A pilot study of respiratory rate derived from a wearable biosensor compared with capnography in emergency department patients.

Purpose: Respiratory rate is assessed less frequently than other vital signs, and documented respiratory rates are often erroneous. This pilot study compared respiratory rates derived from a wearable biosensor to those derived from capnography. Methods: Emergency department patients with respiratory complaints were enrolled and had capnography via nasal cannula and a wireless, wearable biosensor from Philips applied for approximately one hour. Respiratory rates were obtained from both of these methods. We determined the difference between median respiratory rates obtained from the biosensor and capnography and the proportion of biosensor-derived respiratory rates that were within three breaths/minute of the capnography-derived respiratory rates for each patient. A Spearman correlation coefficient was calculated to assess the strength of the correlation between mean respiratory rates derived from both methods. Plots of minute-by-minute respiratory rates, per patient, for each monitoring method were shown to two physicians. The physicians identified time periods in which the respiratory rates appeared invalid. The proportion of time with invalid respiratory rates for each patient, for each method, was calculated and averaged. Results: We analyzed data for 17 patients. Median biosensor-derived respiratory rate was 20 breaths/minute (range: 7-40 breaths/minute) and median capnography-derived respiratory rate was 25 breaths/minute (range: 0-58 breaths/minute). Overall, 72.8% of biosensor-derived respiratory rates were within three breaths per minute of the capnography-derived respiratory rates. Overall mean difference was 3.5 breaths/minute (±5.2 breaths/minute). Respiratory rates appeared invalid 0.7% of the time for the biosensor and 5.0% of the time for capnography. Conclusion: Our pilot study suggests that the Philips wearable biosensor can continuously obtain respiratory rates that are comparable to capnography-derived respiratory rates among emergency department patients with respiratory complaints.

Thermal combination therapies for local drug delivery by magnetic resonance-guided high-intensity focused ultrasound.

Several thermal-therapy strategies such as thermal ablation, hyperthermia-triggered drug delivery from temperature-sensitive liposomes (TSLs), and combinations of the above were investigated in a rhabdomyosarcoma rat tumor model (n = 113). Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) was used as a noninvasive heating device with precise temperature control for image-guided drug delivery. For the latter, TSLs were prepared, coencapsulating doxorubicin (dox) and [Gd(HPDO3A)(H2O)], and injected in tumor-bearing rats before MR-HIFU treatment. Four treatment groups were defined: hyperthermia, ablation, hyperthermia followed by ablation, or no HIFU. The intratumoral TSL and dox distribution were analyzed by single-photon emission computed tomography (SPECT)/computed tomography (CT), autoradiography, and fluorescence microscopy. Dox biodistribution was quantified and compared with that of nonliposomal dox. Finally, the treatment efficacy of all heating strategies plus additional control groups (saline, free dox, and Caelyx) was assessed by tumor growth measurements. All HIFU heating strategies combined with TSLs resulted in cellular uptake of dox deep into the interstitial space and a significant increase of tumor drug concentrations compared with a treatment with free dox. Ablation after TSL injection showed [Gd(HPDO3A)(H2O)] and dox release along the tumor rim, mirroring the TSL distribution pattern. Hyperthermia either as standalone treatment or before ablation ensured homogeneous TSL, [Gd(HPDO3A)(H2O)], and dox delivery across the tumor. The combination of hyperthermia-triggered drug delivery followed by ablation showed the best therapeutic outcome compared with all other treatment groups due to direct induction of thermal necrosis in the tumor core and efficient drug delivery to the tumor rim.

Magnetic resonance guided high-intensity focused ultrasound for image-guided temperature-induced drug delivery.

Magnetic resonance guided high-intensity focused ultrasound (MR-HIFU) is a versatile technology platform for noninvasive thermal therapies in oncology. Since MR-HIFU allows heating of deep-seated tissue to well-defined temperatures under MR image guidance, this novel technology has great potential for local heat-mediated drug delivery from temperature-sensitive liposomes (TSLs). In particular, MR provides the ability for image guidance of the drug delivery when an MRI contrast agent is co-encapsulated with the drug in the aqueous lumen of the liposomes. Monitoring of the tumor drug coverage offers possibilities for a personalized thermal treatment in oncology. This review focuses on MR-HIFU as a noninvasive technology platform, temperature-sensitive liposomal formulations for drug delivery and image-guided drug delivery, and the effect of HIFU-induced hyperthermia on the TSL and drug distribution. Finally, the opportunities and challenges of localized MR-HIFU-mediated drug delivery from temperature-sensitive liposomes in oncology are discussed.

Multifunctional liposomes for MRI and image-guided drug delivery.

Liposomes are a class of nanovesicles that have been explored extensively in the biomedical arena for early diagnosis and treatment of disease. In recent years, several liposomal drug formulations have been clinically approved in oncology. In a modular approach, the properties of liposomes can be tailored for combined molecular MRI, therapy and image-guided delivery of therapeutic drugs. Over the last year, extensive research has been performed in the authors laboratory on paramagnetic liposomes as innovative imaging probes for the detection of specific molecular or cellular targets and image-guided drug delivery using multifunctional, temperature-sensitive liposomes. A number of key achievements by the authors group will be highlighted in this research spotlight.

Stability and trapping of magnetic resonance imaging contrast agents during high-intensity focused ultrasound ablation therapy.

OBJECTIVES: The purpose of this study was to investigate the use of Gd-DTPA shortly before magnetic resonance guided high-intensity focused ultrasound MR-HIFU thermal ablation therapy with respect to dissociation, trapping, and long-term deposition of gadolinium (Gd) in the body. MATERIALS AND METHODS: Magnetic resonance-HIFU ablation treatment was conducted in vivo on both rat muscle and subcutaneous tumor (9L glioma) using a clinical 3T MR-HIFU system equipped with a small-animal coil setup. A human equivalent dose of gadopentetate dimeglumine (Gd-DTPA) (0.6 mmol/kg of body weight) was injected via a tail vein catheter just before ablation (≤5 minutes). Potential trapping of the contrast agent in the ablated area was visualized through the acquisition of R1 maps of the target location before and after therapy. The animals were sacrificed 2 hours or 14 days after the injection (n = 4 per group, a total of 40 animals). Subsequently, the Gd content in the tissue and carcass was determined using inductively coupled plasma techniques to investigate the biodistribution. RESULTS: Temporal trapping of Gd-DTPA in the coagulated tissue was observed on the R1 maps acquired within 2 hours after the ablation, an effect confirmed by the inductively coupled plasma analysis (3 times more Gd was found in the treated muscle volume than in the control muscle tissue). Two weeks after the therapy, the absolute amount of Gd present in the coagulated tissue was low compared with the amount present in the kidneys 14 days after the injection (ablated muscle, 0.009% ± 0.002% ID/g; kidney, 0.144% ± 0.165% ID/g). There was no significant increase in Gd content in the principal target organs for translocated Gdions (liver, spleen, and bone) or in the entire carcasses between the HIFU- and sham-treated animals. Finally, an in vivo relaxivity of 4.6 mmols was found in the HIFU-ablated volume, indicating intact Gd-DTPA. CONCLUSIONS: Magnetic resonance-HIFU treatment does not induce the dissociation of Gd-DTPA. In small-tissue volumes, no significant effect on the long-term in vivo Gd retention was found. However, care must be taken with the use of proton resonance frequency shift-based MR thermometry for HIFU guidance in combination with Gd because the susceptibility artifact induced by Gd can severely influence treatment outcome.

SPECT/CT imaging of temperature-sensitive liposomes for MR-image guided drug delivery with high intensity focused ultrasound.

The goal of this study was to investigate the blood kinetics and biodistribution of temperature-sensitive liposomes (TSLs) for MR image-guided drug delivery. The co-encapsulated doxorubicin and [Gd(HPDO3A)(H2O)] as well as the ¹¹¹In-labeled liposomal carrier were quantified in blood and organs of tumor bearing rats. After TSL injection, mild hyperthermia (T=42 °C) was induced in the tumor using high intensity focused ultrasound under MR image-guidance (MR-HIFU). The biodistribution of the radiolabeled TSLs was investigated using SPECT/CT imaging, where the highest uptake of ¹¹¹In-labeled TSLs was observed in the spleen and liver. The MR-HIFU-treated tumors showed 4.4 times higher liposome uptake after 48 h in comparison with controls, while the doxorubicin concentration was increased by a factor of 7.9. These effects of HIFU-treatment are promising for applications in liposomal drug delivery to tumors.

Magnetic resonance guided high-intensity focused ultrasound mediated hyperthermia improves the intratumoral distribution of temperature-sensitive liposomal doxorubicin.

OBJECTIVES: The aim of this study was to investigate the intratumoral distribution of a temperature-sensitive liposomal carrier and its encapsulated compounds, doxorubicin, and a magnetic resonance (MR) imaging contrast agent after high-intensity focused ultrasound (HIFU)-mediated hyperthermia-induced local drug release. MATERIALS AND METHODS: (111)In-labeled temperature-sensitive liposomes encapsulating doxorubicin and [Gd(HPDO3A) (H(2)O)] were injected intravenously in the tail vein of rats (n = 12) bearing a subcutaneous rhabdomyosarcoma tumor on the hind leg. Immediately after the injection, local tumor hyperthermia (2 × 15 minutes) was applied using a clinical 3 T MR-HIFU system. Release of [Gd(HPDO3A)(H(2)O)] was studied in vivo by measuring the longitudinal relaxation rate R(1) with MR imaging. The presence of the liposomal carriers and the intratumoral distribution of doxorubicin were imaged ex vivo with autoradiography and fluorescence microscopy, respectively, for 2 different time points after injection (90 minutes and 48 hours). RESULTS: In hyperthermia-treated tumors, radiolabeled liposomes were distributed more homogeneously across the tumor than in the control tumors (coefficient of variation(hyp, 90 min) = 0.7 ± 0.2; coefficient of variation(cntrl, 90 min) = 1.1 ± 0.2). At 48 hours after injection, the liposomal accumulation in the tumor was enhanced in the hyperthermia group in comparison with the controls. A change in R(1) was observed in the HIFU-treated tumors, suggesting release of the contrast agent. Fluorescence images showed perivascular doxorubicin in control tumors, whereas in the HIFU-treated tumors, the delivered drug was spread over a much larger area and also taken up by tumor cells at a larger distance from blood vessels. CONCLUSIONS: Treatment with HIFU hyperthermia not only improved the immediate drug delivery, bioavailability, and intratumoral distribution but also enhanced liposomal accumulation over time. The sum of these effects may have a significant contribution to the therapeutic outcome.

The magnetic susceptibility effect of gadolinium-based contrast agents on PRFS-based MR thermometry during thermal interventions.

BACKGROUND: Proton resonance frequency shift (PRFS) magnetic resonance (MR) thermometry exploits the local magnetic field changes induced by the temperature dependence of the electron screening constant of water protons. Any other local magnetic field changes will therefore translate into incorrect temperature readings and need to be considered accordingly. Here, we investigated the susceptibility changes induced by the inflow and presence of a paramagnetic MR contrast agent and their implications on PRFS thermometry. METHODS: Phantom measurements were performed to demonstrate the effect of sudden gadopentetate dimeglumine (Gd-DTPA) inflow on the phase shift measured using a PRFS thermometry sequence on a clinical 3 T magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) system. By proton nuclear magnetic resonance spectroscopy, the temperature dependence of the Gd-DTPA susceptibility was measured, as well as the effect of liposomal encapsulation and release on the bulk magnetic susceptibility of Gd-DTPA. In vivo studies were carried out to measure the temperature error induced in a rat hind leg muscle upon intravenous Gd-DTPA injection. RESULTS: The phantom study showed a significant phase shift inside the phantom of 0.6 ± 0.2 radians (mean ± standard deviation) upon Gd-DTPA injection (1.0 mM, clinically relevant amount). A Gd-DTPA-induced magnetic susceptibility shift of ΔχGd-DTPA = 0.109 ppm/mM was measured in a cylinder parallel to the main magnetic field at 37°C. The temperature dependence of the susceptibility shift showed dΔχGd-DTPA/dT = -0.00038 ± 0.00008 ppm/mM/°C. No additional susceptibility effect was measured upon Gd release from paramagnetic liposomes. In vivo, intravenous Gd-DTPA injection resulted in a perceived temperature change of 2.0°C ± 0.1°C at the center of the hind leg muscle. CONCLUSIONS: The use of a paramagnetic MR contrast agent prior to MR-HIFU treatment may influence the accuracy of the PRFS MR thermometry. Depending on the treatment workflow, Gd-induced temperature errors ranging between -4°C and +3°C can be expected. Longer waiting time between contrast agent injection and treatment, as well as shortening the ablation duration by increasing the sonication power, will minimize the Gd influence. Compensation for the phase changes induced by the changing Gd presence is difficult as the magnetic field changes are arising nonlocally in the surroundings of the susceptibility change.

Dual-isotope 111In/177Lu SPECT imaging as a tool in molecular imaging tracer design.

The synthesis, design and subsequent pre-clinical testing of new molecular imaging tracers are topic of extensive research in healthcare. Quantitative dual-isotope SPECT imaging is proposed here as a tool in the design and validation of such tracers, as it can be used to quantify and compare the biodistribution of a specific ligand and its nonspecific control ligand, labeled with two different radionuclides, in the same animal. Since the biodistribution results are not blurred by experimental or physiological inter-animal variations, this approach allows determination of the ligand's net targeting effect. However, dual-isotope quantification is complicated by crosstalk between the two radionuclides used and the radionuclides should not influence the biodistribution of the tracer. Here, we developed a quantitative dual-isotope SPECT protocol using combined (111)Indium and (177)Lutetium and tested this tool for a well-known angiogenesis-specific ligand (cRGD peptide) in comparison to a potential nonspecific control (cRAD peptide). Dual-isotope SPECT imaging of the peptides showed a similar organ and tumor uptake to single-isotope studies (cRGDfK-DOTA, 1.5 ± 0.8%ID cm(-3); cRADfK-DOTA, 0.2 ± 0.1%ID cm(-3)), but with higher statistical relevance (p-value 0.007, n = 8). This demonstrated that, for the same relevance, seven animals were required in case of a single-isotope test design as compared with only three animals when a dual-isotope test was used. Interchanging radionuclides did not influence the biodistribution of the peptides. Dual-isotope SPECT after simultaneous injection of (111)In and (177)Lu-labeled cRGD and cRAD was shown to be a valuable method for paired testing of the in vivo target specificity of ligands in molecular imaging tracer design.

Tumour hyperthermia and ablation in rats using a clinical MR-HIFU system equipped with a dedicated small animal set-up.

PURPOSE: We report on the design, performance, and specifications of a dedicated set-up for the treatment of rats on a clinical magnetic resonance high intensity focused ultrasound (MR-HIFU) system. MATERIALS AND METHODS: The small animal HIFU-compatible 4-channel MR receiver volume coil and animal support were designed as add-on to a clinical 3T Philips Sonalleve MR-HIFU system. Prolonged hyperthermia (T ≈ 42°C, 15 min) and thermal ablation (T = 65°C) was performed in vivo on subcutaneous rat tumours using 1.44 MHz acoustic frequency. The direct treatment effect was assessed with T(2)-weighted imaging and dynamic contrast enhanced (DCE-) MRI as well as histology. RESULTS: The developed HIFU-compatible coil provided an image quality that was comparable to conventional small animal volume coils (i.e. without acoustic window), and a SNR increase by a factor of 10 as compared to the coil set-up used for clinical MR-HIFU therapy. The use of an animal support minimised far field heating and allowed precise regulation of the animal body core temperature, which varied <1°C during treatment. CONCLUSIONS: The results demonstrated that, by using a designated set-up, both controlled hyperthermia and thermal ablation treatment of malignant tumours in rodents can be performed on a clinical MR-HIFU system. This approach provides all the advantages of clinical MR-HIFU, such as volumetric heating, temperature feedback control and a clinical software interface for use in rodent treatment. The use of a clinical system moreover facilitates a rapid translation of the developed protocols into the clinic.

Synthesis and in vivo evaluation of 201Tl(III)-DOTA complexes for applications in SPECT imaging.

INTRODUCTION: The aim of this study was to assess the use of (201)thallium(3+) ((201)Tl(3+)) as a radiolabel for nuclear imaging tracers. Methods for labeling of 1,4,7,10-tetraazacyclododecane-N,N',N″,N'″ tetraacetic acid (DOTA) and diethylenetriaminepentaacetic acid (DTPA) chelators with (201)Tl(3+) were investigated, and the levels of stability of these chelates were tested in vitro and in vivo. METHODS: (201)Tl(I)Cl was treated with hydrochloric acid and ozone to form (201)Tl(III)Cl(3). The procedure for labeling of DOTA and DTPA was optimized, testing different buffer solutions and pH values. The stability levels of (201)Tl(III)-DOTA and (201)Tl(III)-DTPA were assessed in buffer, mouse serum and human serum (1:1, v/v) at a temperature of 310 K for 48 h. Subsequently, in vivo stability studies with (201)Tl(III)-DOTA were performed, comparing the biodistribution of (201)Tl(III)-DOTA with that of (201)Tl(I)Cl in a single-isotope study and with that of (177)Lu(III)-DOTA in a dual-isotope single photon emission computed tomography study. RESULTS: (201)Tl(III)-DTPA, (201)Tl(III)-DOTA and (177)Lu(III)-DOTA were prepared with >95% radiochemical purity. While (201)Tl(III)-DOTA showed a prolonged level of stability in buffer and serum, (201)Tl was quickly released from DTPA in serum. Apart from some urinary excretion, the biodistribution of DOTA-chelated (201)Tl(3+) was similar to that of free (ionic) (201)Tl(+) and did not match the biodistribution of (177)Lu(III)-DOTA. This indicated a limited stability of (201)Tl(III)-DOTA complexes in vivo. CONCLUSION: Despite promising results on the labeling and in vitro stability of (201)Tl(III)-DOTA, our in vivo results indicate that the integrity of (201)Tl(III)-DOTA decreases to <20% during the time required for urinary excretion, thereby limiting the use of (201)Tl(3+) as a radiolabel for tracer imaging.

Magnetic resonance imaging of high intensity focused ultrasound mediated drug delivery from temperature-sensitive liposomes: an in vivo proof-of-concept study.

Temperature-sensitive liposomes (TSLs) co-encapsulating doxorubicin and 250 mM [Gd(HPDO3A)(H2O)] were evaluated for HIFU-mediated drug delivery under MR image guidance. In vitro studies showed simultaneous and quantitative release of the drug and the MRI contrast agent from the lumen of the TSLs at 42°C, while no leakage was observed over 1 h at 37°C. In a proof-of-concept study, local hyperthermia has been applied for 30 min in 9L rat tumors using a clinical MR-HIFU system. The local temperature-triggered release of [Gd(HPDO3A)(H2O)] was monitored with interleaved T1 mapping of the tumor tissue. A good correlation between the ΔR1, the uptake of doxorubicin and the gadolinium concentration in the tumor was found, implying that the in vivo release of doxorubicin from TSLs can be probed in situ with the longitudinal relaxation time of the co-released MRI contrast agent.