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Localized delivery of doxorubicin in vivo from polymer-modified thermosensitive liposomes with MR-guided focused ultrasound-mediated heating.

ABSTRACT: Thermosensitive liposomes have emerged as a viable strategy for localized delivery and triggered release of chemotherapy. MR-guided focused ultrasound (MRgFUS) has the capability of heating tumors in a controlled manner, and when combined with thermosensitive liposomes can potentially reduce tumor burden in vivo. However, the impact of this drug delivery strategy has rarely been investigated. We have developed a unique liposome formulation modified with p(NIPAAm-co-PAA), a polymer that confers sensitivity to both temperature and pH. These polymer-modified thermosensitive liposomes (PTSL) demonstrated sensitivity to focused ultrasound, and required lower thermal doses and were more cytotoxic than traditional formulations in vitro. A set of acoustic parameters characterizing optimal release from PTSL in vitro was applied in the design of a combined MRgFUS/PTSL delivery platform. This platform more effectively reduced tumor burden in vivo when compared to free drug and traditional formulations. Histological analysis indicated greater tumor penetration, more extensive ECM remodeling, and greater cell destruction in tumors administered PTSL, correlating with improved response to the therapy.

SUBMITTER: Ta T

PROVIDER: S-EPMC4254020 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Localized delivery of doxorubicin in vivo from polymer-modified thermosensitive liposomes with MR-guided focused ultrasound-mediated heating.

Ta Terence T Bartolak-Suki Elizabeth E Park Eun-Joo EJ Karrobi Kavon K McDannold Nathan J NJ Porter Tyrone M TM

Journal of controlled release : official journal of the Controlled Release Society 20140823

Thermosensitive liposomes have emerged as a viable strategy for localized delivery and triggered release of chemotherapy. MR-guided focused ultrasound (MRgFUS) has the capability of heating tumors in a controlled manner, and when combined with thermosensitive liposomes can potentially reduce tumor burden in vivo. However, the impact of this drug delivery strategy has rarely been investigated. We have developed a unique liposome formulation modified with p(NIPAAm-co-PAA), a polymer that confers s ...[more]

PMID: 25151982

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Project description:IntroductionMagnetic-resonance-guided focused ultrasound (MRgFUS) thalamotomy uses multiple converging high-energy ultrasonic beams to produce thermal lesions in the thalamus. Early postoperative MR imaging demonstrates the location and extent of the lesion, but there is no consensus on the utility or frequency of postoperative imaging. We aimed to evaluate the evolution of MRgFUS lesions and describe the incidence, predictors, and clinical effects of lesion persistence in a large patient cohort.MethodsA total of 215 unilateral MRgFUS thalamotomy procedures for essential tremor (ET) by a single surgeon were retrospectively analyzed. All patients had MR imaging 1 day postoperatively; 106 had imaging at 3 months and 32 had imaging at 1 year. Thin cut (2 mm) axial and coronal T2-weighted MRIs at these timepoints were analyzed visually on a binary scale for lesion presence and when visible, lesion volumes were measured. SWI and DWI sequences were also analyzed when available. Clinical outcomes including tremor scores and side effects were recorded at these same time points. We analyzed if patient characteristics (age, skull density ratio), preoperative tremor score, and sonication parameters influenced lesion evolution and if imaging characteristics correlated with clinical outcomes.ResultsVisible lesions were present in all patients 1 day post- MRgFUS and measured 307.4 ± 128.7 mm3. At 3 months, residual lesions (excluding patients where lesions were not visible) were 83.6% smaller and detectable in only 54.7% of patients (n = 58). At 1 year, residual lesions were detected in 50.0% of patients (n = 16) and were 90.7% smaller than 24 h and 46.5% smaller than 3 months. Lesions were more frequently visible on SWI (100%, n = 17), DWI (n = 38, 97.4%) and ADC (n = 36, 92.3%). At 3 months, fewer treatment sonications, higher maximum power, and greater distance between individual sonications led to larger lesion volumes. Volume at 24 h did not predict if a lesion was visible later. Lesion visibility at 3 months predicted sensory side effects but was not correlated with tremor outcomes.DiscussionOverall, lesions are visible on T2-weighted MRI in about half of patients at both 3 months and 1 year post-MRgFUS thalamotomy. Certain sonication parameters significantly predicted persistent volume, but residual lesions did not correlate with tremor outcomes.

Project description:Background and purposeTranscranial MR imaging-guided focused ultrasound is a promising novel technique to treat multiple disorders and diseases. Planning for transcranial MR imaging-guided focused ultrasound requires both a CT scan for skull density estimation and treatment-planning simulation and an MR imaging for target identification. It is desirable to simplify the clinical workflow of transcranial MR imaging-guided focused ultrasound treatment planning. The purpose of this study was to examine the feasibility of deep learning techniques to convert MR imaging ultrashort TE images directly to synthetic CT of the skull images for use in transcranial MR imaging-guided focused ultrasound treatment planning.Materials and methodsThe U-Net neural network was trained and tested on data obtained from 41 subjects (mean age, 66.4 ± 11.0 years; 15 women). The derived neural network model was evaluated using a k-fold cross-validation method. Derived acoustic properties were verified by comparing the whole skull-density ratio from deep learning synthesized CT of the skull with the reference CT of the skull. In addition, acoustic and temperature simulations were performed using the deep learning CT to predict the target temperature rise during transcranial MR imaging-guided focused ultrasound.ResultsThe derived deep learning model generates synthetic CT of the skull images that are highly comparable with the true CT of the skull images. Their intensities in Hounsfield units have a spatial correlation coefficient of 0.80 ± 0.08, a mean absolute error of 104.57 ± 21.33 HU, and a subject-wise correlation coefficient of 0.91. Furthermore, deep learning CT of the skull is reliable in the skull-density ratio estimation (r = 0.96). A simulation study showed that both the peak target temperatures and temperature distribution from deep learning CT are comparable with those of the reference CT.ConclusionsThe deep learning method can be used to simplify workflow associated with transcranial MR imaging-guided focused ultrasound.

Project description:The future of nanomedicines in oncology requires leveraging more than just the passive drug accumulation in tumors through the enhanced permeability and retention effect. Promising results combining mild hyperthermia (HT) with lyso-thermosensitive liposomal doxorubicin (LTSL-DOX) has led to improved drug delivery and potent antitumor effects in pre-clinical studies. The ultimate patient benefit from these treatments can only be realized when robust methods of HT can be achieved clinically. One of the most promising methods of non-invasive HT is the use of focused ultrasound (FUS) with MRI thermometry for anatomical targeting and feedback. MRI-guided focused ultrasound (MRgFUS) is limited by respiratory motion and large blood vessel cooling. In order to translate exciting pre-clinical results to the clinic, novel heating approaches capable of overcoming the limitations on clinical MRgFUS+HT must be tested and evaluated on their ability to locally release drug from LTSL-DOX. Methods: In this work, a new system is described to integrate focused ultrasound (FUS) into a two-photon microscopy (2PM) setting to image the release of drug from LTSL-DOX in real-time during FUS+HT in vivo. A candidate scheme for overcoming the limitations of respiratory motion and large blood vessel cooling during MRgFUS+HT involves applying FUS+HT to 42°C in short ~30s bursts. The spatiotemporal drug release pattern from LTSL-DOX as a result is quantified using 2PM and compared against continuous (3.5min and 20min at 42°C) FUS+HT schemes and unheated controls. Results: It was observed for the first time in vivo that these short duration temperature elevations could produce substantial drug release from LTSL-DOX. Ten 30s bursts of FUS+HT was able to achieve almost half of the interstitial drug concentration as 20min of continuous FUS+HT. There was no significant difference between the intravascular area under the concentration-time curve for ten 30s bursts of FUS+HT and 3.5min of continuous FUS+HT. Conclusion: We have successfully combined 2PM with FUS+HT for imaging the release of DOX from LTSL-DOX in vivo in real-time, which will permit the investigation of FUS+HT heating schemes to improve drug delivery from LTSL-DOX. We have evaluated the ability to release DOX in short 30s FUS+HT bursts to 42°C as a method to overcome limitations on clinical MRgFUS+HT and have found that such exposures are capable of releasing measurable amounts of drug. Such an exposure has the potential to overcome limitations that hamper conventional MRgFUS+HT treatments in targets that are associated with substantial tissue motion.

Project description:Background: Trigeminal neuralgia (TN) is a recognized pain condition the treatment of which can be very challenging. Various surgical interventions can be applied in cases of therapy-resistance to drug treatments. The central lateral thalamotomy (CLT) against neurogenic (or neuropathic) pain is based on multiarchitectonic histological as well as physiopathological studies, and integrates the nucleus in a large thalamocortical (TC) and corticocortical network responsible for the sensory, cognitive and affective/emotional components of pain. The advent of the magnetic resonance imaging guided high intensity focused ultrasound (MRgFUS) brought a strong reduction in morbidity and increase in accuracy compared to penetration techniques. Objective: This study was aimed at analyzing the outcome of bilateral MRgFUS CLT for chronic therapy-resistant trigeminal pain, all performed in one single center. Methods: Patients were categorized in Classical, Idiopathic and Secondary TN. By definition, paroxysms lasted for seconds up to 2 min. All patients were screened for trigeminal neurovascular conflict. In case of classical TN, microvascular decompression was proposed. Therapy-resistance and thus indication for MRgFUS CLT was based on the lack of efficacy and/or side effects of antiepileptic and antidepressant drugs. Good outcome was defined by a pain relief ?50%. Results: Eight patients suffering from chronic therapy-resistant trigeminal neuralgia were treated. All suffered from pain with paroxysmal character. Six patients reported additionally continuous pain. Mean follow-up was 53 months (range: 12-92, median: 60 months). The mean pain relief assessed by patients was 51% (median: 58%, range: 0-90%) at 3 months, 71% (median: 65%, range: 40-100%) at 1 year and 78% (median: 75%, range: 50-100%) at their longest follow-up. This represents 63% good outcomes at 3 months, 88% at 1 year and 100% at last follow-up. Frequency of the mean pain paroxysms decreased from 84 per day preoperative to 3.9 at 1 year postoperatively. There were no serious adverse events in this series. Conclusion: Our study provides preliminary support for the safety and efficacy of MRgFUS CLT, a histologically and pathophysiologically based medial thalamotomy against chronic therapy-resistant trigeminal neuralgia.

Dataset Information

Localized delivery of doxorubicin in vivo from polymer-modified thermosensitive liposomes with MR-guided focused ultrasound-mediated heating.

Publications

Localized delivery of doxorubicin in vivo from polymer-modified thermosensitive liposomes with MR-guided focused ultrasound-mediated heating.

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