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1.
Phys Med ; 122: 103382, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38820805

ABSTRACT

PURPOSE: In this work, we define a signal detection based metrology to characterize the separability of two different multi-dimensional signals in spectral CT acquisitions. METHOD: Signal response was modelled as a random process with a deterministic signal and stochastic noise component. A linear Hotelling observer was used to estimate a scalar test statistic distribution that predicts the likelihood of an intensity value belonging to a signal. Two distributions were estimated for two materials of interest and used to derive two metrics separability: a separability index (s') and the area under the curve of the test statistic distributions. Experimental and simulated data of photon-counting CT scanners were used to evaluate each metric. Experimentally, vials of iodine and gadolinium (2, 4, 8 mg/mL) were scanned at multiple tube voltages, tube currents and energy thresholds. Additionally, a simulated dataset with low tube current (10-150 mAs) and material concentrations (0.25-4 mg/mL) was generated. RESULTS: Experimental data showed that conditions favorable for low noise and expression of k-edge signal produced the highest separability. Material concentration had the greatest impact on separability. The simulated data showed that under more difficult separation conditions, difference in material concentration still had the greatest impact on separability. CONCLUSION: The results demonstrate the utility of a task specific metrology to measure the overlap in signal between different materials in spectral CT. Using experimental and simulated data, the separability index was shown to describe the relationship between image formation factors and the signal responses of material.


Subject(s)
Tomography, X-Ray Computed , Iodine , Signal-To-Noise Ratio , Image Processing, Computer-Assisted/methods , Gadolinium/chemistry , Phantoms, Imaging
2.
J Vasc Interv Radiol ; 35(3): 452-461.e3, 2024 Mar.
Article in English | MEDLINE | ID: mdl-37852601

ABSTRACT

PURPOSE: To develop and evaluate a smartphone augmented reality (AR) system for a large 50-mm liver tumor ablation with treatment planning for composite overlapping ablation zones. MATERIALS AND METHODS: A smartphone AR application was developed to display tumor, probe, projected probe paths, ablated zones, and real-time percentage of the ablated target tumor volume. Fiducial markers were attached to phantoms and an ablation probe hub for tracking. The system was evaluated with tissue-mimicking thermochromic phantoms and gel phantoms. Four interventional radiologists performed 2 trials each of 3 probe insertions per trial using AR guidance versus computed tomography (CT) guidance approaches in 2 gel phantoms. Insertion points and optimal probe paths were predetermined. On Gel Phantom 2, serial ablated zones were saved and continuously displayed after each probe placement/adjustment, enabling feedback and iterative planning. The percentages of tumor ablated for AR guidance versus CT guidance, and with versus without display of recorded ablated zones, were compared among interventional radiologists with pairwise t-tests. RESULTS: The means of percentages of tumor ablated for CT freehand and AR guidance were 36% ± 7 and 47% ± 4 (P = .004), respectively. The mean composite percentages of tumor ablated for AR guidance were 43% ± 1 (without) and 50% ± 2 (with display of ablation zone) (P = .033). There was no strong correlation between AR-guided percentage of ablation and years of experience (r < 0.5), whereas there was a strong correlation between CT-guided percentage of ablation and years of experience (r > 0.9). CONCLUSIONS: A smartphone AR guidance system for dynamic iterative large liver tumor ablation was accurate, performed better than conventional CT guidance, especially for less experienced interventional radiologists, and enhanced more standardized performance across experience levels for ablation of a 50-mm tumor.


Subject(s)
Augmented Reality , Liver Neoplasms , Surgery, Computer-Assisted , Humans , Smartphone , Tomography, X-Ray Computed/methods , Phantoms, Imaging , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/surgery
4.
Sci Rep ; 12(1): 21886, 2022 12 19.
Article in English | MEDLINE | ID: mdl-36535979

ABSTRACT

Hepatocellular carcinoma (HCC) is an aggressive liver cancer with limited effective treatment options. In this study, we selected TLR agonists imiquimod (IMQ), gardiquimod (GARD), GS-9620 and DSR 6434, and a small molecule checkpoint inhibitor, BMS-202, for characterization of drug loading and release from radiopaque embolic beads (DC Bead LUMI) for potential use in image-guided transarterial embolization (TACE) of HCC. The maximum drug loading capacity and amount of drug released over time were determined by high performance liquid chromatography and compared with the commonly used anthracycline, doxorubicin hydrochloride (Dox). Maximum drug loading was 204.54 ± 3.87, 65.28 ± 3.09, 65.95 ± 6.96, 65.97 ± 1.54, and 148.05 ± 2.24 mg of drug per milliliter of DC Bead LUMI for Dox, GARD, DSR 6434, IMQ, and BMS-202, respectively. Fast loading and subsequent rapid release in saline were observed for IMQ, GARD, and DSR 6434. These drugs could also be partially removed from the beads by repeated washing with de-ionized water suggesting weak interaction with the beads. Aggregation of IMQ was observed in water and saline. GS-9620 partially decomposed in the solubilizing solution, so loading and release were not characterized. Compared to TLR agonists, slower loading and release were observed for Dox and BMS-202. Potential factors influencing drug loading into and release from DC Bead LUMI including steric hinderance, hydrophobicity, drug pKa, and the electrostatic nature of the beads are discussed. The maximum loading capacity of BMS-202 and Dox in DC Bead LUMI exceeded the maximum theoretical loading capacity of the beads expected from ionic interaction alone suggesting additional drug-bead or drug-drug interactions may play a role. Slightly more release was observed for BMS-202 at early time points followed by a slower release compared to Dox. Further study of these drug-bead combinations is warranted in search of new tools for locoregional delivery of immune-modulating agents for treatment of HCC via drug-eluting bead chemoembolization.


Subject(s)
Carcinoma, Hepatocellular , Chemoembolization, Therapeutic , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/therapy , Liver Neoplasms/therapy , Chemoembolization, Therapeutic/methods , Doxorubicin/chemistry , Antibiotics, Antineoplastic/chemistry , Microspheres
5.
Invest Radiol ; 57(8): 495-501, 2022 08 01.
Article in English | MEDLINE | ID: mdl-35239613

ABSTRACT

OBJECTIVES: The aims of this study were to develop a model to estimate drug dose delivered to tumors after transarterial chemoembolization (TACE) with radiopaque drug-eluting beads (DEBs) based on DEB density on cone-beam computed tomography (CT) and to evaluate drug penetration into tissue in a woodchuck hepatoma model. MATERIALS AND METHODS: Transarterial chemoembolization was performed in woodchucks with hepatocellular carcinoma (N = 5) using DEBs (70-150 µm, LC Bead LUMI) loaded with doxorubicin. Livers were resected 45 minutes after embolization, immediately frozen, and cut using liver-specific, 3D-printed sectioning molds. Doxorubicin levels in tumor specimens were measured by high-performance liquid chromatography and correlated with DEB iodine content that was measured using prototype cone-beam CT-based embolization treatment planning software. Doxorubicin penetration into tissue surrounding DEBs was assessed by fluorescence microscopy of tumor sections. Fluorescence intensity was converted into doxorubicin concentration using calibration standards. Intensity-thresholded color heatmaps were generated representing extravascular drug penetration. RESULTS: Consistent segmentation of DEBs on cone-beam CT was achieved using a semiautomated intensity thresholding method. A positive linear correlation (0.96) was found between DEB iodine content measured on cone-beam CT and the amount of doxorubicin measured in tumor specimens. Prediction of doxorubicin levels in tumor sections that were not included in model development was accurate, with a root-mean-square error of 0.08 mg of doxorubicin. Tumor penetration of eluted doxorubicin resulted in concentration gradients where drug content decreased with increasing distance from blood vessels containing DEBs. Drug penetration was greater for blood vessels containing DEB clusters compared with single DEB, with higher doxorubicin concentrations extending further away from the vessels. CONCLUSIONS: Estimation of drug dose delivered during transarterial chemoembolization in a woodchuck hepatocellular carcinoma model was possible using DEB radiopacity on cone-beam CT as a surrogate marker. Doxorubicin penetration was greatest adjacent to vessels containing DEB clusters compared with single DEB. Intraprocedural estimation of the spatial distribution of drug dose within the tumor could enable real-time adjustments to DEB delivery, to maximize treatment coverage or identify regions of tumor at risk for undertreatment.


Subject(s)
Carcinoma, Hepatocellular , Chemoembolization, Therapeutic , Iodine , Liver Neoplasms , Animals , Antibiotics, Antineoplastic , Carcinoma, Hepatocellular/diagnostic imaging , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/therapy , Chemoembolization, Therapeutic/methods , Cone-Beam Computed Tomography/methods , Doxorubicin , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/pathology , Liver Neoplasms/therapy , Marmota , Treatment Outcome
6.
Int J Pharm ; 616: 121466, 2022 Mar 25.
Article in English | MEDLINE | ID: mdl-35065205

ABSTRACT

Cancer immunotherapy has yet to reach its full potential due in part to limited response rates and side effects inherent to systemic delivery of immune-modulating drugs. Local administration of immunotherapy using drug-eluting embolic (DEE) microspheres as drug delivery vehicles for direct infusion into tumor-feeding arteries might increase and prolong tumor drug concentrations and reduce systemic drug exposure, potentially improving the risk-to-benefit ratio of these agents. The purpose of this study was to evaluate the ability of four immune modulators affecting two different immune pathways to potentiate replication of immune cells from a woodchuck model of hepatocellular carcinoma. DSR 6434, a Toll-like receptor agonist, and BMS-202, a PD-L1 checkpoint inhibitor, induced immune cell replication and were successfully loaded into radiopaque DEE microspheres in high concentrations. Release of DSR 6434 from the DEE microspheres was rapid (t99% = 0.4 h) upon submersion in a physiologic saline solution while BMS-202 demonstrated a more sustained release profile (t99% = 17.9 h). These findings demonstrate the feasibility of controlled delivery of immune-modulating drugs via a local DEE microsphere delivery paradigm.


Subject(s)
Carcinoma, Hepatocellular , Chemoembolization, Therapeutic , Liver Neoplasms , Carcinoma, Hepatocellular/pathology , Chemoembolization, Therapeutic/adverse effects , Doxorubicin , Humans , Liver Neoplasms/pathology , Microspheres , Pharmaceutical Preparations
7.
Expert Opin Drug Deliv ; 18(3): 383-398, 2021 03.
Article in English | MEDLINE | ID: mdl-33480306

ABSTRACT

INTRODUCTION: Drug-eluting embolic (DEE) microspheres, or drug-eluting beads (DEB), delivered by transarterial chemoembolization (TACE) serve as a therapeutic embolic to stop blood flow to tumors and a drug delivery vehicle. New combinations of drugs and DEE microspheres may exploit the potential synergy between mechanisms of drug activity and local tissue responses generated by TACE to enhance the efficacy of this mainstay therapy. AREAS COVERED: This review provides an overview of key drug delivery concepts related to DEE microspheres with a focus on recent technological developments and promising emerging clinical applications as well as speculation into the future. EXPERT OPINION: TACE has been performed for nearly four decades by injecting chemotherapy drugs into the arterial supply of tumors while simultaneously cutting off their blood supply, trying to starve and kill cancer cells, with varying degrees of success. The practice has evolved over the decades but has yet to fulfill the promise of truly personalized therapies envisioned through rational selection of drugs and real-time multi-parametric image guidance to target tumor clonality or heterogeneity. Recent technologic and pharmacologic developments have opened the door for potentially groundbreaking advances in how TACE with DEE microspheres is performed with the goal of achieving advancements that benefit patients.


Subject(s)
Carcinoma, Hepatocellular , Chemoembolization, Therapeutic , Liver Neoplasms , Pharmaceutical Preparations , Carcinoma, Hepatocellular/therapy , Doxorubicin , Humans , Liver Neoplasms/drug therapy , Microspheres , Retrospective Studies , Treatment Outcome
8.
Sci Rep ; 11(1): 533, 2021 01 12.
Article in English | MEDLINE | ID: mdl-33436734

ABSTRACT

Current therapy for hypervascular cancers, e.g., hepatocellular carcinoma, includes occlusion of the tumor blood supply by arterial infusion of embolic microspheres (beads) suspended in iodine-based contrast under fluoroscopic guidance. Available radiopaque, imageable beads use iodine as the radiopacifier and cannot be differentiated from contrast. This study aimed to synthesize and characterize imageable beads using bismuth as the radiopacifier that could be distinguished from iodine contrast based upon the difference in the binding energy of k-shell electrons (k-edge). Radiodense bismuth beads were successfully synthesized some with uniform bismuth distribution across the beads. The beads were spherical and could be infused through clinical microcatheters. The bismuth beads could be imaged with clinical dual-energy computed tomography (CT), where iodine-based contrast could be distinguished from the microspheres. The ability to separate iodine from bismuth may enhance the diagnostic information acquired on follow-up CT, identifying the distribution of the embolic beads separately from the contrast. Furthermore, with sequential use of iodine- and bismuth-based beads, the two radiopaque beads could be spatially distinguished on imaging, which may enable the development of dual drug delivery and dual tracking.


Subject(s)
Bismuth/chemistry , Carcinoma, Hepatocellular/diagnostic imaging , Carcinoma, Hepatocellular/therapy , Contrast Media/chemical synthesis , Embolization, Therapeutic/methods , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/therapy , Microspheres , Tomography, X-Ray Computed/methods , Carcinoma, Hepatocellular/blood supply , Contrast Media/chemistry , Iodine/chemistry , Liver Neoplasms/blood supply
9.
Int J Comput Assist Radiol Surg ; 15(11): 1921-1930, 2020 Nov.
Article in English | MEDLINE | ID: mdl-32734314

ABSTRACT

PURPOSE: To compare the system accuracy and needle placement performance of smartphone- and smartglasses-based augmented reality (AR) for percutaneous needle interventions. METHODS: An AR platform was developed to enable the superimposition of annotated anatomy and a planned needle trajectory onto a patient in real time. The system accuracy of the AR display on smartphone (iPhone7) and smartglasses (HoloLens1) devices was evaluated on a 3D-printed phantom. The target overlay error was measured as the distance between actual and virtual targets (n = 336) on the AR display, derived from preprocedural CT. The needle overlay angle was measured as the angular difference between actual and virtual needles (n = 12) on the AR display. Three operators each used the iPhone (n = 8), HoloLens (n = 8) and CT-guided freehand (n = 8) to guide needles into targets in a phantom. Needle placement error was measured with post-placement CT. Needle placement time was recorded from needle puncture to navigation completion. RESULTS: The target overlay error of the iPhone was comparable to the HoloLens (1.75 ± 0.59 mm, 1.74 ± 0.86 mm, respectively, p = 0.9). The needle overlay angle of the iPhone and HoloLens was similar (0.28 ± 0.32°, 0.41 ± 0.23°, respectively, p = 0.26). The iPhone-guided needle placements showed reduced error compared to the HoloLens (2.58 ± 1.04 mm, 3.61 ± 2.25 mm, respectively, p = 0.05) and increased time (87 ± 17 s, 71 ± 27 s, respectively, p = 0.02). Both AR devices reduced placement error compared to CT-guided freehand (15.92 ± 8.06 mm, both p < 0.001). CONCLUSION: An augmented reality platform employed on smartphone and smartglasses devices may provide accurate display and navigation guidance for percutaneous needle-based interventions.


Subject(s)
Augmented Reality , Needles , Smart Glasses , Smartphone , Feasibility Studies , Humans , Phantoms, Imaging
10.
Cardiovasc Intervent Radiol ; 43(12): 1918-1924, 2020 Dec.
Article in English | MEDLINE | ID: mdl-32803282

ABSTRACT

PURPOSE: Topotecan is a camptothecin analogue with potential advantages over irinotecan for transarterial chemoembolization (TACE) of hepatic colorectal metastases including greater anti-neoplastic activity without enzymatic activation. The purpose of this study was to assess safety and tolerability of topotecan-loaded radiopaque microspheres (ROMTOP) administered by TACE in a rabbit model and to compare the in vitro elution of topotecan from microspheres to irinotecan. MATERIALS AND METHODS: Topotecan was loaded into radiopaque microspheres (70-150 µm, DC Bead LUMI™, Biocompatibles UK Ltd-Boston Scientific Corporation) to the maximum capacity of 80 mg/mL of microspheres. Six healthy New Zealand White rabbits underwent hepatic TACE with ROMTOP under fluoroscopic guidance until angiographic stasis. Assessment of toxicities included regular liver function tests and complete blood counts until euthanasia 28 days post-TACE. In vitro topotecan elution from the microspheres was assessed using an open-loop flow-through system and compared to irinotecan. RESULTS: The mean bead volume and topotecan dose delivered were 0.086 mL (0.076-0.105 mL) and 1.99 mg/kg (1.51-2.55 mg/kg), respectively. Aspartate aminotransferase and alanine aminotransferase were elevated post-embolization but resolved within 2 weeks. One rabbit died two days after TACE with pyloric duodenal perforation observed at necropsy, potentially due to non-target embolization. In vitro elution of topotecan from ROMTOP was complete in 10 h compared to 3 h for irinotecan-loaded microspheres. CONCLUSION: Selective embolization with ROMTOP was tolerated at a dose of 2 mg/kg (24 mg/m2) in rabbits. In vitro topotecan elution from microspheres was more prolonged compared to irinotecan.


Subject(s)
Carcinoma, Hepatocellular/therapy , Chemoembolization, Therapeutic/methods , Liver Neoplasms, Experimental/therapy , Topotecan/pharmacology , Animals , Carcinoma, Hepatocellular/diagnosis , Humans , Irinotecan , Liver Neoplasms/diagnosis , Liver Neoplasms/therapy , Liver Neoplasms, Experimental/diagnosis , Microspheres , Rabbits , Topoisomerase I Inhibitors/pharmacology
11.
Int J Hyperthermia ; 36(1): 817-826, 2019.
Article in English | MEDLINE | ID: mdl-31451077

ABSTRACT

Objective: Thermosensitive liposomal doxorubicin (TSL-Dox) is a promising stimuli-responsive nanoparticle drug delivery system that rapidly releases the contained drug in response to hyperthermia (HT) (>40 °C). Combined with localized heating, TSL-Dox allows highly localized delivery. The goals of this study were to demonstrate that real-time fluorescence imaging can visualize drug uptake during delivery, and can predict tumor drug uptake. Methods: Nude mice carrying subcutaneous tumors (Lewis lung carcinoma) were anesthetized and injected with TSL-Dox (5 mg/kg dose). Localized HT was induced by heating tumors for 15, 30 or 60 min via a custom-designed HT probe placed superficially at the tumor location. In vivo fluorescence imaging (excitation 523 nm, emission 610 nm) was performed before, during, and for 5 min following HT. After imaging, tumors were extracted, drug uptake was quantified by high-performance liquid chromatography, and correlated with in vivo fluorescence. Plasma samples were obtained before and after HT to measure TSL-Dox pharmacokinetics. Results: Local drug uptake could be visualized in real-time during HT. Compared to unheated control tumors, fluorescence of heated tumors increased by 4.6-fold (15 min HT), 9.3-fold (30 min HT), and 13.2-fold (60 min HT). HT duration predicted tumor drug uptake (p = .02), with tumor drug concentrations of 4.2 ± 1.3 µg/g (no HT), 7.1 ± 5.9 µg/g (15 min HT), 14.1 ± 6.7 µg/g (30 min HT) and 21.4 ± 12.6 µg/g (60 min HT). There was good correlation (R2 = 0.67) between fluorescence of the tumor region and tumor drug uptake. Conclusions: Real-time in vivo fluorescence imaging can visualize drug uptake during delivery, and can predict tumor drug uptake.


Subject(s)
Antibiotics, Antineoplastic/administration & dosage , Carcinoma, Lewis Lung/diagnostic imaging , Carcinoma, Lewis Lung/therapy , Doxorubicin/analogs & derivatives , Hyperthermia, Induced , Optical Imaging , Animals , Antibiotics, Antineoplastic/blood , Antibiotics, Antineoplastic/pharmacokinetics , Carcinoma, Lewis Lung/metabolism , Doxorubicin/administration & dosage , Doxorubicin/blood , Doxorubicin/pharmacokinetics , Drug Delivery Systems , Female , Mice, Inbred BALB C , Mice, Nude , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/pharmacokinetics , Temperature
12.
Int J Hyperthermia ; 36(1): 518-529, 2019.
Article in English | MEDLINE | ID: mdl-31046513

ABSTRACT

PURPOSE: Tissue-mimicking phantoms (TMPs) are synthetic materials designed to replicate properties of biological tissues. There is a need to quantify temperature changes following ultrasound or magnetic resonance imaging-guided high intensity focused ultrasound (MR-HIFU). This work describes development, characterization and evaluation of tissue-mimicking thermochromic phantom (TMTCP) for direct visualization and quantification of HIFU heating. The objectives were to (1) develop an MR-imageable, HIFU-compatible TMTCP that reports absolute temperatures, (2) characterize TMTCP physical properties and (3) examine TMTCP color change after HIFU. METHODS AND MATERIALS: A TMTCP was prepared to contain thermochromic ink, silicon dioxide and bovine serum albumin (BSA) and its properties were quantified. A clinical MRI-guided and a preclinical US-guided HIFU system were used to perform sonications in TMTCP. MRI thermometry was performed during HIFU, followed by T2-weighted MRI post-HIFU. Locations of color and signal intensity change were compared to the sonication plan and to MRI temperature maps. RESULTS: TMTCP properties were comparable to those in human soft tissues. Upon heating, the TMTCP exhibited an incremental but permanent color change for temperatures between 45 and 70 °C. For HIFU sonications the TMTCP revealed spatially sharp regions of color change at the target locations, correlating with MRI thermometry and hypointense regions on T2-weighted MRI. TMTCP-based assessment of various HIFU applications was also demonstrated. CONCLUSIONS: We developed a novel MR-imageable and HIFU-compatible TMTCP to characterize HIFU heating without MRI or thermocouples. The HIFU-optimized TMTCP reports absolute temperatures and ablation zone geometry with high spatial resolution. Consequently, the TMTCP can be used to evaluate HIFU heating and may provide an in vitro tool for peak temperature assessment, and reduce preclinical in vivo requirements for clinical translation.


Subject(s)
High-Intensity Focused Ultrasound Ablation/methods , Magnetic Resonance Imaging/methods , Thermometry/methods , Humans
13.
Plast Reconstr Surg Glob Open ; 6(7): e1739, 2018 Jul.
Article in English | MEDLINE | ID: mdl-30175003

ABSTRACT

BACKGROUND: Enhancing drug delivery to the skin has importance in many therapeutic strategies. In particular, the outcome in vascularized composite allotransplantation mainly depends on systemic immunosuppression to prevent and treat episodes of transplant rejection. However, the side effects of systemic immunosuppression may introduce substantial risk to the patient and are weighed against the expected benefits. Successful enhancement of delivery of immunosuppressive agents to the most immunogenic tissues would allow for a reduction in systemic doses, thereby minimizing side effects. Nanoparticle-assisted transport by low temperature-sensitive liposomes (LTSLs) has shown some benefit in anticancer therapy. Our goal was to test whether delivery of a marker agent to the skin could be selectively enhanced. METHODS: In an in vivo model, LTSLs containing doxorubicin (dox) as a marker were administered intravenously to rats that were exposed locally to mild hyperthermia. Skin samples of the hyperthermia treated hind limb were compared with skin of the contralateral normothermia hind limb. Tissue content of dox was quantified both via high-performance liquid chromatography and via histology in skin and liver. RESULTS: The concentration of dox in hyperthermia-treated skin was significantly elevated over both normothermic skin and liver. (P < 0.02). CONCLUSIONS: We show here that delivery of therapeutics to the skin can be targeted and enhanced using LTSLs. Targeting drug delivery with this method may reduce the systemic toxicity seen in a systemic free-drug administration. Development of more hydrophilic immunosuppressants in the future would increase the applicability of this system in the treatment of rejection reactions in vascularized composite allotransplantation. The treatment of other skin condition might be another potential application.

14.
Radiology ; 289(2): 396-404, 2018 11.
Article in English | MEDLINE | ID: mdl-30106347

ABSTRACT

Purpose To correlate bead location and attenuation on CT images with the quantity and distribution of drug delivered to the liver following transarterial chemoembolization (TACE) with radiopaque drug-eluting beads (DEB) in a rabbit tumor model. Materials and Methods All procedures were performed with a protocol approved by the Institutional Animal Care and Use Committee. TACE was performed in rabbits (n = 4) bearing VX2 liver tumors by using radiopaque DEB (70-150 µm) loaded with doxorubicin (DOX). Livers were resected 1 hour after embolization, immediately frozen, and cut by using liver-specific three-dimensional-printed molds for colocalization of liver specimens and CT imaging. DOX penetration into tissue surrounding beads was evaluated with fluorescence microscopy. DOX levels in liver specimens were predicted by using statistical models correlating DOX content measured in tissue with bead volume and attenuation measured on CT images. Model predictions were then compared with actual measured DOX concentrations to assess the models' predictive power. Results Eluted DOX remained in close proximity (<600 µm) to beads in the liver 1 hour after TACE. Bead volume and attenuation measured on CT images demonstrated positive linear correlations (0.950 and 0.965, respectively) with DOX content in liver specimens. DOX content model predictions based on CT images were accurate compared with actual liver DOX levels at 1 hour. Conclusion CT may be used to estimate drug dose delivery and distribution in the liver following transarterial chemoembolization (TACE) with doxorubicin-loaded radiopaque drug-eluting beads (DEB). Although speculative, this informational map might be helpful in planning and understanding the spatial effects of TACE with DEB. © RSNA, 2018.


Subject(s)
Antibiotics, Antineoplastic/administration & dosage , Chemoembolization, Therapeutic/methods , Doxorubicin/administration & dosage , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/therapy , Tomography, X-Ray Computed/methods , Animals , Disease Models, Animal , Drug Delivery Systems , Liver/diagnostic imaging , Microspheres , Rabbits
15.
Future Oncol ; 14(26): 2741-2760, 2018 Nov.
Article in English | MEDLINE | ID: mdl-29944007

ABSTRACT

This review describes the historical development of an imageable spherical embolic agent and focuses on work performed in collaboration between Biocompatibles UK Ltd (a BTG International group company) and the NIH to demonstrate radiopaque bead utility and bring a commercial offering to market that meets a clinical need. Various chemistries have been investigated and multiple prototypes evaluated in search of an optimized product with the right balance of handling and imaging properties. Herein, we describe the steps taken in the development of DC Bead LUMI™, the first commercially available radiopaque drug-eluting bead, ultimately leading to the first human experience of this novel embolic agent in the treatment of liver tumors.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Chemoembolization, Therapeutic/methods , Drug Carriers/chemistry , Drug Development , Liver Neoplasms/therapy , Animals , Chemoembolization, Therapeutic/instrumentation , Contrast Media/chemistry , Disease Models, Animal , Humans , Liver Neoplasms/diagnostic imaging , Microspheres , Tomography, X-Ray Computed , Treatment Outcome
16.
Int J Hyperthermia ; 34(6): 786-794, 2018 09.
Article in English | MEDLINE | ID: mdl-29284329

ABSTRACT

PURPOSE: Current release assays have inadequate temporal resolution ( ∼ 10 s) to characterise temperature sensitive liposomes (TSL) designed for intravascular triggered drug release, where release within the first few seconds is relevant for drug delivery. MATERIALS AND METHODS: We developed a novel release assay based on a millifluidic device. A 500 µm capillary tube was heated by a temperature-controlled Peltier element. A TSL solution encapsulating a fluorescent compound was pumped through the tube, producing a fluorescence gradient along the tube due to TSL release. Release kinetics were measured by analysing fluorescence images of the tube. We measured three TSL formulations: traditional TSL (DPPC:DSPC:DSPE-PEF2000,80:15:5), MSPC-LTSL (DPPC:MSPC:DSPE-PEG2000,85:10:5) and MPPC-LTSL (DPPC:MMPC:PEF2000,86:10:4). TSL were loaded with either carboxyfluorescein (CF), Calcein, tetramethylrhodamine (TMR) or doxorubicin (Dox). TSL were diluted in one of the four buffers: phosphate buffered saline (PBS), 10% bovine serum albumin (BSA) solution, foetal bovine serum (FBS) or human plasma. Release was measured between 37-45 °C. RESULTS: The millifluidic device allowed measurement of release kinetics within the first few seconds at ∼5 ms temporal resolution. Dox had the fastest release and highest release %, followed by CF, Calcein and TMR. Of the four buffers, release was fastest in human plasma, followed by FBS, BSA and PBS. CONCLUSIONS: The millifluidic device allows measurement of TSL release at unprecedented temporal resolution, thus allowing adequate characterisation of TSL release at time scales relevant for intravascular triggered drug release. The type of buffer and encapsulated compound significantly affect release kinetics and need to be considered when designing and evaluating novel TSL-drug combinations.


Subject(s)
Drug Delivery Systems/methods , Drug Liberation/drug effects , Hyperthermia, Induced/methods , Liposomes/chemistry , Microfluidics/methods , Humans , Temperature
17.
Int J Hyperthermia ; 33(7): 733-740, 2017 11.
Article in English | MEDLINE | ID: mdl-28540814

ABSTRACT

PURPOSE: To evaluate lyso-thermosensitive liposomal doxorubicin (LTLD, ThermoDox®) in combination with loco-regional mild hyperthermia (HT) for targeted drug delivery to the bladder wall and potential treatment of bladder cancer. MATERIAL AND METHODS: Porcine in vivo studies were performed with the following groups: (i) intravenous (IV) LTLD with hyperthermia (LTLD + HT); (ii) IV doxorubicin (DOX) with hyperthermia (IV DOX + HT) and (iii) IV LTLD without hyperthermia (LTLD - HT). Drug formulations were delivered via 30 min IV infusion coinciding with 1-h bladder irrigation (45 °C water for HT groups, 37 °C for non-HT group), followed by immediate bladder resection. DOX concentrations were measured in consecutive sections parallel to the bladder lumen by liquid chromatography following drug extraction. Computer models were developed to simulate tissue heating and drug release from LTLD. RESULTS: Comparing mean DOX concentrations at increasing depths from the lumen to outer surface of the bladder wall, the ranges for LTLD + HT, IV DOX + HT and LTLD - HT, respectively, were 20.32-3.52 µg/g, 2.34-0.61 µg/g and 2.18-0.51 µg/g. The average DOX concentrations in the urothelium/lamina and muscularis, respectively, were 9.7 ± 0.67 and 4.09 ± 0.81 µg/g for IV LTLD + HT, 1.2 ± 0.39 and 0.86 ± 0.24 µg/g for IV DOX + HT, and 1.15 ± 0.38 and 0.62 ± 0.15 µg/g for LTLD - HT. Computational model results were similar to measured DOX levels and suggest adequate temperatures were reached within the bladder wall for drug release from LTLD. CONCLUSIONS: Doxorubicin accumulation and distribution within the bladder wall was achieved at concentrations higher than with free IV doxorubicin by mild bladder hyperthermia combined with systemic delivery of LTLD.


Subject(s)
Antibiotics, Antineoplastic/administration & dosage , Doxorubicin/analogs & derivatives , Drug Delivery Systems , Hyperthermia, Induced , Animals , Antibiotics, Antineoplastic/pharmacokinetics , Combined Modality Therapy , Doxorubicin/administration & dosage , Doxorubicin/pharmacokinetics , Female , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/pharmacokinetics , Swine , Urinary Bladder/metabolism , Urinary Bladder Neoplasms/therapy
18.
J Control Release ; 250: 36-47, 2017 03 28.
Article in English | MEDLINE | ID: mdl-28188808

ABSTRACT

We have developed a straightforward and efficient method of introducing radiopacity into Polyvinyl alcohol (PVA)-2-Acrylamido-2-methylpropane sulfonic acid (AMPS) hydrogel beads (DC Bead™) that are currently used in the clinic to treat liver malignancies. Coupling of 2,3,5-triiodobenzaldehyde to the PVA backbone of pre-formed beads yields a uniformly distributed level of iodine attached throughout the bead structure (~150mg/mL) which is sufficient to be imaged under standard fluoroscopy and computed tomography (CT) imaging modalities used in treatment procedures (DC Bead LUMI™). Despite the chemical modification increasing the density of the beads to ~1.3g/cm3 and the compressive modulus by two orders of magnitude, they remain easily suspended, handled and administered through standard microcatheters. As the core chemistry of DC Bead LUMI™ is the same as DC Bead™, it interacts with drugs using ion-exchange between sulfonic acid groups on the polymer and the positively charged amine groups of the drugs. Both doxorubicin (Dox) and irinotecan (Iri) elution kinetics for all bead sizes evaluated were within the parameters already investigated within the clinic for DC Bead™. Drug loading did not affect the radiopacity and there was a direct relationship between bead attenuation and Dox concentration. The ability (Dox)-loaded DC Bead LUMI™ to be visualized in vivo was demonstrated by the administration of into hepatic arteries of a VX2 tumor-bearing rabbit under fluoroscopy, followed by subsequent CT imaging.


Subject(s)
Antineoplastic Agents/administration & dosage , Camptothecin/analogs & derivatives , Doxorubicin/administration & dosage , Animals , Antineoplastic Agents/chemistry , Benzaldehydes/chemistry , Camptothecin/administration & dosage , Camptothecin/chemistry , Cell Line, Tumor , Chemoembolization, Therapeutic , Delayed-Action Preparations , Doxorubicin/chemistry , Drug Carriers , Drug Liberation , Female , Humans , Iodobenzenes/chemistry , Ion Exchange , Irinotecan , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/therapy , Microspheres , Optical Imaging , Particle Size , Polyvinyl Alcohol/chemistry , Rabbits , Surface Properties , Tomography, X-Ray Computed
19.
Med Phys ; 43(7): 4304, 2016 Jul.
Article in English | MEDLINE | ID: mdl-27370145

ABSTRACT

PURPOSE: This work describes the characterization and evaluation of a tissue-mimicking thermochromic phantom (TMTCP) for direct visualization and quantitative determination of temperatures during radiofrequency ablation (RFA). METHODS: TMTCP material was prepared using polyacrylamide gel and thermochromic ink that permanently changes color from white to magenta when heated. Color vs temperature calibration was generated in matlab by extracting RGB color values from digital photographs of phantom standards heated in a water bath at 25-75 °C. RGB and temperature values were plotted prior to curve fitting in mathematica using logistic functions of form f(t) = a + b/(1 + e((c(t-d)))), where a, b, c, and d are coefficients and t denotes temperature. To quantify temperatures based on TMTCP color, phantom samples were heated to temperatures blinded to the investigators, and two methods were evaluated: (1) visual comparison of sample color to the calibration series and (2) in silico analysis using the inverse of the logistic functions to convert sample photograph RGB values to absolute temperatures. For evaluation of TMTCP performance with RFA, temperatures in phantom samples and in a bovine liver were measured radially from an RF electrode during heating using fiber-optic temperature probes. Heating and cooling rates as well as the area under the temperature vs time curves were compared. Finally, temperature isotherms were generated computationally based on color change in bisected phantoms following RFA and compared to temperature probe measurements. RESULTS: TMTCP heating resulted in incremental, permanent color changes between 40 and 64 °C. Visual and computational temperature estimation methods were accurate to within 1.4 and 1.9 °C between 48 and 67 °C, respectively. Temperature estimates were most accurate between 52 and 62 °C, resulting in differences from actual temperatures of 0.6 and 1.6 °C for visual and computational methods, respectively. Temperature measurements during RFA using fiber-optic probes matched closely with maximum temperatures predicted by color changes in the TMTCP. Heating rate and cooling rate, as well as the area under the temperature vs time curve were similar for TMTCP and ex vivo liver. CONCLUSIONS: The TMTCP formulated for use with RFA can be used to provide quantitative temperature information in mild hyperthermic (40-45 °C), subablative (45-50 °C), and ablative (>50 °C) temperature ranges. Accurate visual or computational estimates of absolute temperatures and ablation zone geometry can be made with high spatial resolution based on TMTCP color. As such, the TMTCP can be used to assess RFA heating characteristics in a controlled, predictable environment.


Subject(s)
Ablation Techniques/instrumentation , Models, Anatomic , Phantoms, Imaging , Radiofrequency Therapy , Ablation Techniques/methods , Acrylic Resins , Animals , Calibration , Cattle , Color , Liver/surgery , Logistic Models , Optical Imaging/methods , Software , Temperature , Thermography/methods , Time Factors
20.
Pharm Res ; 33(10): 2459-69, 2016 10.
Article in English | MEDLINE | ID: mdl-27343000

ABSTRACT

PURPOSE: Low temperature sensitive liposome (LTSL) encapsulated docetaxel were combined with mild hyperthermia (40-42°C) to investigate in vivo biodistribution and efficacy against a castrate resistant prostate cancer. METHOD: Female athymic nude mice with human prostate PC-3 M-luciferase cells grown subcutaneously into the right hind leg were randomized into six groups: saline (+/- heat), free docetaxel (+/- heat), and LTSL docetaxel (+/- heat). Treatment (15 mg docetaxel/kg) was administered via tail vein once tumors reached a size of 200-300 mm(3). Mice tumor volumes and body weights were recorded for up to 60 days. Docetaxel concentrations of harvested tumor and organ/tissue homogenates were determined by LC-MS. Histological evaluation (Mean vessel density, Ki67 proliferation, Caspase-3 apoptosis) of saline, free Docetaxel and LTSL docetaxel (+/- heat n = 3-5) was performed to determine molecular mechanism responsible for tumor cell killing. RESULT: LTSL/heat resulted in significantly higher tumor docetaxel concentrations (4.7-fold greater compared to free docetaxel). Adding heat to LTSL Docetaxel or free docetaxel treatment resulted in significantly greater survival and growth delay compared to other treatments (p < 0.05). Differences in body weight between all Docetaxel treatments were not reduced by >10% and were not statistically different from each other. Molecular markers such as caspase-3 were upregulated, and Ki67 expression was significantly decreased in the chemo-hyperthermia group. Vessel density was similar post treatment, but the heated group had reduced vessel area, suggesting thermal enhancement in efficacy by reduction in functional perfusion. CONCLUSION: This technique of hyperthermia sensitization and enhanced docetaxel delivery has potential for clinical translation for prostate cancer treatment.


Subject(s)
Antineoplastic Agents/metabolism , Disease Models, Animal , Hyperthermia, Induced/methods , Prostatic Neoplasms/metabolism , Taxoids/metabolism , Animals , Antineoplastic Agents/administration & dosage , Cell Line, Tumor , Docetaxel , Drug Delivery Systems/methods , Female , Humans , Liposomes , Male , Mice , Mice, Nude , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/mortality , Random Allocation , Survival Rate/trends , Taxoids/administration & dosage , Temperature , Tissue Distribution/drug effects , Tissue Distribution/physiology , Xenograft Model Antitumor Assays/methods
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