Special Issue "Drug Delivery to Brain Tumors"

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Delivery and Controlled Release".

Deadline for manuscript submissions: closed (30 November 2020).

Special Issue Editors

Prof. Dr. Waldemar Debinski
Website
Guest Editor
Tom and Laura Hearn Professor for the Brain Tumor Center of Excellence, Department of Cancer Biology, Wake Forest University School of Medicine, Comprehensive Cancer Center of Wake Forest Baptist Medical Center, 1 Medical Center Boulevard, Winston-Salem, NC 27157, USA
Interests: bioimmunotherapy; tumor micro environment; CNS drug delivery
Prof. Dr. Michael Vogelbaum
Website
Guest Editor
Program Leader of NeuroOncology and Chief of Neurosurgery, Department of NeuroOncology, Moffitt Cancer Center, Tampa, Florida, USA
Interests: glioblastoma; glioma; brain metastasis; neurosurgical oncology; convection enhanced delivery; innovation

Special Issue Information

Dear Colleagues,

Clinical outcomes following treatment of primary malignant brain tumors are far from satisfactory. One of the main obstacles to the development of effective therapies is failure to achieve therapeutically relevant concentrations in the CNS due to the presence of blood–brain and/or blood–brain–tumor barriers. Some of the approaches explored to address this challenge include blood–brain barrier disruption and drug modifications to enhance CNS permeability; unfortunately, neither approach has proven successful. Another approach is to deliver therapeutics locoregionally, directly into the tumor mass and surrounding tumor-infiltrated brain parenchyma. The most widely used method for direct brain delivery is convection-enhanced delivery (CED), whereby specially designed catheters are introduced into target tissue and the infusate is delivered slowly over a prolonged period of time. CED enables delivery of conventional, nano-, bio-, gene, and even cellular therapies. This Special Issue provides a highlight of the most recent progress made to improve the efficacy of therapeutics delivered directly to brain tumors.

Prof. Dr. Waldemar Debinski
Prof. Dr. Michael Vogelbaum
Guest Editors

Manuscript Submission Information

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Keywords

  • brain tumors
  • blood–brain barrier (BBB)
  • convection-enhanced delivery (CED)
  • electric fields
  • high-intensity focused ultrasound (HIFU)
  • MRI monitoring
  • intraventricular and intrathecal delivery
  • drug formulation
  • preclinical models

Published Papers (4 papers)

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Research

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Open AccessArticle
Determinants of Intraparenchymal Infusion Distributions: Modeling and Analyses of Human Glioblastoma Trials
Pharmaceutics 2020, 12(9), 895; https://doi.org/10.3390/pharmaceutics12090895 - 21 Sep 2020
Abstract
Intra-parenchymal injection and delivery of therapeutic agents have been used in clinical trials for brain cancer and other neurodegenerative diseases. The complexity of transport pathways in tissue makes it difficult to envision therapeutic agent distribution from clinical MR images. Computer-assisted planning has been [...] Read more.
Intra-parenchymal injection and delivery of therapeutic agents have been used in clinical trials for brain cancer and other neurodegenerative diseases. The complexity of transport pathways in tissue makes it difficult to envision therapeutic agent distribution from clinical MR images. Computer-assisted planning has been proposed to mitigate risk for inadequate delivery through quantitative understanding of infusion characteristics. We present results from human studies and simulations of intratumoral infusions of immunotoxins in glioblastoma patients. Gd-DTPA and 124I-labeled human serum albumin (124I-HSA) were co-infused with the therapeutic, and their distributions measured in MRI and PET. Simulations were created by modeling tissue fluid mechanics and physiology and suggested that reduced distribution of tracer molecules within tumor is primarily related to elevated loss rates computed from DCE. PET-tracer on the other hand shows that the larger albumin molecule had longer but heterogeneous residence times within the tumor. We found over two orders of magnitude variation in distribution volumes for the same infusion volumes, with relative error ~20%, allowing understanding of even anomalous infusions. Modeling and measurement revealed that key determinants of flow include infusion-induced expansion and loss through compromised BBB. Opportunities are described to improve computer-assisted CED through iterative feedback between simulations and imaging. Full article
(This article belongs to the Special Issue Drug Delivery to Brain Tumors)
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Open AccessArticle
Controlled Catheter Movement Affects Dye Dispersal Volume in Agarose Gel Brain Phantoms
Pharmaceutics 2020, 12(8), 753; https://doi.org/10.3390/pharmaceutics12080753 - 11 Aug 2020
Abstract
The standard of care for treatment of glioblastoma results in a mean survival of only 12 to 15 months. Convection-enhanced delivery (CED) is an investigational therapy to treat glioblastoma that utilizes locoregional drug delivery via a small-caliber catheter placed into the brain parenchyma. [...] Read more.
The standard of care for treatment of glioblastoma results in a mean survival of only 12 to 15 months. Convection-enhanced delivery (CED) is an investigational therapy to treat glioblastoma that utilizes locoregional drug delivery via a small-caliber catheter placed into the brain parenchyma. Clinical trials have failed to reach their endpoints due to an inability of standard catheters to fully saturate the entire brain tumor and its margins. In this study, we examine the effects of controlled catheter movement on dye dispersal volume in agarose gel brain tissue phantoms. Four different catheter movement control protocols (stationary, continuous retraction, continuous insertion, and intermittent insertion) were applied for a single-port stepped catheter capable of intrainfusion movement. Infusions of indigo carmine dye into agarose gel brain tissue phantoms were conducted during the controlled catheter movement. The dispersal volume (Vd), forward dispersal volume (Vdf), infusion radius, backflow distance, and forward flow distance were quantified for each catheter movement protocol using optical images recorded throughout the experiment. Vd and Vdf for the retraction and intermittent insertion groups were significantly higher than the stationary group. The stationary group had a small but significantly larger infusion radius than either the retracting or the intermittent insertion groups. The stationary group had a greater backflow distance and lower forward flow distance than either the retraction or the intermittent insertion groups. Continuous retraction of catheters during CED treatments can result in larger Vd than traditional stationary catheters, which may be useful for improving the outcomes of CED treatment of glioblastoma. However, catheter design will be crucial in preventing backflow of infusate up the needle tract, which could significantly alter both the Vd and shape of the infusion. Full article
(This article belongs to the Special Issue Drug Delivery to Brain Tumors)
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Review

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Open AccessReview
Pharmacokinetic Principles and Their Application to Central Nervous System Tumors
Pharmaceutics 2020, 12(10), 948; https://doi.org/10.3390/pharmaceutics12100948 - 06 Oct 2020
Abstract
Despite increasing knowledge of the biologic drivers of central nervous system tumors, most targeted agents trialed to date have not shown activity against these tumors in clinical trials. To effectively treat central nervous system tumors, an active drug must achieve and maintain an [...] Read more.
Despite increasing knowledge of the biologic drivers of central nervous system tumors, most targeted agents trialed to date have not shown activity against these tumors in clinical trials. To effectively treat central nervous system tumors, an active drug must achieve and maintain an effective exposure at the tumor site for a long enough period of time to exert its intended effect. However, this is difficult to assess and achieve due to the constraints of drug delivery to the central nervous system. To address this complex problem, an understanding of pharmacokinetic principles is necessary. Pharmacokinetics is classically described as the quantitative study of drug absorption, distribution, metabolism, and elimination. The innate chemical properties of a drug, its administration (dose, route and schedule), and host factors all influence these four key pharmacokinetic phases. The central nervous system adds a level of complexity to standard plasma pharmacokinetics as it is a coupled drug compartment. This review will discuss special considerations of pharmacokinetics in the context of therapeutic development for central nervous system tumors. Full article
(This article belongs to the Special Issue Drug Delivery to Brain Tumors)
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Open AccessReview
Convection Enhanced Delivery for Diffuse Intrinsic Pontine Glioma: Review of a Single Institution Experience
Pharmaceutics 2020, 12(7), 660; https://doi.org/10.3390/pharmaceutics12070660 - 14 Jul 2020
Abstract
Diffuse intrinsic pontine gliomas (DIPGs) are a pontine subtype of diffuse midline gliomas (DMGs), primary central nervous system (CNS) tumors of childhood that carry a terrible prognosis. Because of the highly infiltrative growth pattern and the anatomical position, cytoreductive surgery is not an [...] Read more.
Diffuse intrinsic pontine gliomas (DIPGs) are a pontine subtype of diffuse midline gliomas (DMGs), primary central nervous system (CNS) tumors of childhood that carry a terrible prognosis. Because of the highly infiltrative growth pattern and the anatomical position, cytoreductive surgery is not an option. An initial response to radiation therapy is invariably followed by recurrence; mortality occurs approximately 11 months after diagnosis. The development of novel therapeutics with great preclinical promise has been hindered by the tightly regulated blood–brain barrier (BBB), which segregates the tumor comportment from the systemic circulation. One possible solution to this obstacle is the use of convection enhanced delivery (CED), a local delivery strategy that bypasses the BBB by direct infusion into the tumor through a small caliber cannula. We have recently shown CED to be safe in children with DIPG (NCT01502917). In this review, we discuss our experience with CED, its advantages, and technical advancements that are occurring in the field. We also highlight hurdles that will likely need to be overcome in demonstrating clinical benefit with this therapeutic strategy. Full article
(This article belongs to the Special Issue Drug Delivery to Brain Tumors)
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