This work was supported by the National Natural Science Foundation of China (81601608) and NUPTSF (NY216024).

All animal experiments were performed in accordance with the protocols approved by the OG Pharmaceutical guidelines for Animal Care and Use of Laboratory Animals. The protocols followed the guidelines of Ethics Committee for laboratory animals of OG Pharmaceutical.
1. Nanoparticle shelled microbubbles (NSMs) synthesis
<ol>
	<li>Disperse magnetic nanoparticles (Fe3O4, iron oxide) in deionized water to form a 10 mg/mL stock solution.</li>
	<li>Place the tube containing the IONPs solution in an ultrasonic cleaning machine for 20 min. Obtain a uniformly dispersed IONPs solution before use.</li>
	<li>Add 150 &#956;L of deionized water, 150 &#956;L of 10 mM sodium dodecyl sulfate (SDS), and 400 &#956;L of a stock solution of IONPs from step 1.1. in 1.5 mL centrifuge tube.&#160;</li>
	<li>Fix the homogenizer with a scaffold in an ice bath.</li>
	<li>Place the tube of the mixture in an ice bath and position the homogenizer probe precisely to be immersed in the mixture solution.</li>
	<li>Adjust the homogenizer speed to 20,000 rpm and turn on the homogenizer for 3 min.</li>
	<li>Turn off the homogenizer and remove the tube from the ice bath.</li>
	<li>Place the tube to the tube rack for 12 h stabilization at room temperature.</li>
	<li>Adsorb the resulted NSMs to the tube wall by a magnet and remove the supernatant. Then replenish with 1 mL of fresh deionized water.</li>
	<li>Repeat the wash process for three times and re-suspend NSMs in 1 mL of fresh distilled water.</li>
	<li>Transfer 10 &#956;L of NSMs suspension to a clean glass slide after slightly shaking.</li>
	<li>Use a fluorescence microscope at 20x magnification to visualize NSMs morphology. Ensure taking photos at random area.</li>
	<li>Measure the diameter of the NSMs from the photos using an open access Nano Measurer 1.2 software. Count at least 200 microbubbles.
	<ol>
		<li>Click &#8220;File&#8221; and &#8220;Open&#8221; to select the image file to be processed. After the image is imported, press the &#8220;ruler&#8221;. Draw a red line with the same length as the ruler.</li>
		<li>Then press &#8220;Settings&#8221; | &#8220;Ruler&#8221; and enter the length of the ruler. Draw lines of the same lengths as the diameters of the individual microbubbles in the image. Complete all the measurements, then click on &#8220;Report&#8221; | &#8220;View Report&#8221;.</li>
	</ol>
	</li>
</ol>
2. Acoustic response of NSMs
<ol>
	<li>Dilute 200 &#956;L of NSMs with 800 &#956;L deionized water, then transfer into a 1.5 mL centrifuge tube to form a stock solution.</li>
	<li>Connect the function generator, amplifier, impedance matching, and homemade focused transducer. Place the transducer in the center at the bottom of the artificial cuboid sink and connect the hydrophone with an oscilloscope to monitor the output ultrasound intensity (Figure 1). Add deionized water into the sink to immerse the transducer.</li>
	<li>Adjust the function generator to the sweep mode, tune the frequency range from 10 kHz to 900 kHz and set the amplitude to 20 Vpp (Voltage peak-peak). Adjust the power of ultrasound to 0.1% by the amplifier. Each cycle&#8217;s duration is 4 s with a time interval of 1 s.</li>
	<li>Prepare 1 mL NSMs stock solution samples in the tube and fix the tube with a scaffold on the top of the homemade focused transducer. Attach the magnet to the bottom of the tube and attract the NSMs.</li>
	<li>Turn on the power of the function generator and the amplifier. Switch off the function generator after application of 5 cycles (25 s) of ultrasound. Remove the magnet and collect 1 mL of the solution containing the released IONPs. Add 1 mL of deionized water to the centrifuge tube.</li>
	<li>Repeat step 2.5. until NSMs in the tube collapse completely.</li>
	<li>Quantify all the released IONPs by the inductively coupled plasma optical emission spectrometry (ICP-OES) as described previously13.</li>
</ol>
3. Optical response of NSMs
NOTE: In this work, a laser system containing 808 nm laser power and an infrared thermal imaging camera previously described by Xu et al. is utilized20.
<ol>
	<li>Laser system preparation
	<ol>
		<li>Turn on the power supply of the laser and allow it to warm for several minutes. Fix a fiber coupled 808 nm laser diode on a retort stand.</li>
		<li>Direct the laser beam to the sample stage through an optical fiber and focus on the sample stage to achieve a 6 mm light spot (in diameter) by a convex lens.</li>
		<li>Measure the power output with a laser power meter and adjust the power to 1 W/cm2.</li>
		<li>Fix the infrared thermal imaging camera on the tripod. Turn on the camera and check the if working (e.g., monitor the focused region of interest (ROI) temperature). Turn off the power supply and the infrared thermal imaging camera.</li>
	</ol>
	</li>
	<li>Photothermal measurement in aqueous solution
	<ol>
		<li>Prepare the 1 mL sample at different IONPs concentration (1.05 mg/mL, 1.35 mg/mL, 3.65 mg/mL, 5 mg/mL) in a 1.5 mL centrifuge tube.</li>
		<li>Place the tube of interest at the focused region of the laser beam and record the baseline temperature of the sample.</li>
		<li>Turn on the laser power and the infrared thermal imaging camera and irradiate the sample for 10 min continuously. At the same time, record the temperature in real time.</li>
		<li>Turn off the laser power and infrared thermal imaging camera after 10 min of irradiation. Wait for the temperature of the region to return to the baseline.</li>
		<li>Repeat 3.2.2 to 3.2.4 for the measurement of other samples. 
		NOTE: Use deionized water at 20 &#176;C as a control for the photothermal measurement.</li>
	</ol>
	</li>
	<li>Photothermal measurement in cultured cells 
	NOTE: Murine breast cancer cells (4T1) were selected as a model to investigate the inhibition effect by photothermal treatment.
	<ol>
		<li>Feed the cells with Roswell Park Memorial Institute-1640 (RPMI-1640) medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin. Set the culturing environment as 37 &#176;C and 5% CO2.</li>
		<li>Culture 4T1 cells in T25 flasks and passage the cells in a 1:2 ratio when 90% confluence is reached. 
		NOTE: The subculture ratio can be adjusted according to the specific cell conditions in different labs.</li>
		<li>Remove and discard the culture medium. Rinse the cell layer with 1x PBS solution to remove the residual serum containing trypsin inhibitor.</li>
		<li>Add 2 mL of Trypsin-EDTA solution (0.25%) to the flask for detachment. Then add 3 mL of 1640 medium and aspirate cells by gently pipetting.</li>
		<li>Collect 5 mL of the cell suspension and centrifuge at 500 x g for 3 min.</li>
		<li>Remove the supernatant and add 1 mL of fresh 1640 medium to form a cell suspension.</li>
		<li>Add 100 &#956;L of the cell suspension to a confocal dish containing 1 mL of the culture medium. Ensure that the concentration of cell suspension is 9 x 105/mL, and the final cell concentration in cell culture confocal dish is 8.1 x 104/mL.</li>
		<li>Place the inoculated cell culture confocal dish in an incubator for 24 h.</li>
		<li>Dilute different concentration (1.05 mg/mL, 1.35 mg/mL, 3.65 mg/mL, 5 mg/mL) of the IONPs sample to make 1 mL solution with serum-free 1640 medium.</li>
		<li>Aspirate the culture medium from the confocal dish and add the prepared sample solution.</li>
		<li>Turn on the laser power. Focus the laser beam at the center of the dish and adjust the output power to 1 W/cm2. Turn on the infrared thermal imaging camera, irradiate the cells in the confocal dish for 10 min continuously. Record the temperature in real time for the focused region.</li>
		<li>Turn off the laser and infrared thermal imaging camera. Transfer the irradiated dish to the incubator for another 24 h.</li>
		<li>Remove and discard the culture medium, add 1 mL of the fresh culture medium in the confocal dish. Add 5 &#956;L of Calcein-AM solution (1 mg/mL) into the dish.</li>
		<li>Incubate the confocal dish at 37 &#176;C and 5% CO2 for 15 min. Rinse the cell layer with 1x PBS solution twice.</li>
		<li>Observe and image the cells by a confocal fluorescence microscope with an excitation wavelength of 488 nm and an emission wavelength of 500-540 nm.</li>
		<li>Choose 5 areas in the confocal images randomly and count the number of live 4T1 cells in each area manually. Quantify the viability of 4T1 cells by comparing the number of live cells in all experimental groups with the control group. 
		NOTE: Use the serum-free 1640 medium at 20 &#176;C as a control for the photothermal measure. Use the sample without laser irradiation as cell viability control group.</li>
	</ol>
	</li>
	<li>Photothermal measurement in vivo
	<ol>
		<li>Prepare 3 of 8-week-old ICR male mice with a mean weight of 25 &#177; 2 g.</li>
		<li>Add 2 g of gelatin powder to 20 mL of deionized water. Heat the solution to 40 - 50 &#176;C, dissolve the gelatin gel completely to form a transparent and clear solution.</li>
		<li>Add 100 mg IONPs to the solution from 3.4.2.</li>
		<li>Heat the gel to 40 &#8211; 50 &#176;C, immediately inject 500 &#956;L of the gelatin solution into the right breast pad of the mouse.</li>
		<li>Turn on the laser power and focus the laser beam at the interest region (right breast pad of the mice). Adjust the output power to 1 W/cm2. Turn on the infrared thermal imaging camera, irradiate the interest region for 10 min continuously. Record the temperature of the region of interest in real time.</li>
		<li>Turn off the laser and infrared thermal imaging camera.</li>
		<li>Euthanize mice by CO2 asphyxiation and cervical vertebra dislocation or any method approved by the Institute&#8217;s animal research committee.</li>
	</ol>
	</li>
</ol>
4. Magnetic hyperthermia measurement
NOTE: Here, a magnetic hyperthermia system previously described by Wu et al. is utilized (21).
<ol>
	<li>Prepare a magnetic hyperthermia system include an alternating magnetic field (AFM) generator and an infrared thermal imaging camera.
	<ol>
		<li>Turn on the chiller for 10 min and then power on the moderate radio frequency heating machine (i.e., AFM generator).</li>
		<li>Set the parameters of the machine as follows: frequency (f) = 415 kHz, magnetic field intensity = 1.8 kA/m.</li>
	</ol>
	</li>
	<li>Magnetic hyperthermia measurement in aqueous solution
	<ol>
		<li>Prepare 1 mL of the sample at different IONPs concentration (1.05 mg/mL, 1.35 mg/mL, 3.65 mg/mL, 5 mg/mL) in a 1.5 mL centrifuge tube.</li>
		<li>Place the tube in the center of a water-cooled magnetic induction copper coil.</li>
		<li>Turn on the alternating magnetic field (AFM) and the infrared thermal imaging camera. Induce the sample for 10 min continuously and record the temperature in real time. 
		NOTE: The camera is located at the top of the sample, supplying a cross-sectional view of the sample.</li>
		<li>Turn off the AFM and the infrared thermal imaging camera. Wait for the temperature of the copper coil to come back to the baseline for 10 min. 
		NOTE: Be careful of high temperature, avoid direct contact with hands and wait for cooling before removing samples.</li>
		<li>Repeat 4.2.2 to 4.2.4 for the measurement of the other samples.</li>
		<li>Power off the moderate radio frequency heating machine (AFM) and chiller. 
		NOTE: Use the deionized water at 20 &#176;C as a control for magnetic hyperthermia measurement.</li>
	</ol>
	</li>
	<li>Magnetic hyperthermia measurement in vivo
	<ol>
		<li>Prepare 3 of 8-week-old ICR male mice with a mean weight of 25 &#177; 2 g.</li>
		<li>Prepare 20 mL of 10 % gelatin gel containing 5 mg/mL IONPs solution.</li>
		<li>Heat the gelatin gel to 40 - 50 &#176;C, immediately inject 500 &#956;L of the gelatin solution into the right breast pad of the animal. 
		NOTE: Magnetic-induced hyperthermia experiments were conducted with the heating machine using the same parameters as the in vitro test.</li>
		<li>Turn on the alternating magnetic field (AFM) and the infrared thermal imaging camera. Place the right breast pad of the mice in the center of a water-cooled magnetic induction copper coil.</li>
		<li>Turn on the infrared thermal imaging camera, image the interest region (right breast pad of the mice) for 10 min continuously and record the temperature of the interest region in real time.</li>
		<li>Turn off the power switch of the machine and infrared thermal imaging camera after 10 min of induction. Wait for the temperature of the copper coil to return to the baseline for 10 min.</li>
		<li>Repeat 4.3.4 to 4.3.6 for the measurement of other samples.</li>
		<li>Power off the moderate radio frequency heating machine (AFM) and chiller. 
		NOTE: Be careful of high temperature, avoid direct contact with hands and wait for cooling before removing samples.</li>
		<li>Euthanize mice by CO2 asphyxiation and cervical vertebra dislocation or any method approved by the Institute&#8217;s animal research committee.</li>
	</ol>
	</li>
</ol>

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The authors have nothing to disclose.

Here, we presented a protocol of fabricating iron oxide nanoparticle shelled microbubbles (NSMs) through self-assembly, synergizing magnetic, acoustic, and optical responsiveness in one nanotherapeutic platform. The IONPs were densely packed around the air core to form a magnetic shell, which can be controlled by the external magnetic field for targeting. Once delivered, the release of IONPs can be achieved by ultrasound trigger. The released IONPs can be activated by both NIR light and AFM for PTT and MHT, or the combin...

Cancer is one of the deadliest diseases, causing millions of deaths every year worldwide and huge economic losses1. In clinics, conventional anticancer therapies, such as surgical resection, radiotherapy, and chemotherapy still cannot provide a satisfactory therapeutic efficacy2. Limitations of these therapies are high toxic side effects, high recurrence rate and high metastasis rate3. For example, chemotherapy is suffered from the low delivery efficiency of chemo drugs precisely to the tumor site4. The inability of drugs to penetrate deep into the tumor tissue across the biological barriers, including extracellular matrix and high tumor interstitial fluid pressure, is also responsible for the low therapeutic efficacy5. Besides, the tumor resistance usually happens in the patients who received treatment by single chemotherapy6. Therefore, techniques where thermal ablation of tumor occurs, such as photothermal therapy (PTT) and magnetic hyperthermia therapy (MHT), have shown promising results to reduce tumor resistance and have been emerging in clinical trials7,8,9.
PTT triggers thermal ablation of cancer cells by the action of photothermal conversion agents under the irradiation of the laser energy. The generated high temperature (above 50 &#730;C) induces complete cell necrosis10. Very recently, iron oxide nanoparticles (IONPs) were demonstrated to be a photothermal conversion agent that can be activated by near-infrared (NIR) light11. &#160;Despite the low molar absorption coefficient in the near infrared region, IONPs are candidates for low-temperature (43&#160; &#730;C) photothermal therapy, a modified therapy to reduce the damage caused by heat exposure to normal tissues and to initiate antitumor immunity against tumor metastasis12. One of the limitations of PTT is the low penetration depth of the laser. For deep seated tumors, alternating magnetic field (AFM) induced heating of iron oxide nanoparticles, also called magnetic hyperthermia, is an alternative therapy for PTT13,14. The main advantage of MHT is the high penetration of magnetic field15. However, the required relatively high concentration of IONPs remains a major disadvantage for its clinical application. The delivery efficiency of nanomedicine (or nanoparticles) to solid tumors in animals has been 1-10% due to a series of obstacles including circulation, accumulation, and penetration16,17. Therefore, a controlled and targeted IONPs delivery strategy with the ability to achieve high tissue penetration is of great interest in cancer treatment.
Ultrasound mediated nanoparticle delivery has shown its ability to facilitate the penetration of nanoparticles deep into the tumor tissue, due to the phenomenon called microbubble cavitation18,19. In the present study, we fabricate IONPs shelled microbubbles (NSMs) through self-assembly, synergizing magnetic, acoustic, and optical responsiveness in one nanotherapeutic platform. The NSM contains an air core and a shell of iron oxide nanoparticles, with a diameter of approximately 5.4 &#181;m. The NSMs can be magnetically guided to the tumor site. Then the release of IONPs is triggered by ultrasound, accompanied by microbubble cavitation and microstreaming. The momentum received from the microstreaming facilitates the penetration of IONPs into the tumor tissue. The PTT and MHT can be achieved by NIR laser irradiation or AFM application, or with the combination of both.

<table><tbody><tr><td>808 nm laser power</td><td>Changchun New Industries Optoelectronics Tech</td><td>MDL-F-808-5W-18017023</td><td></td></tr><tr><td>Calcein-AM</td><td>Thermo Fisher SCIENTIFIC</td><td>C3099</td><td></td></tr><tr><td>Fetal bovine serum</td><td>Invitrogen</td><td>16000-044</td><td></td></tr><tr><td>Fluorescence Microscope</td><td>Olympus</td><td>IX71</td><td></td></tr><tr><td>Function generator</td><td>Keysight</td><td>33500B series</td><td>20 MHz, 2 channels with arbitrary waveform generation capability</td></tr><tr><td>Gelatin gel</td><td>Sigma</td><td>9000-70-8</td><td></td></tr><tr><td>Heating machine</td><td>Shuangping</td><td>SPG-06- II</td><td></td></tr><tr><td>Homemade focused transducer</td><td></td><td></td><td>Frequency=855, R-X=36.2W+5.8W, |Z|-&amp;theta;=37W+8&amp;deg;</td></tr><tr><td>Homogenizer</td><td>SCILOGEX</td><td>D-160</td><td>8000-30000 rpm</td></tr><tr><td>Hydrophone</td><td>T&amp;amp;C</td><td>NH1000</td><td></td></tr><tr><td>ICR male mice</td><td>OG Pharmaceutical. Co. Ltd</td><td></td><td>8-week-old</td></tr><tr><td>Inductively coupled plasma optical emission spectrometry</td><td>PerkinElmer</td><td></td><td></td></tr><tr><td>Infrared thermal imaging camera.</td><td>FLIR</td><td>E50</td><td></td></tr><tr><td>Iron(II,III) oxide</td><td>Alfa Aesar</td><td>1317-61-9</td><td>50-100nm APS Powder</td></tr><tr><td>Laser power meter</td><td>Changchun New Industries Optoelectronics Tech</td><td></td><td></td></tr><tr><td>Oscilloscope</td><td>Keysight</td><td>DSOX3054T</td><td>Bandwidth 500 MHz, Sampling Rate 5 GS/S, 4 channels</td></tr><tr><td>RF Power Amplifier</td><td>T&amp;amp;C</td><td>AG1020</td><td>The signal source can also be connected to an external signal source. The gain can be adjusted from 0 to 100%. It has multiple functions such as frequency sweep, pulse, and triangle.</td></tr><tr><td>Roswell Park Memorial Institute-1640</td><td>KeyGEN BioTECH</td><td>KGM31800</td><td></td></tr><tr><td>Sodium dodecyl sulfate</td><td>Sigma</td><td>151-21-3</td><td></td></tr></tbody></table>

magnetic-, acoustic-, and optical-triple-responsive microbubbles for magnetic hyperthermia and pothotothermal combination cancer therapy

The precision delivery of anti-cancer agents which aim for targeted and deep-penetrated delivery as well as a controlled release at the tumor site has been challenged. Here, we fabricate iron oxide nanoparticle shelled microbubbles (NSMs) through self-assembly, synergizing magnetic, acoustic, and optical responsiveness in one nanotherapeutic platform. Iron oxide nanoparticles serve as both magnetic and photothermal agents. Once intravenously injected, NSMs can be magnetically guided to the tumor site. Ultrasound triggers the release of iron oxide nanoparticles, facilitating the penetration of nanoparticles deep into the tumor due to the cavitation effect of microbubbles. Thereafter, magnetic hyperthermia and photothermal therapy can be performed on the tumor for combinational cancer therapy, a solution for cancer resistance due to the tumor heterogeneity. In this protocol, the synthesis and characterization of NSMs including structural, chemical, magnetic and acoustic properties were performed. In addition, the anti-cancer efficacy by thermal therapy was investigated using in vitro cell cultures. The proposed delivery strategy and combination therapy holds great promise in cancer treatment to improve both delivery and anticancer efficacies.

The triple-responsive nanoparticle-shelled microbubbles (NSMs) used in this study were prepared by agitating the mixture of the surfactant and IONPs. The IONPs (50 nm) self-assembled at the interface of liquid and gas core, to form a densely packed magnetic shell. The morphology of NSMs is shown in Figure. 1A. The resulted NSMs presented a spherical shape and with an average diameter of 5.41 &#177; 1.78 &#956;m (Figure 1B). The results indicated the NSMs were prepared successfully. When ...

Watch this Scientific Journal Video about Magnetic-, Acoustic-, and Optical-Triple-Responsive Microbubbles for Magnetic Hyperthermia and Pothotothermal Combination Cancer Therapy at JoVE.com

Magnetic-, Acoustic-, and Optical-Triple-Responsive Microbubbles for Magnetic Hyperthermia and Pothotothermal Combination Cancer Therapy

Presented here is a protocol for the fabrication of iron oxide nanoparticle-shelled microbubbles (NSMs) through self-assembly, synergizing magnetic, acoustic, and optical responsiveness in one nanotherapeutic platform for magnetic hyperthermia and photothermal combination cancer therapy.

The precision delivery of anti-cancer agents which aim for targeted and deep-penetrated delivery as well as a controlled release at the tumor site has ...

magnetic-acoustic-optical-triple-responsive-microbubbles-for-magnetic

Research

JoVE Journal

Bioengineering

3.1K Views.  Nanjing University of Posts & Telecommunications. Hier wordt een protocol gepresenteerd voor de fabricage van ijzeroxide nanodeeltjes-shelled microbubbels (NSM's) door middel van zelfassemblage, synergetische magnetische, akoestische en optische responsiviteit in één nanotherapeutisch platform voor magnetische hyperthermie en fototherme combinatie kankertherapie.

Video: Magnetic-, Acoustic-, and Optical-Triple-Responsive Microbubbles for Magnetic Hyperthermia and Pothotothermal Combination Cancer Therapy

Contrast Ultrasound Targeted Treatment of Gliomas in Mice via Drug-Bearing Nanoparticle Delivery and Microvascular Ablation

We are developing minimally-invasive contrast agent microbubble based therapeutic approaches in which the permeabilization and/or ablation of the microvasculature are controlled by varying ultrasound pulsing parameters.  Specifically, we are testing whether such approaches may be used to treat malignant brain tumors through drug delivery and microvascular ablation.  Preliminary studies have been performed to determine whether targeted drug-bearing nanoparticle delivery can be facilitated by the ultrasound mediated destruction of "composite" delivery agents comprised of 100nm poly(lactide-co-glycolide) (PLAGA) nanoparticles that are adhered to albumin shelled microbubbles. We denote these agents as microbubble-nanoparticle composite agents (MNCAs). When targeted to subcutaneous C6 gliomas with ultrasound, we observed an immediate 4.6-fold increase in nanoparticle delivery in MNCA treated tumors over tumors treated with microbubbles co-administered with nanoparticles and a 8.5 fold increase over non-treated tumors. Furthermore, in many cancer applications, we believe it may be desirable to perform targeted drug delivery in conjunction with ablation of the tumor microcirculation, which will lead to tumor hypoxia and apoptosis. To this end, we have tested the efficacy of non-theramal cavitation-induced microvascular ablation, showing that this approach elicits tumor perfusion reduction, apoptosis, significant growth inhibition, and necrosis. Taken together, these results indicate that our ultrasound-targeted approach has the potential to increase therapeutic efficiency by creating tumor necrosis through microvascular ablation and/or simultaneously enhancing the drug payload in gliomas.

Insonation of microbubbles is a promising strategy for tumor ablation at reduced time-averaged acoustic powers, as well as for the targeted delivery of therapeutics. The purpose of the present study is to develop low duty cycle ultrasound pulsing strategies and nanocarriers to maximize non-thermal microvascular ablation and payload delivery to subcutaneous C6 gliomas.

We are developing minimally-invasive contrast agent microbubble based therapeutic approaches in which the permeabilization and/or ablation of the ...

Magnetic Tweezers for the Measurement of Twist and Torque

Single-molecule techniques make it possible to investigate the behavior of individual biological molecules in solution in real time. These techniques include so-called force spectroscopy approaches such as atomic force microscopy, optical tweezers, flow stretching, and magnetic tweezers. Amongst these approaches, magnetic tweezers have distinguished themselves by their ability to apply torque while maintaining a constant stretching force. Here, it is illustrated how such a &#8220;conventional&#8221; magnetic tweezers experimental configuration can, through a straightforward modification of its field configuration to minimize the magnitude of the transverse field, be adapted to measure the degree of twist in a biological molecule. The resulting configuration is termed the freely-orbiting magnetic tweezers. Additionally, it is shown how further modification of the field configuration can yield a transverse field with a magnitude intermediate between that of the &#8220;conventional&#8221; magnetic tweezers and the freely-orbiting magnetic tweezers, which makes it possible to directly measure the torque stored in a biological molecule. This configuration is termed the magnetic torque tweezers. The accompanying video explains in detail how the conversion of conventional magnetic tweezers into freely-orbiting magnetic tweezers and magnetic torque tweezers can be accomplished, and demonstrates the use of these techniques. These adaptations maintain all the strengths of conventional magnetic tweezers while greatly expanding the versatility of this powerful instrument.

Magnetic tweezers, a powerful single-molecule manipulation technique, can be adapted for the direct measurements of the twist (using a configuration called freely-orbiting magnetic tweezers) and torque (using a configuration termed magnetic torque tweezers) in biological macromolecules. Guidelines for performing such measurements are given, including applications to the study of DNA and associated nucleo-protein filaments.

Single-molecule techniques make it possible to investigate the behavior of individual biological molecules in solution in real time. These techniques ...

Fabrication of a Functionalized Magnetic Bacterial Nanocellulose with Iron Oxide Nanoparticles

In this study, bacterial nanocellulose (BNC) produced by the bacteria Gluconacetobacter xylinus is synthesized and impregnated in situ with iron oxide nanoparticles (IONP) (Fe3O4) to yield a magnetic bacterial nanocellulose (MBNC). The synthesis of MBNC is a precise and specifically designed multi-step process. Briefly, bacterial nanocellulose (BNC) pellicles are formed from preserved G. xylinus strain according to our experimental requirements of size and morphology. A solution of iron(III) chloride hexahydrate (FeCl3&#183;6H2O) and iron(II) chloride tetrahydrate (FeCl2&#183;4H2O) with a 2:1 molar ratio is prepared and diluted in deoxygenated high purity water. A BNC pellicle is then introduced in the vessel with the reactants. This mixture is stirred and heated at 80 &#176;C in a silicon oil bath and ammonium hydroxide (14%) is then added by dropping to precipitate the ferrous ions into the BNC mesh. This last step allows forming in situ magnetite nanoparticles (Fe3O4) inside the bacterial nanocellulose mesh to confer magnetic properties to BNC pellicle. A toxicological assay was used to evaluate the biocompatibility of the BNC-IONP pellicle. Polyethylene glycol (PEG) was used to cover the IONPs in order to improve their biocompatibility. Scanning electron microscopy (SEM) images showed that the IONP were located preferentially in the fibril interlacing spaces of the BNC matrix, but some of them were also found along the BNC ribbons. Magnetic force microscope measurements performed on the MBNC detected the presence magnetic domains with high and weak intensity magnetic field, confirming the magnetic nature of the MBNC pellicle. Young&#39;s modulus values obtained in this work are also in a reasonable agreement with those reported for several blood vessels in previous studies.

Here, we present a protocol to make a bacterial nanocellulose (BNC) magnetic for applications in damaged blood vessel reconstruction. The BNC was synthesized by G. xylinus strain. On the other hand, magnetization of the BNC was realized through in situ precipitation of Fe2+ and Fe3+ ferrous ions inside the BNC mesh.

In this study, bacterial nanocellulose (BNC) produced by the bacteria Gluconacetobacter xylinus is synthesized and impregnated in situ with iron oxide ...

Custom-designed Laser-based Heating Apparatus for Triggered Release of Cisplatin from Thermosensitive Liposomes with Magnetic Resonance Image Guidance

Liposomes have been employed as drug delivery systems to target solid tumors through exploitation of the enhanced permeability and retention (EPR) effect resulting in significant reductions in systemic toxicity. Nonetheless, insufficient release of encapsulated drug from liposomes has limited their clinical efficacy. Temperature-sensitive liposomes have been engineered to provide site-specific release of drug in order to overcome the problem of limited tumor drug bioavailability. Our lab has designed and developed a heat-activated thermosensitive liposome formulation of cisplatin (CDDP), known as HTLC, to provide triggered release of CDDP at solid tumors. Heat-activated delivery in vivo was achieved in murine models using a custom-built laser-based heating apparatus that provides a conformal heating pattern at the tumor site as confirmed by MR thermometry (MRT). A fiber optic temperature monitoring device was used to measure the temperature in real-time during the entire heating period with online adjustment of heat delivery by alternating the laser power. Drug delivery was optimized under magnetic resonance (MR) image guidance by co-encapsulation of an MR contrast agent (i.e.,&#160;gadoteridol) along with CDDP into the thermosensitive liposomes as a means to validate the heating protocol and to assess tumor accumulation. The heating protocol consisted of a preheating period of 5 min prior to administration of HTLC and 20 min heating post-injection. This heating protocol resulted in effective release of the encapsulated agents with the highest MR signal change observed in the heated tumor in comparison to the unheated tumor and muscle. This study demonstrated the successful application of the laser-based heating apparatus for preclinical thermosensitive liposome development and the importance of MR-guided validation of the heating protocol for optimization of drug delivery.

AN MRI-compatible&#160;custom-designed laser-based heating apparatus has been developed to provide local heating of subcutaneous tumors in order to activate release of agents from thermosensitive liposomes specifically at the tumor region.

Liposomes have been employed as drug delivery systems to target solid tumors through exploitation of the enhanced permeability and retention (EPR) effect ...

Magnetic Resonance-Guided High Intensity Focused Ultrasound Generated Hyperthermia: A Feasible Treatment Method in a Murine Rhabdomyosarcoma Model

Magnetic resonance-guided high intensity focused ultrasound (MRgHIFU) is an established method for producing localized hyperthermia. Given the real-time imaging and acoustic energy modulation, this modality enables precise temperature control within a defined area. Many thermal applications are being explored with this noninvasive, nonionizing technology, such as hyperthermia generation, to release drugs from thermosensitive liposomal carriers. These drugs can include chemotherapies such as doxorubicin, for which targeted release is desired due to the dose-limiting systemic side effects, namely cardiotoxicity. Doxorubicin is a mainstay for treating a variety of malignant tumors and is commonly used in relapsed or recurrent rhabdomyosarcoma (RMS). RMS is the most common solid soft tissue extracranial tumor in children and young adults. Despite aggressive, multimodal therapy, RMS survival rates have remained the same for the past 30 years. To explore a solution for addressing this unmet need, an experimental protocol was developed to evaluate the release of thermosensitive liposomal doxorubicin (TLD) in an immunocompetent, syngeneic RMS mouse model using MRgHIFU as the source of hyperthermia for drug release.

Presented here is a protocol to use controlled hyperthermia, generated by magnetic resonance-guided high intensity focused ultrasound, to trigger drug release from temperature-sensitive liposomes in a rhabdomyosarcoma mouse model.

Magnetic resonance-guided high intensity focused ultrasound (MRgHIFU) is an established method for producing localized hyperthermia. Given the real-time ...

Cancer Research

Fabricating and Labeling Microbubbles with Fluorescent and Radioactive Tracers

Microbubbles are lipid-shelled, gas-filled particles that have evolved from vascular ultrasound contrast agents into revolutionary cancer therapy platforms. When combined with therapeutic focused ultrasound (FUS), they can safely and locally overcome physiological barriers (e.g., blood-brain barrier), deliver drugs to otherwise inaccessible cancers (e.g., glioblastoma and pancreatic cancer), and treat neurodegenerative diseases. The therapeutic arsenal of microbubble-FUS is advancing in new directions, including synergistic combination radiotherapy, multimodal imaging, and all-in-one drug loading and delivery from microbubble shells.
Labeling microbubbles with radiotracers is key to establishing these expanded theranostic capabilities. However, existing microbubble radiolabeling strategies rely on purification methodologies known to perturb microbubble physicochemical properties, use short-lived radioisotopes, and do not always yield stable chelation. Collectively, this creates ambiguity surrounding the accuracy of microbubble radioimaging and the efficiency of tumor radioisotope delivery.
This protocol describes a new one-pot, purification-free microbubble labeling methodology that preserves microbubble physicochemical properties while achieving &#62;95% radioisotope chelation efficiency. It is versatile and can be applied successfully across custom and commercial microbubble formulations with differing acyl lipid chain length, charge, and chelator/probe (porphyrin, DTPA, DiI) composition. It can be adaptively applied during ground-up microbubble fabrication and to pre-made microbubble formulations with modular customizability of fluorescence and multimodal fluorescence/radioactive properties. Accordingly, this flexible method enables the production of tailored, traceable (radio, fluorescent, or radio/fluorescent active) multimodal microbubbles that are useful for advancing mechanistic, imaging, and therapeutic microbubble-FUS applications.

This protocol outlines the fabrication of lipid microbubbles and a compatible one-pot microbubble radiolabeling method with purification-free &gt;95% labeling efficiency that conserves microbubble physicochemical properties. This method is effective across diverse lipid microbubble formulations and can be tailored to generate radioactive and/or fluorescent microbubbles.

Microbubbles are lipid-shelled, gas-filled particles that have evolved from vascular ultrasound contrast agents into revolutionary cancer therapy ...

Studying Cavitation Enhanced Therapy

Interest in the therapeutic applications of ultrasound is significant and growing, with potential clinical targets ranging from cancer to Alzheimer&#8217;s disease. Cavitation - the formation and subsequent motion of bubbles within an ultrasound field - represents a key phenomenon underpinning many of these treatments. There remains, however, considerable uncertainty regarding the detailed mechanisms of action by which cavitation promotes therapeutic effects and there is a need to develop reliable monitoring techniques that can be implemented clinically. In particular, there is significant variation between studies in the exposure parameters reported as successfully delivering therapeutic effects and the corresponding acoustic emissions. The aim of this paper is to provide design guidelines and an experimental protocol using widely available components for performing studies of cavitation-mediated bioeffects, and&#160;include real-time acoustic monitoring. It is hoped that the protocol will enable more widespread incorporation of acoustic monitoring into therapeutic ultrasound experiments and facilitate easier comparison across studies of exposure conditions and their correlation to relevant bio-effects.

The presented experimental protocol can be used to perform real time measurements of cavitation activity in a cell culture device with the aim of enabling investigation of the conditions required for successful drug delivery and/or other bioeffects.

Interest in the therapeutic applications of ultrasound is significant and growing, with potential clinical targets ranging from cancer to ...

Simulating the Influence of a Bipolar Radiofrequency Hyperthermia System on Tumors

A Computational Modeling Approach to Investigate the Influence of Hyperthermia on the Tumor Microenvironment

The biophysical properties of the tumor microenvironment differ substantially from normal tissues. A constellation of features, including decreased vascularity, lack of lymphatic drainage, and elevated interstitial pressure, diminishes the penetration of therapeutics into tumors. Local&#160;hyperthermia within the tumor can alter microenvironmental properties, such as interstitial fluid pressure, potentially leading to improvements in drug penetration. In this context, multi-physics computational models can provide insight into the interplay between the biophysical parameters within the tumor microenvironment and can guide the design and interpretation of experiments that test the bioeffects of local hyperthermia.
This paper describes a step-by-step workflow for a computational model coupling partial differential equations describing electrical current distribution, bioheat transfer, and fluid dynamics. The main objective is to study the effects of hyperthermia delivered by a bipolar radiofrequency device on the interstitial fluid pressure within the tumor.&#160;The system of mathematical expressions linking electrical current distribution, bioheat transfer, and interstitial fluid pressure is presented, emphasizing the changes in the distribution of the interstitial fluid pressure that could be induced by the thermal intervention.

Author Spotlight: Computing the Effects of a Local Radiofrequency Hyperthermia Intervention on Tumor Biomechanics

The article describes a protocol to simulate the transient temperature profiles and the coupled spatiotemporal variation of the interstitial fluid pressure following the heating delivered by a dipolar radiofrequency hyperthermia system. The protocol can be used to assess the response of biophysical parameters characterizing the tumor microenvironment to interventional hyperthermia techniques.

The biophysical properties of the tumor microenvironment differ substantially from normal tissues. A constellation of features, including decreased ...

Real-Time Magnetic Resonance Guided Focused Ultrasound for Painful Bone Metastases

Bones are one of the most common sites of cancer metastasis, which usually causes pain and impairs quality of life. Radiation therapy combined with opioids is the standard treatment for painful bone metastases. This treatment achieves effective pain control in 60&#8722;74% of patients, but limited treatment choices with limited benefits are available for recurrent or residual painful bone metastases after radiotherapy. More than 40% of patients still experience moderate to severe bone pain after reirradiation. Magnetic resonance-guided focused ultrasound (MRgFUS) combines high-intensity focused ultrasound, which achieves thermal ablation of bone metastases and subsequent pain reduction, with real-time magnetic resonance (MR) thermometry to monitor the temperature of anatomic MR images, with an accuracy of 1 &#176;C, spatial resolution of 1 mm, and temporal resolution within 3 s. As well as being increasingly used clinically for controlling metastatic bone pain, the use of MRgFUS for other diseases has also been tested. However, the use of MR software as a thermometer is the only technique available to verify the accuracy of the software and assure energy delivery. Here, we describe an efficient method of quality assurance we developed for thermal detection and energy delivery before each MRgFUS treatment and also propose a modified workflow to expedite the treatment course as well as to reduce patients&#39; pain during the procedure.

Magnetic resonance could offer real-time monitoring of the position and temperature of focused ultrasound in thermal ablation for painful bone metastases, regardless of cancer type or previous local treatments. Our innovative method of quality assurance could facilitate the application of this effective and safe treatment.

Bones are one of the most common sites of cancer metastasis, which usually causes pain and impairs quality of life. Radiation therapy combined with ...

Medicine

In Vitro and In Vivo Delivery of Magnetic Nanoparticle Hyperthermia Using a Custom-Built Delivery System

Hyperthermia has long been used in the treatment of cancer. Techniques have varied from the intra-tumoral insertion of hot iron rods, to systemically delivered tumor antibody-targeted magnetic nanoparticles, at temperatures from 39 &#730;C (fever-level) to 1,000 &#730;C (electrocautery) and treatment times from seconds to hours. The temperature-time relationship (thermal dose) dictates the effect with high thermal doses resulting in the tissue ablation and lower thermal doses resulting in sublethal effects such as increased blood flow, accumulation of drugs and immune stimulation. One of the most promising current medical therapies is magnetic nanoparticle hyperthermia&#160; (mNPH). This technique involves activating magnetic nanoparticles, that can be delivered systemically or intratumorally, with a non-invasive, non-toxic alternating magnetic field. The size, construct and association of the magnetic nanoparticles and the frequency and field strength of the magnetic field are major heating determinants. We have developed sophisticated instrumentation and techniques for delivering reproducible magnetic nanoparticle hyperthermia in large and small animal models and cultured cells. This approach, using continuous, real time temperature monitoring in multiple locations, allows for the delivery of well-defined thermal doses to the target tissue (tumor) or cells while limiting non-target tissue heating. Precise control and monitoring of temperature, in multiple sites, and use of the industry standard algorithm (cumulative equivalent minutes at 43 &#730;C /CEM43), allows for an accurate determination and quantification of thermal dose. Our system, which allows for a wide variety of temperatures, thermal doses, and biological effects, was developed through a combination of commercial acquisitions and inhouse engineering and biology developments. This system has been optimized in a manner that allows for the rapid conversion between ex vivo, in vitro, and in vivo techniques. The goal of this protocol is to demonstrate how to design, develop and implement an effective technique and system for delivering reproducible and accurate magnetic nanoparticle therapy (mNP) hyperthermia.

This protocol presents techniques and methodology necessary for the accurate delivery of magnetic nanoparticle hyperthermia using a sophisticated delivery and monitoring system.

Hyperthermia has long been used in the treatment of cancer. Techniques have varied from the intra-tumoral insertion of hot iron rods, to systemically ...

Magnetic-, Acoustic-, and Optical-Triple-Responsive Microbubbles for Magnetic Hyperthermia and Pothotothermal Combination Cancer Therapy

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