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.

On the microstructural origin of brain white matter hydraulic permeability

2021 ◽  
Vol 118 (36) ◽  
pp. e2105328118
Author(s):  
Marco Vidotto ◽  
Andrea Bernardini ◽  
Marco Trovatelli ◽  
Elena De Momi ◽  
Daniele Dini
Keyword(s):  
White Matter ◽  
Corpus Callosum ◽  
Drug Transport ◽  
Three Dimensional ◽  
Principal Component ◽  
Hydraulic Permeability ◽  
Convection Enhanced Delivery ◽  
Brain White Matter ◽  
Significant Difference ◽  
The Brain

Brain microstructure plays a key role in driving the transport of drug molecules directly administered to the brain tissue, as in Convection-Enhanced Delivery procedures. The proposed research analyzes the hydraulic permeability of two white matter (WM) areas (corpus callosum and fornix) whose three-dimensional microstructure was reconstructed starting from the acquisition of electron microscopy images. We cut the two volumes with 20 equally spaced planes distributed along two perpendicular directions, and, on each plane, we computed the corresponding permeability vector. Then, we considered that the WM structure is mainly composed of elongated and parallel axons, and, using a principal component analysis, we defined two principal directions, parallel and perpendicular, with respect to the axons’ main direction. The latter were used to define a reference frame onto which the permeability vectors were projected to finally obtain the permeability along the parallel and perpendicular directions. The results show a statistically significant difference between parallel and perpendicular permeability, with a ratio of about two in both the WM structures analyzed, thus demonstrating their anisotropic behavior. Moreover, we find a significant difference between permeability in corpus callosum and fornix, which suggests that the WM heterogeneity should also be considered when modeling drug transport in the brain. Our findings, which demonstrate and quantify the anisotropic and heterogeneous character of the WM, represent a fundamental contribution not only for drug-delivery modeling, but also for shedding light on the interstitial transport mechanisms in the extracellular space.

Diagnosis and Treatment of Recurrent High-Grade Astrocytoma

2006 ◽  
Vol 24 (8) ◽  
pp. 1273-1280 ◽  
Author(s):  
Nicholas A. Butowski ◽  
Patricia K. Sneed ◽  
Susan M. Chang
Keyword(s):  
Imaging Techniques ◽  
Intensity Modulated Radiotherapy ◽  
Systemic Exposure ◽  
Clinical Trial Design ◽  
Cytotoxic Agents ◽  
Resonance Spectroscopy ◽  
High Grade ◽  
Convection Enhanced Delivery ◽  
Formidable Challenge ◽  
The Brain

High-grade gliomas represent a significant source of cancer-related death, and usually recur despite treatment. In this analysis of current brain tumor medicine, we review diagnosis, standard treatment, and emerging therapies for recurrent astrocytomas. Difficulties in interpreting radiographic evidence, especially with regard to differentiating between tumor and necrosis, present a formidable challenge. The most accurate diagnoses come from tissue confirmation of recurrent tumor, but a combination of imaging techniques, such as magnetic resonance spectroscopy imaging, may also be relevant for diagnosis. Repeat resection can prolong life, but repeat irradiation of the brain poses serious risks and results in necrosis of healthy brain tissue; therefore, reirradiation is usually not offered to patients with recurrent tumors. We describe the use of conventional radiotherapy, intensity-modulated radiotherapy, brachytherapy, radiosurgery, and photodynamic therapy for recurrent high-grade glioma. The use of chemotherapy is limited by drug distribution and toxicity, but the development of new drug-delivery techniques such as convection-enhanced delivery, which delivers therapeutic molecules at an effective concentration directly to the brain, may provide a way to reduce systemic exposure to cytotoxic agents. We also discuss targeted therapies designed to inhibit aberrant cell-signaling pathways, as well as new experimental therapies such as immunotherapy. The treatment of this devastating disease has so far been met with limited success, but emerging knowledge of neuroscience and the development of novel therapeutic agents will likely give patients new options and require the neuro-oncology community to redefine clinical trial design and strategy continually.

scholarly journals Understanding Drug Delivery to the Brain Using Liposome-Based Strategies: Studies that Provide Mechanistic Insights Are Essential

2021 ◽  
Vol 23 (6) ◽  
Author(s):  
Firda Juhairiyah ◽  
Elizabeth C. M. de Lange
Keyword(s):  
Drug Delivery ◽  
Drug Transport ◽  
Animal Studies ◽  
Time Course ◽  
Liposomal Formulation ◽  
Liposomal Drug ◽  
Brain Drug Delivery ◽  
Liposomal Formulations ◽  
The Impact ◽  
The Brain

AbstractBrain drug delivery may be restricted by the blood-brain barrier (BBB), and enhancement by liposome-based drug delivery strategies has been investigated. As access to the human brain is limited, many studies have been performed in experimental animals. Whereas providing interesting data, such studies have room for improvement to provide mechanistic insight into the rate and extent of specifically BBB transport and intrabrain distribution processes that all together govern CNS target delivery of the free drug. This review shortly summarizes BBB transport and current liposome-based strategies to overcome BBB transport restrictions, with the emphasis on how to determine the individual mechanisms that all together determine the time course of free drug brain concentrations, following their administration as such, and in liposomes. Animal studies using microdialysis providing time course information on unbound drug in plasma and brain are highlighted, as these provide the mechanistic information needed to understand BBB drug transport of the drug, and the impact of a liposomal formulations of that drug on BBB transport. Overall, these studies show that brain distribution of a drug administered as liposomal formulation depends on both drug properties and liposomal formulation characteristics. In general, evidence suggests that active transporters at the BBB, either being influx or efflux transporters, are circumvented by liposomes. It is concluded that liposomal formulations may provide interesting changes in BBB transport. More mechanistic studies are needed to understand relevant mechanisms in liposomal drug delivery to the brain, providing an improved basis for its prediction in human using animal data.

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

Designing and Testing of Backflow-Free Catheters

2011 ◽  
Vol 133 (6) ◽  
Author(s):  
O. Ivanchenko ◽  
V. Ivanchenko
Keyword(s):  
Porous Media ◽  
Hydraulic Conductivity ◽  
Flow Direction ◽  
Drug Distribution ◽  
Fluid Injection ◽  
Conductivity Anisotropy ◽  
Convection Enhanced Delivery ◽  
Delivery Technique ◽  
Catheter Design ◽  
The Impact

Convection-enhanced delivery (CED) is a drug delivery technique used to target specific regions of the central nervous system (CNS) for the treatment of neurodegenerative diseases and cancer while bypassing the blood–brain barrier (BBB). The application of CED is limited by low volumetric flow rate infusions in order to prevent the possibility of backflow. Consequently, a small convective flow produces poor drug distribution inside the treatment region, which can render CED treatment ineffective. Novel catheter designs and CED protocols are needed in order to improve the drug distribution inside the treatment region and prevent backflow. In order to develop novel backflow-free catheter designs, the impact of the micro-fluid injection into deformable porous media was investigated experimentally as well as numerically. Fluid injection into the porous media has a considerable effect on local transport properties such as porosity and hydraulic conductivity because of the local media deformation. These phenomena not only alter the bulk flow velocity distribution of the micro-fluid flow due to the changing porosity, but significantly modify the flow direction, and even the volumetric flow distribution, due to induced local hydraulic conductivity anisotropy. These findings help us to design backflow-free catheters with safe volumetric flow rates up to 10 μl/min. A first catheter design reduces porous media deformation in order to improve catheter performance and control an agent volumetric distribution. A second design prevents the backflow by reducing the porosity and hydraulic conductivity along a catheter’s shaft. A third synergistic catheter design is a combination of two previous designs. Novel channel-inducing and dual-action catheters, as well as a synergistic catheter, were successfully tested without the occurrence of backflow and are recommended for future animal experiments.

scholarly journals ELIMINATOR: Essentiality anaLysIs using MultIsystem Networks And inTeger prOgRamming

2021 ◽  
Author(s):  
Asier Antoranz ◽  
Maria Ortiz ◽  
Jon Pey
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
In Silico ◽  
Large Scale ◽  
Gene Knockout ◽  
Patient Specific ◽  
Gene Essentiality ◽  
Molecular Features ◽  
The Impact

A gene is considered as essential when it is indispensable for cells to grow and replicate under a certain environment. However, gene essentiality is not a structural property but rather a contextual one, which depends on the specific biological conditions affecting the cell. This circumstantial essentiality of genes is what brings the attention of scientist since we can identify genes essential for cancer cells but not essential for healthy cells. This same contextuality makes their identification extremely challenging. Huge experimental efforts such as Project Achilles where the essentiality of thousands of genes is measured in over one thousand cell lines together with a plethora of molecular data (transcriptomics, copy number, mutations, etc.) can shed light on the causality behind the essentiality of a gene in a given environment by associating the measured essentiality to molecular features of the cell line. Here, we present an in-silico method for the identification of patient-specific essential genes using constraint-based modelling (CBM). Our method expands the ideas behind traditional CBM to accommodate multisystem networks, that is a biological network that focuses on complex interactions within several biological systems. In essence, it first calculates the minimum number of non-expressed genes required to be active by the cell to sustain life as defined by a set of requirements; and second, it performs an exhaustive in-silico gene knockout to find those that lead to the need of activating extra non-expressed genes. We validated the proposed methodology using a set of 452 cancer cell lines derived from the Cancer Cell Line Encyclopedia where an exhaustive experimental large-scale gene knockout study using CRISPR (Achilles Project) evaluates the impact of each removal. We also show that the integration of different essentiality predictions per gene, what we called Essentiality Congruity Score, (derived from multiple pathways) reduces the number of false positives. Finally, we explored the gene essentiality predictions for a breast cancer patient dataset, and our results showed high concordance with previous publications. These findings suggest that identifying genes whose activity are fundamental to sustain cellular life in a patient-specific manner is feasible using in-silico methods. The patient-level gene essentiality predictions can pave the way for precision medicine by identifying potential drug targets whose deletion can induce death in tumour cells.

The Impact of Diagnostic MRI on the Early Detection of Lethal Genes in Human Genome and to Develop Genomic Medicine to Treat Brain Cancers

2021 ◽  
Vol 5 (6) ◽  
Author(s):  
Hameed Khan A
Keyword(s):  
Early Detection ◽  
Brain Cancer ◽  
Genomic Medicine ◽  
Three Dimensional ◽  
Good Health ◽  
Rational Approach ◽  
Chemotherapeutic Approach ◽  
The Impact ◽  
The Brain ◽  
Lethal Genes

Early detection of the onset of diseases are essential if we want to maintain good health. MRI technique provides a three-dimensional image of a microscopic lesion in an organ. Human body is made of 220 different tissues which interact to make an organ and several organs interact to make a human. As a part of medical record, taking MRI of each organ every year and comparing them with each other will identify the appearance of microscopic changes. For example, if you are diagnosed with Brain cancer today, you did not get the cancer yesterday. Abnormal changes are the result of accumulation of harmful mutations over the years predicting the onset of diseases. Once the brain tumor is confirmed, the patient dies within fourteen months. To save the life of the patient, the following three strategies are available and they are Surgery, Radiation and Chemotherapy. This article describes the Chemotherapeutic approach to treat cancers in general and brain cancer, Glioblastoma, in particular. Using rational approach, we designed AZQ (US Patent 4,146,622 & 4,233,215) to treat Glioblastomas. MRI Would identify appearance of microscopic lesions of Glioblastoma and help us start treatment with AZQ long before the disease is confirmed. Using similar rational approach of early diagnosis with MRI, we could design drugs to treat other diseases including cancers.

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.

scholarly journals Liposomal Formulations for Nose-to-Brain Delivery: Recent Advances and Future Perspectives

Pharmaceutics ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 540 ◽  
Author(s):  
Soon-Seok Hong ◽  
Kyung Taek Oh ◽  
Han-Gon Choi ◽  
Soo-Jeong Lim
Keyword(s):  
Drug Transport ◽  
Drug Carrier ◽  
Systemic Circulation ◽  
Direct Access ◽  
Comprehensive Overview ◽  
Transport Pathways ◽  
Therapeutic Compounds ◽  
Intranasal Drug Administration ◽  
The Impact ◽  
The Brain

Restricted drug entry to the brain that is closely associated with the existence of the blood brain barrier (BBB) has limited the accessibility of most potential active therapeutic compounds to the brain from the systemic circulation. Recently, evidences for the presence of direct nose-to-brain drug transport pathways have been accumulated by several studies and an intranasal drug administration route has gained attention as a promising way for providing direct access to the brain without the needs to cross to the BBB. Studies aiming for developing nanoparticles as an intranasal drug carrier have shown considerable promise in overcoming the challenges of intranasal drug delivery route. This review gives a comprehensive overview of works having investigated liposomes as a potential vehicle to deliver drugs to the brain through nose-to-brain route while considering the excellent biocompatibility and high potential of liposomes for clinical development. Herein, studies are reviewed with special emphasis on the impact of formulation factors, such as liposome composition and surface modification of liposomes with targeting moieties, in addition to intranasal environmental factors that may affect the extent/site of absorption of intranasally administered, liposome-encapsulated drugs.

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.

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