scholarly journals PET, image-guided HDAC inhibition of pediatric diffuse midline glioma improves survival in murine models

2020 ◽  
Vol 6 (30) ◽  
pp. eabb4105 ◽  
Author(s):  
Umberto Tosi ◽  
Harikrishna Kommidi ◽  
Oluwaseyi Adeuyan ◽  
Hua Guo ◽  
Uday Bhanu Maachani ◽  
...  
Keyword(s):  
Convection Enhanced Delivery ◽  
Treatment Algorithms ◽  
Image Guided ◽  
Dismal Prognosis ◽  
Positron Emission ◽  
Survival Prolongation ◽  
Theranostic Agents ◽  
Image Guided Drug Delivery ◽  
Diffuse Midline Glioma

Efforts at altering the dismal prognosis of pediatric midline gliomas focus on direct delivery strategies like convection-enhanced delivery (CED), where a cannula is implanted into tumor. Successful CED treatments require confirmation of tumor coverage, dosimetry, and longitudinal in vivo pharmacokinetic monitoring. These properties would be best determined clinically with image-guided dosimetry using theranostic agents. In this study, we combine CED with novel, molecular-grade positron emission tomography (PET) imaging and show how PETobinostat, a novel PET-imageable HDAC inhibitor, is effective against DIPG models. PET data reveal that CED has significant mouse-to-mouse variability; imaging is used to modulate CED infusions to maximize tumor saturation. The use of PET-guided CED results in survival prolongation in mouse models; imaging shows the need of CED to achieve high brain concentrations. This work demonstrates how personalized image-guided drug delivery may be useful in potentiating CED-based treatment algorithms and supports a foundation for clinical translation of PETobinostat.

scholarly journals EXTH-55. PET, IMAGE-GUIDED HDAC INHIBITION OF PEDIATRIC DIFFUSE MIDLINE GLIOMA IMPROVES SURVIVAL IN MURINE MODELS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii99-ii99
Author(s):  
Umberto Tosi ◽  
Harikrishna Kommidi ◽  
Oluwaseyi Adeuyan ◽  
Hua Guo ◽  
Uday Bhanu Maachani ◽  
...  
Keyword(s):  
Hdac Inhibitor ◽  
Systemic Delivery ◽  
Convection Enhanced Delivery ◽  
Image Guided ◽  
Dismal Prognosis ◽  
Positron Emission ◽  
Dividing Cells ◽  
Image Guided Drug Delivery

Abstract Efforts at altering the dismal prognosis of pediatric midline gliomas focus on direct-delivery strategies like convection-enhanced delivery (CED), where a cannula is implanted into tumor. Successful CED treatments require confirmation of tumor coverage, dosimetry, and longitudinal in vivo pharmacokinetics monitoring. These properties would be best determined clinically with image guided dosimetry using theranostic compounds, agents with both therapeutic and imaging properties. In this study, we combine CED with novel, molecular-grade positron emission tomography (PET) imaging. We synthesized PETobinostat, a novel PET-imageable HDAC inhibitor, and showed its effectiveness against DIPG models in vitro and in vivo. Cell studies against a library of DIPG cells show nanomolar IC50, allowing for rapid in vivo translation. When injected in mice, PET shows the need of CED to achieve high brain concentrations, as systemic delivery yields inferior brain permeation. PET also shows that CED has significant mouse-to-mouse variability: imaging is used to modulate CED infusions to maximize tumor saturation over time. By determining condition-specific clearance half-life (ranging between 60 and 120 minutes), we maximized tumor permeation above therapeutic concentrations for at least 12 hours. This PET-guided approach resulted in decrease tumor cellularity (p= 0.001), increased apoptosis (p= 0.034), decreased dividing cells (p= 0.003), and recovery of histone-3 acetylation (p < 0.0001) when compared against vehicle and systemic-treated controls in tumor-bearing mice. Further, the PET-guided CED of PETobinostat resulted in survival prolongation (67.5 vs. 35 days, p = 0.0001) when compared to systemic administration of another potent HDAC inhibitor (Panobinostat). CED without PET guidance failed at improving survival (37.5 vs. 35 days, p = 0.74). No significant toxicity was observed following CED of PETobinostat. This work demonstrates how personalized image-guided drug delivery of a novel HDAC inhibitor may be useful in potentiating CED-based treatment platforms, and supports a foundation for the clinical translation of PETobinostat.

Porphyrin-lipid nanovesicles (Porphysomes) are effective photosensitizers for photodynamic therapy

Nanophotonics ◽  
2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Keegan Guidolin ◽  
Lili Ding ◽  
Juan Chen ◽  
Brian C. Wilson ◽  
Gang Zheng
Keyword(s):  
Photodynamic Therapy ◽  
Tumor Growth ◽  
Intrinsic Structure ◽  
Therapeutic Applications ◽  
Positron Emission ◽  
Theranostic Agents ◽  
Negative Controls ◽  
And Control ◽  
Complete Tumor

Abstract Porphysomes (PS) are liposome-like nanoparticles comprising pyropheophorbide-conjugated phospholipids that have demonstrated potential as multimodal theranostic agents for applications that include phototherapies, targeted drug delivery and in vivo fluorescence, photoacoustic, magnetic resonance or positron emission imaging. Previous therapeutic applications focused primarily on photothermal therapy (PTT) and suggested that PSs require target-triggered activation for use as photodynamic therapy (PDT) sensitizers. Here, athymic nude mice bearing subcutaneous A549 human lung tumors were randomized into treatment and control groups: PS-PDT at various doses, PS-only and no treatment negative controls, as well as positive controls using the clinical photosensitizer Photofrin. Animals were followed for 30 days post-treatment. PS-PDT at all doses demonstrated a significant tumor ablative effect, with the greatest effect seen with 10 mg/kg PS at a drug-light interval of 24 h. By comparison, negative controls (PS-only, Photofrin-only, and no treatment) showed uncontrolled tumor growth. PDT with Photofrin at 5 mg/kg and PS at 10 mg/kg demonstrated similar tumor growth suppression and complete tumor response rates (15 vs. 25%, p = 0.52). Hence, porphysome nanoparticles are an effective PDT agent and have the additional advantages of multimodal diagnostic and therapeutic applications arising from their intrinsic structure. Porphysomes may also be the first single all-organic agent capable of concurrent PDT and PTT.

scholarly journals Image-Guided Drug Delivery to Tumors using Ultrasound-Activated Perfluorocarbon Nanoemulsions as Drug Carriers

2018 ◽  
Author(s):  
Natalya Rapoport ◽  
Allison Payne ◽  
Christopher Dillon ◽  
Jill Shea ◽  
Courtney Scaife
Keyword(s):  
Drug Delivery ◽  
Pancreatic Cancer ◽  
Nude Mice ◽  
Drug Carriers ◽  
Predominant Role ◽  
Image Guided ◽  
Image Guided Drug Delivery ◽  
Perfluorocarbon Nanoemulsions ◽  
Ultrasound Action

It is still not known which mode of ultrasound action - thermal or mechanical - plays the predominant role in ultrasound mediated drug delivery. This project will combine results from two powerful imaging modalities, MRI and RFP imaging, to better understand and quantify the major effects. Several experimental variables will be tested in vivo using RFP-transfected pancreatic cancer MiaPaCa2 subcutaneous tumors grown in nude mice, providing information to better understand the mechanisms involved in ultrasound-mediated drug delivery.

scholarly journals In Vivo Tumor Targeting and Image-Guided Drug Delivery with Antibody-Conjugated, Radiolabeled Mesoporous Silica Nanoparticles

ACS Nano ◽  
2013 ◽  
Vol 7 (10) ◽  
pp. 9027-9039 ◽  
Author(s):  
Feng Chen ◽  
Hao Hong ◽  
Yin Zhang ◽  
Hector F. Valdovinos ◽  
Sixiang Shi ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Mesoporous Silica ◽  
Silica Nanoparticles ◽  
Tumor Targeting ◽  
Mesoporous Silica Nanoparticles ◽  
Image Guided ◽  
Image Guided Drug Delivery

scholarly journals ET-03 Convection-enhanced delivery of EZH2 inhibitor for the treatment of diffuse midline glioma

2020 ◽  
Vol 2 (Supplement_3) ◽  
pp. ii5-ii6
Author(s):  
Takahiro Sasaki ◽  
Hiroaki Katagi ◽  
Becker Oren ◽  
Goldman Stewart ◽  
Naoyuki Nakao ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Systemic Administration ◽  
High Concentration ◽  
Convection Enhanced Delivery ◽  
Brainstem Tumor ◽  
Animal Survival ◽  
Dismal Prognosis ◽  
Xenograft Models ◽  
The Brain ◽  
Diffuse Midline Glioma

Abstract Background: Diffuse midline glioma (DMG) is a fatal childhood brain tumor and the majority of patients die within 2 years after initial diagnosis. Factors that contribute to the dismal prognosis of these patients include the infiltrative nature and anatomic location in an eloquent area of the brain, which precludes total surgical resection, and the presence of the blood-brain barrier (BBB), which reduces the distribution of systemically administered agents. Convection-enhanced delivery (CED) is a direct infusion technique to deliver therapeutic agents into a target site in the brain and able to deliver a high concentration drug to the infusion site without systemic toxicities. Objective: This study aims to assess the efficacy of enhancer of zeste homolog-2 (EZH2) inhibitor by CED against human DMG xenograft models. Methods: The concentration of EZH2 inhibitor (EPZ-6438) in the brainstem tumor was evaluated by liquid chromatography mass spectrometry (LC/MS). We treated mice bearing human DMG xenografts with EPZ-6438 using systemic (intraperitoneal) or CED administration. Intracranial tumor growth was monitored by bioluminescence image and the therapeutic response was evaluated by animal survival. Results: LC/MS analysis showed that the concentration of EPZ-6438 in the brainstem tumor was 3.74% of serum concentration after systemic administration. CED of EPZ-6438 suppressed tumor growth and significantly extended animal survival when compared to systemic administration of EPZ-6438 (P = 0.0475). Conclusion: Our results indicate that CED of an EZH2 inhibitor is a promising strategy to bypass the BBB and to increase the efficacy of an EZH2 inhibitor for the treatment of DMG.

Functional characterization of human brown adipose tissue metabolism

2020 ◽  
Vol 477 (7) ◽  
pp. 1261-1286 ◽  
Author(s):  
Marie Anne Richard ◽  
Hannah Pallubinsky ◽  
Denis P. Blondin
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Functional Characterization ◽  
Human Infants ◽  
Positron Emission ◽  
Brown Adipose ◽  
Treatment Of Obesity ◽  
And Function

Brown adipose tissue (BAT) has long been described according to its histological features as a multilocular, lipid-containing tissue, light brown in color, that is also responsive to the cold and found especially in hibernating mammals and human infants. Its presence in both hibernators and human infants, combined with its function as a heat-generating organ, raised many questions about its role in humans. Early characterizations of the tissue in humans focused on its progressive atrophy with age and its apparent importance for cold-exposed workers. However, the use of positron emission tomography (PET) with the glucose tracer [18F]fluorodeoxyglucose ([18F]FDG) made it possible to begin characterizing the possible function of BAT in adult humans, and whether it could play a role in the prevention or treatment of obesity and type 2 diabetes (T2D). This review focuses on the in vivo functional characterization of human BAT, the methodological approaches applied to examine these features and addresses critical gaps that remain in moving the field forward. Specifically, we describe the anatomical and biomolecular features of human BAT, the modalities and applications of non-invasive tools such as PET and magnetic resonance imaging coupled with spectroscopy (MRI/MRS) to study BAT morphology and function in vivo, and finally describe the functional characteristics of human BAT that have only been possible through the development and application of such tools.

Click Chemistry Expedited Radiosynthesis: Sulfur [18F]fluoride Exchange of Aryl Fluorosulfates

2019 ◽  
Author(s):  
Qinheng Zheng ◽  
Hongtao Xu ◽  
Hua Wang ◽  
Wen-Ge Han Du ◽  
Nan Wang ◽  
...  
Keyword(s):  
Click Chemistry ◽  
High Performance ◽  
Isotopic Exchange ◽  
Tumor Imaging ◽  
Radiochemical Yield ◽  
Exchange Method ◽  
Molar Activity ◽  
Positron Emission ◽  
Sulfur Fluoride

The lack of simple, efficient [<sup>18</sup>F]fluorination processes and new target-specific organofluorine probes remains the major challenge of fluorine-18-based positron emission tomography (PET). We report here a fast isotopic exchange method for the radiosynthesis of aryl [<sup>18</sup>F]fluorosulfate based PET agents enabled by the emerging sulfur fluoride exchange (SuFEx) click chemistry. The method has been applied to the fully-automated <sup>18</sup>F-radiolabeling of twenty-five structurally diverse aryl fluorosulfates with excellent radiochemical yield (83–100%) and high molar activity (up to 281 GBq µmol<sup>–1</sup>) at room temperature in 30 seconds. The purification of radiotracers requires no time-consuming high-performance liquid chromatography (HPLC), but rather a simple cartridge filtration. The utility of aryl [<sup>18</sup>F]fluorosulfate is demonstrated by the <i>in vivo</i> tumor imaging by targeting poly(ADP-ribose) polymerase 1 (PARP1).

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