scholarly journals SCIDOT-17. UNDERSTANDING THE EFFECTS OF MOLECULAR SIZE ON VOLUME OF DISTRIBUTION IN CONVECTION-ENHANCED DELIVERY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi275-vi275
Author(s):  
Julian S Rechberger ◽  
Erica A Power ◽  
Liang Zhang ◽  
Ian Olson ◽  
Victor M Lu ◽  
...  
Keyword(s):  
Xenograft Model ◽  
Drug Distribution ◽  
Molecular Size ◽  
Pediatric Brain Tumors ◽  
Volume Of Distribution ◽  
Hydraulic Pressure ◽  
Convection Enhanced Delivery ◽  
Cross Sectional ◽  
Orthotopic Xenograft Model ◽  
The Brain

Abstract Diffuse midline gliomas harboring the H3K27M mutation, previously known as diffuse intrinsic pontine gliomas (DIPG), are rare and aggressive pediatric brain tumors without cure. One of the major challenge sin DIPG treatment is the effective delivery of therapeutic agents across the blood-brain barrier (BBB) to the tumor and surrounding infiltrating cells. Therefore, strategies that enhance drug delivery to the brain are of great interest. Convection-enhanced delivery (CED) is a technique that bypasses the BBB and increases drug distribution by applying hydraulic pressure to deliver compounds directly and evenly into a target region. However, knowledge in CED pharmacology and convective kinetics is still lacking. In an effort to characterize the feasibility, safety, and distribution in the brain based on molecular size of the delivered agent, we performed infusions of FITC-dextran (range 3,000 Da–150,000 Da) comparing CED and osmotic pump-based delivery into the brainstem of rodents. We calculated the area and volume of distribution (Vd) of the FITC-dextran throughout the brain. Our data showed that the Vd decreased exponentially with increased molecular weight of the FITC-dextran. Interestingly, the Vdcan maintain linearity at lower molecular weights. Maximal cross-sectional area and craniocaudal extension of fluorescence also decreased when lowering the infusate size. In addition, we developed a patient-derived DIPG orthotopic xenograft model and performed an image-guided CED cannula installation in the tumor bed. Using 3D bioluminescence imaging and computed tomography, we determined the tumor volume and the positioning of the cannula in the bulk tumor. The summation of these results supports CED as a promising technique for treating DIPG tumors. A better understanding of how drugs distribute by convection will allow us to optimize treatment regimens and, ultimately, offers hope to patients and families with this devastating disease.

scholarly journals PDTM-30. UNDERSTANDING THE EFFECTS OF MOLECULAR SIZE ON VOLUME OF DISTRIBUTION IN CONVECTION-ENHANCED DELIVERY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi193-vi194
Author(s):  
Erica Power ◽  
Julian Rechberger ◽  
Liang Zhang ◽  
David Daniels
Keyword(s):  
Molecular Weight ◽  
Single Injection ◽  
Fluorescent Microscopy ◽  
Molecular Size ◽  
Volume Of Distribution ◽  
Sprague Dawley ◽  
Convection Enhanced Delivery ◽  
Microscopy Imaging ◽  
Delivery Technique ◽  
The Brain

Abstract BACKGROUND Diffuse midline gliomas harboring the H3K27M mutation, previously known as diffuse intrinsic pontine gliomas (DIPG), are rare and aggressive pediatric brain tumors. Over 100 clinical trials with different chemotherapeutics have failed to show any therapeutic benefit. One reason for failure is likely due to poor delivery of these agents to the brainstem. Convection-enhanced delivery (CED) is an emerging delivery technique used to directly inject the agent of interest into the brainstem under pressure. While there is evidence that this may be an effective delivery method, little work has been done to understand the optimal physical properties of these drugs. We sought characterize volume of distribution in the brain based on molecular size of the agent delivered via CED. METHODS Sprague- Dawley rats underwent a single injection of FITC-dextran (3,000 Da, 10,000 Da, 20,000 Da, 70,000 Da, 150,000 Da) via CED into the pons. Post-injection, animals were sacrificed and their brains harvested. Fluorescent microscopy imaging was used to calculate the volume of distribution of the FITC-dextran throughout the brain. RESULTS The volume of distribution (Vd) decreased exponentially according to a two-phase delay (r2= 0.94) as the molecular size of the FITC-dextran increased. The highest mean Vd (107.87mm3) was at a molecular weight of 3,000 Da, and lowest mean Vd (26.48 mm3) was at a molecular weight of 150,000 Da. ANOVA analysis was statistically significant (p= 0.0017). CONCLUSIONS As the molecular size of the FITC-dextran increased, the volume of distribution within the brain following a single injection via CED into the pons decreased. A better understanding of how drugs distribute by convection will allow us to optimize treatment regimens for DIPG tumors.

scholarly journals Convection-Enhanced Arborizing Catheter System Improves Local/Regional Delivery of Infusates Versus a Single-Port Catheter in Ex Vivo Porcine Brain Tissue

2020 ◽  
Vol 4 (1) ◽  
Author(s):  
Egleide Y. Elenes ◽  
Jason N. Mehta ◽  
Fang-Chi Hsu ◽  
Christopher T. Whitlow ◽  
Waldermar Debinski ◽  
...  
Keyword(s):  
Standard Treatment ◽  
Single Port ◽  
Ex Vivo ◽  
Volume Of Distribution ◽  
Port Catheter ◽  
Convection Enhanced Delivery ◽  
Alternative Approach ◽  
The Brain ◽  
Regional Delivery ◽  
Porcine Brain Tissue

Abstract Standard treatment for glioblastoma is noncurative and only partially effective. Convection-enhanced delivery (CED) was developed as an alternative approach for effective loco-regional delivery of drugs via a small catheter inserted into the diseased brain. However, previous CED clinical trials revealed the need for improved catheters for controlled and satisfactory distribution of therapeutics. In this study, the arborizing catheter, consisting of six infusion ports, was compared to a reflux-preventing single-port catheter. Infusions of iohexol at a flow rate of 1 μL/min/microneedle were performed, using the arborizing catheter on one hemisphere and a single-port catheter on the contralateral hemisphere of excised pig brains. The volume dispersed (Vd) of the contrast agent was quantified for each catheter. Vd for the arborizing catheter was significantly higher than for the single-port catheter, 2235.8 ± 569.7 mm3 and 382.2 ± 243.0 mm3, respectively (n = 7). Minimal reflux was observed; however, high Vd values were achieved with the arborizing catheter. With simultaneous infusion using multiple ports of the arborizing catheter, high Vd was achieved at a low infusion rate. Thus, the arborizing catheter promises a highly desirable large volume of distribution of drugs delivered to the brain for the purpose of treating brain tumors.

Imaging and reconstruction of the cytoarchitecture of axonal fibres: enabling biomedical engineering studies involving brain microstructure

2021 ◽  
Author(s):  
Andrea Bernardini ◽  
Marco Trovatelli ◽  
Michal Klosowski ◽  
Matteo Pederzani ◽  
Davide Zani ◽  
...  
Keyword(s):  
Focused Ion Beam ◽  
Ion Beam ◽  
Cell Organelles ◽  
Convection Enhanced Delivery ◽  
Cross Sectional ◽  
Drug Molecules ◽  
Fiber Tracts ◽  
Brain Microstructure ◽  
3D Volume ◽  
The Brain

Abstract There is an increased need and focus to understand how local brain microstructure affects the transport of drug molecules directly administered to the brain tissue, for example in convection-enhanced delivery procedures. This study reports the first systematic attempt to characterize the cytoarchitecture of commissural, long association and projection fibers, namely: the corpus callosum, the fornix and the corona radiata. Ovine samples from three different subjects were stained with osmium tetroxide (to enhance contrast from cell organelles and the fibers), embedded in resin and then imaged using scanning electron microscope combined with focused ion beam milling to generate 3D volume reconstructions of the tissue at subcellular spatial resolution. Particular focus has been given to the characteristic cytological feature of the white matter: the axons and their alignment in the tissue. Via 2D images a homogeneous myelination has been estimated via detection of ~40% content of lipids in all the different fiber tracts. Additionally, for each tract, a 3D reconstruction of relatively large volumes (15μm x 15μm x 15μm – including a significant number of axons) has been performed. Namely, outer axonal ellipticity, outer axonal cross-sectional area and their relative perimeter have been measured. The study of well-resolved microstructural features provides useful insight into the fibrous organization of the tissue, whose micromechanical behaviour is that of a composite material presenting elliptical tortuous tubular fibers embedded in the extra-cellular matrix. Drug flow can be captured through microstructurally-based models, leading to a workflow to enable physically-accurate simulations of drug delivery to the targeted tissue.

scholarly journals Convection-Enhanced Delivery in silico study for personalized brain cancer treatment

2021 ◽  
Author(s):  
Chryso Lambride ◽  
Vasileios Vavourakis ◽  
Triantafyllos Stylianopoulos
Keyword(s):  
Brain Cancer ◽  
In Silico ◽  
Drug Transport ◽  
Drug Distribution ◽  
Local Drug Delivery ◽  
Patient Specific ◽  
Convection Enhanced Delivery ◽  
Formidable Challenge ◽  
The Impact ◽  
The Brain

Abstract Brain cancer therapy remains a formidable challenge in oncology. Convection-enhanced delivery (CED) is an innovative and promising local drug delivery method for the treatment of brain cancer, overcoming the challenges of the systemic delivery of drugs to the brain. To improve our understanding about CED efficacy and drug transport, we present an in silico methodology for brain cancer CED treatment simulation. To achieve this, a three-dimensional finite element biomechanics formulation is utilized which employs patient-specific brain model representation and is used to predict the drug deposition in CED regimes. The model encompasses nonlinear biomechanics and the transport of drugs in the brain parenchyma. Drug distribution was studied under various patho-physiological conditions of the tumor, in terms of tumor vessel wall pore size and tumor tissue hydraulic conductivity as well as for drugs of various sizes, spanning from small molecules to nanoparticles. Our contribution reports for the first time the impact of the size of the vascular wall pores and that of the therapeutic agent on drug distribution during and after CED. The in silico findings provide useful insights of the spatio-temporal distribution and average drug concentration in the tumor towards an effective treatment of brain cancer.

scholarly journals Effect of ependymal and pial surfaces on convectionenhanced delivery

2008 ◽  
Vol 109 (3) ◽  
pp. 547-552 ◽  
Author(s):  
Jay Jagannathan ◽  
Stuart Walbridge ◽  
John A. Butman ◽  
Edward H. Oldfield ◽  
Russell R. Lonser
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Mr Imaging ◽  
Real Time ◽  
Drug Distribution ◽  
Leading Edge ◽  
Volume Of Distribution ◽  
Clinical Effects ◽  
Convection Enhanced Delivery ◽  
Pia Mater

Object Convection-enhanced delivery (CED) is increasingly used to investigate new treatments for central nervous system disorders. Although the properties of CED are well established in normal gray and white matter central nervous system structures, the effects on drug distribution imposed by ependymal and pial surfaces are not precisely defined. To determine the effect of these anatomical boundaries on CED, the authors infused low MW and high MW tracers for MR imaging near ependymal (periventricular) and pial (pericisternal) surfaces. Methods Five primates underwent CED of Gd-diethylenetriamine pentaacetic acid (Gd-DTPA; MW 590 D) or Gd-bound albumin (Gd-albumin; MW 72,000 D) during serial real-time MR imaging (FLAIR and T1-weighted sequences). Periventricular (caudate) infusions were performed unilaterally in 1 animal (volume of infusion [Vi] 57 μl) and bilaterally in 1 animal with Gd-DTPA (Vi = 40 μl on each side), and bilaterally in 1 animal with Gd-albumin (Vi = 80 μl on each side). Pericisternal infusions were performed in 2 animals with Gd-DTPA (Vi = 190 μl) or with Gd-albumin (Vi = 185 μl) (1 animal each). Clinical effects, MR imaging, and histology were analyzed. Results Large regions of the brain and brainstem were perfused with both tracers. Intraparenchymal distribution was successfully tracked in real time by using T1-weighted MR imaging. During infusion, the volume of distribution (Vd) increased linearly (R2 = 0.98) with periventricular (mean Vd/Vi ratio ± standard deviation; 4.5 ± 0.5) and pericisternal (5.2 ± 0.3) Vi, but did so only until the leading edge of distribution reached the ependymal or pial surfaces, respectively. After the infusate reached either surface, the Vd/Vi decreased significantly (ependyma 2.9 ± 0.8, pia mater 3.6 ± 1.0; p < 0.05) and infusate entry into the ventricular or cisternal cerebrospinal fluid (CSF) was identified on FLAIR but not on T1-weighted MR images. Conclusions Ependymal and pial boundaries are permeable to small and large molecules delivered interstitially by convection. Once infusate reaches these surfaces, a portion enters the adjacent ventricular or cisternal CSF and the tissue Vd/Vi ratio decreases. Although T1-weighted MR imaging is best for tracking intraparenchymal infusate distribution, FLAIR MR imaging is the most sensitive and accurate for detecting entry of Gd-labeled imaging compounds into CSF during CED.

Real-Time, in Vivo Correlation of Molecular Structure with Drug Distribution in the Brain Striatum Following Convection Enhanced Delivery

2019 ◽  
Vol 10 (5) ◽  
pp. 2287-2298 ◽  
Author(s):  
Umberto Tosi ◽  
Harikrishna Kommidi ◽  
Vanessa Bellat ◽  
Christopher S. Marnell ◽  
Hua Guo ◽  
...  
Keyword(s):  
Molecular Structure ◽  
Real Time ◽  
Drug Distribution ◽  
Convection Enhanced Delivery ◽  
The Brain ◽  
Brain Striatum

Predictions of Drug Distribution During Infusions Into the Brain Using an Axisymmetric Finite Element Biphasic Model That Includes Backflow

2013 ◽  
Author(s):  
Alejandro Orozco ◽  
Joshua H. Smith ◽  
José Jaime García
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Drug Distribution ◽  
Therapeutic Agents ◽  
Positive Pressure ◽  
Convection Enhanced Delivery ◽  
Biphasic Model ◽  
Limited Efficacy ◽  
The Central Nervous System ◽  
The Brain

Convection-enhanced delivery is a technique to infuse therapeutic agents into the brain under positive pressure for the treatment of disorders of the central nervous system. Recent clinical trials [1] have shown limited efficacy of this procedure, attributed to poor distribution of the infused agent that may be due to backflow, in which the infused fluid preferentially flows along the outside of the catheter toward the surface of the brain.

A phase I study of convection-enhanced delivery of 124I-8H9 radio-labeled monoclonal antibody in children with diffuse intrinsic pontine glioma: An update with dose-response assessment.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2008-2008 ◽  
Author(s):  
Mark M. Souweidane ◽  
Kim Kramer ◽  
Neeta Pandit-Taskar ◽  
Zhiping Zhou ◽  
Pat Zanzonico ◽  
...  
Keyword(s):  
Dose Level ◽  
Therapeutic Strategy ◽  
Absorbed Dose ◽  
Volume Of Distribution ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Overall Survival Rate ◽  
Pontine Glioma ◽  
Convection Enhanced Delivery ◽  
The Mean ◽  
The Brain

2008 Background: Diffuse intrinsic pontine glioma (DIPG) represents one of the most deadly central nervous system tumors of childhood with a median survival of less than 12 months. Convection-enhanced delivery (CED) has been recently hypothesized as a means for efficiently distributing therapeutic agents within the brain stem. We conducted this study to evaluate CED in children with DIPG. Methods: We performed a standard phase I dose escalation study in patients with non-progressive DIPG 4 to 14 weeks post-completion of radiation therapy. Seven dose levels of a single injection of 124I-8H9 (Omburtamab) (range 0.25 to 4.0 mCi) were studied. Results: 37 children were treated with 34 evaluable for primary and secondary endpoints. The median age at enrollment was 6.8 years old (range 3.2 - 17.9). There was no dose limiting toxicity (DLT). Among adverse events that were at least possibly related to the treatment, there were no grade 4 or 5 events, and only 4 reversible grade 3 events in 4 patients (2 hemiparesis, 1 skin infection and 1 anxiety). Estimations of distribution volumes based on T2-weighted imaging were dose dependent and ranged from 1.5 to 20.8 cm3, and for dose level 7, 10.5 - 19.0 cm3. The mean volume of distribution/volume of infusion ratio (Vd/Vi) was 3.4 ±1.1, and for dose level 7, 3.5 ± 1.0. The mean lesion absorbed dose was 33.3 ± 25.9 Gy, and for dose level 7, 50.1 ± 22.9 Gy. The mean ratio of lesion-to-whole body absorbed dose was 910. The mean volume of distribution/tumor volume ratio on dose level 7 was 82.5%, but the mean tumor overlap was 40.5%. No death occurred as a result of the treatment. Median survival was 15.3 months (n = 29, 95% CI 12.7 - 17.4). Median follow-up time of the 5 surviving patients is 27.2 months (range 11.5 - 72.4). Overall survival rate at 12 months was 64.7% (22/34, 4 alive), and overall survival rate at 24 months 14.7% (5/34, 3 alive). Conclusions: CED in the brain stem of children with DIPG who were previously irradiated is a safe therapeutic strategy. An infusion volume of 4,000 mcl appears to be a reasonable single dose for a target distribution volume but enhanced tumor coverage is likely needed. There seems to be a survival benefit using this therapeutic strategy and outcomes might be dependent on dosimetry and distribution patterns. Clinical trial information: NCT01502917.

scholarly journals Intraparenchymal ultrasound application and improved distribution of infusate with convection-enhanced delivery in rodent and nonhuman primate brain

2016 ◽  
Vol 124 (5) ◽  
pp. 1490-1500 ◽  
Author(s):  
Yui Mano ◽  
Ryuta Saito ◽  
Yoichi Haga ◽  
Tadao Matsunaga ◽  
Rong Zhang ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Nonhuman Primate ◽  
Drug Distribution ◽  
Gadopentetate Dimeglumine ◽  
Volume Of Distribution ◽  
T Test ◽  
Control Group ◽  
Blue Dye ◽  
Convection Enhanced Delivery ◽  
Resonance Frequencies

OBJECT Convection-enhanced delivery (CED) is an effective drug delivery method that delivers high concentrations of drugs directly into the targeted lesion beyond the blood-brain barrier. However, the drug distribution attained using CED has not satisfactorily covered the entire targeted lesion in tumors such as glioma. Recently, the efficacy of ultrasound assistance was reported for various drug delivery applications. The authors developed a new ultrasound-facilitated drug delivery (UFD) system that enables the application of ultrasound at the infusion site. The purpose of this study was to demonstrate the efficacy of the UFD system and to examine effective ultrasound profiles. METHODS The authors fabricated a steel bar-based device that generates ultrasound and enables infusion of the aqueous drug from one end of the bar. The volume of distribution (Vd) after infusion of 10 ml of 2% Evans blue dye (EBD) into rodent brain was tested with different frequencies and applied voltages: 252 kHz/30 V; 252 kHz/60 V; 524 kHz/13 V; 524 kHz/30 V; and 524 kHz/60 V. In addition, infusion of 5 mM gadopentetate dimeglumine (Gd-DTPA) was tested with 260 kHz/60 V, the distribution of which was evaluated using a 7-T MRI unit. In a nonhuman primate (Macaca fascicularis) study, 300 μl of 1 mM Gd-DTPA/EBD was infused. The final distribution was evaluated using MRI. Two-sample comparisons were made by Student t-test, and 1-way ANOVA was used for multiple comparisons. Significance was set at p < 0.05. RESULTS After infusion of 10 μl of EBD into the rat brain using the UFD system, the Vds of EBD in the UFD groups were significantly larger than those of the control group. When a frequency of 252 kHz was applied, the Vd of the group in which 60 V was applied was significantly larger than that of the group in which 30 V was used. When a frequency of 524 kHz was applied, the Vd tended to increase with application of a higher voltage; however, the differences were not significant (1-way ANOVA). The Vd of Gd-DTPA was also significantly larger in the UFD group than in the control group (p < 0.05, Student t-test). The volume of Gd-DTPA in the nonhuman primate used in this study was 1209.8 ± 193.6 mm3. This volume was much larger than that achieved by conventional CED (568.6 ± 141.0 mm3). CONCLUSIONS The UFD system facilitated the distribution of EBD and Gd-DTPA more effectively than conventional CED. Lower frequency and higher applied voltage using resonance frequencies might be more effective to enlarge the Vd. The UFD system may provide a new treatment approach for CNS disorders.

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