIR-V showed consistency with body size and collimation. Hence, ASIR-V may be useful for improving image quality of chest CT at ultra-low doses.

Contact-mediated intracellular delivery of hydrophobic drugs from polymeric nanoparticles.

Encapsulation of drugs in nanoparticles can enhance the accumulation of drugs in tumours, reduce toxicity toward healthy tissue, and improve pharmacokinetics compared to administration of free drug. To achieve efficient delivery and release of drugs at the target site, mechanisms of interaction between the nanoparticles and cells and the mechanism of delivery of the encapsulated drug are crucial to understand. Our aim was to determine the mechanisms for cellular uptake of a fluorescent hydrophobic model drug from poly(butylcyanoacrylate) nanoparticles. Prostate adenocarcinoma cells were incubated with Nile Red-loaded nanoparticles or free Nile Red. Uptake and intracellular distribution were evaluated by flow cytometry and confocal laser scanning microscopy. The nanoparticles mediated a higher intracellular level and more rapid uptake of encapsulated Nile Red compared to model drug administered alone. The main mechanism for delivery was not by endocytosis of nanoparticles but by nanoparticle-cell contact-mediated transfer directly to the cytosol and, to a smaller extent, release of payload from nanoparticles into the medium followed by diffusion into cells. The payload thus avoids entering the endocytic pathway, evading lysosomal degradation and instead gains direct access to intracellular targets. The nanoparticles are promising tools for efficient intracellular delivery of hydrophobic anticancer drugs; therefore, they are clinically relevant for improved cancer therapy.

Ultrasound improves the uptake and distribution of liposomal Doxorubicin in prostate cancer xenografts.

Combining liposomally encapsulated cytotoxic drugs with ultrasound exposure has improved the therapeutic response to cancer in animal models; however, little is known about the underlying mechanisms. This study focused on investigating the effect of ultrasound exposures (1 MHz and 300 kHz) on the delivery and distribution of liposomal doxorubicin in mice with prostate cancer xenografts. The mice were exposed to ultrasound 24 h after liposome administration to study the effect on release of doxorubicin and its penetration through the extracellular matrix. Optical imaging methods were used to examine the effects at both microscopic subcellular and macroscopic tissue levels. Confocal laser scanning microscopy revealed that ultrasound-exposed tumors had increased levels of released doxorubicin compared with unexposed control tumors and that the distribution of liposomes and doxorubicin through the tumor tissue was improved. Whole-animal optical imaging revealed that liposomes were taken up by both abdominal organs and tumors.

Mechanisms of the ultrasound-mediated intracellular delivery of liposomes and dextrans.

The mechanism involved in the ultrasoundenhanced intracellular delivery of fluorescein-isothiocyanate (FITC)-dextran (molecular weight 4 to 2000 kDa) and liposomes containing doxorubicin (Dox) was studied using HeLa cells and an ultrasound transducer at 300 kHz, varying the acoustic power. The cellular uptake and cell viability were measured using flow cytometry and confocal microscopy. The role of endocytosis was investigated by inhibiting clathrin- and caveolae-mediated endocytosis, as well as macropinocytosis. Microbubbles were found to be required during ultrasound treatment to obtain enhanced cellular uptake. The percentage of cells internalizing Dox and dextran increased with increasing mechanical index. Confocal images and flow cytometric analysis indicated that the liposomes were disrupted extracellularly and that released Dox was taken up by the cells. The percentage of cells internalizing dextran was independent of the molecular weight of dextrans, but the amount of the small 4-kDa dextran molecules internalized per cell was higher than for the other dextrans. The inhibition of endocytosis during ultrasound exposure resulted in a significant decrease in cellular uptake of dextrans. Therefore, the improved uptake of Dox and dextrans may be a result of both sonoporation and endocytosis.

Effect of ultrasound parameters on the release of liposomal calcein.

The ultrasound exposure parameters that maximize drug release from dierucoyl-phosphatidylcholine (DEPC)-based liposomes were studied using two transducers operating at 300 kHz and 1 MHz. Fluorescent calcein was used as a model drug, and the release from liposomes in solution was measured using a spectrophotometer. The release of calcein was more efficient at 300 kHz than at 1 MHz, with thresholds of peak negative pressures of 0.9 MPa and 1.9 MPa, respectively. Above this threshold, the release increased with increasing peak negative pressure, mechanical index (MI), and duty cycle. The amount of drug released followed first-order kinetics and increased with exposure time to a maximal release. To increase the release further, the MI had to be increased. The results demonstrate that the MI and the overall exposure time are the major parameters that determine the drug's release. The drug's release is probably due to mechanical (cavitation) rather than thermal effects, and that was also confirmed by the detection of hydroxide radicals.