image guided drug delivery
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2021 ◽  
Vol 4 (8) ◽  
pp. 8026-8038 ◽  
Author(s):  
Catalina-Paula Spatarelu ◽  
Austin Van Namen ◽  
Geoffrey P. Luke

2021 ◽  
pp. 45-71
Author(s):  
Ruby Varghese ◽  
Namitha Vijay ◽  
Yogesh Bharat Dalvi

2020 ◽  
pp. 39-68
Author(s):  
Jong Hoon Choi ◽  
Eunsoo Yoo ◽  
Jung Hoon Kim ◽  
Dongin Kim

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii99-ii99
Author(s):  
Umberto Tosi ◽  
Harikrishna Kommidi ◽  
Oluwaseyi Adeuyan ◽  
Hua Guo ◽  
Uday Bhanu Maachani ◽  
...  

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.


2020 ◽  
Vol 6 (30) ◽  
pp. eabb4105 ◽  
Author(s):  
Umberto Tosi ◽  
Harikrishna Kommidi ◽  
Oluwaseyi Adeuyan ◽  
Hua Guo ◽  
Uday Bhanu Maachani ◽  
...  

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.


2019 ◽  
Author(s):  
Kévin RENAULT ◽  
Sylvain DEBIEU ◽  
Jean-Alexandre RICHARD ◽  
Anthony ROMIEU

We report a rational and systematic study devoted to structural optimisation of a novel class of protease-sensitive fluorescent probes recently reported by us (<i>Org. Biomol. Chem.</i>, 2017, <b>15</b>, 2575-2584), based on the "covalent-assembly" strategy and using the targeted enzyme (penicilin G acylase as model protease) to build a fluorescent pyronin dye by triggering a biocompatible domino cyclisation-aromatisation reaction. The aim is to identify <i>ad hoc</i> probe candidate(s) that might combine fast/reliable fluorogenic "turn-on" response, full stability in complex biological media and ability to release a second molecule of interest (drug or second fluorescent reporter), for applications in disease diagnosis and therapy. We base our strategy on screening a set of active methylene compounds (C-nucleophiles) to convert the parent probe to various pyronin caged precursors bearing Michael acceptor moieties of differing reactivity. <i>In vitro</i> stability and fluorescent enzymatic assays combined to HPLC-fluorescence analyses provide data useful to define the most appropriate structural features for these fluorogenic scaffolds depending on the specifications required by the biomedical application (<i>e.g.</i>, <i>in vivo</i> molecular imaging, image-guided drug delivery and theranostics) for which they will be used.


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