Research

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12 pages, 1615 KiB

Open AccessArticle

Real-Time Positron Emission Tomography Evaluation of Topotecan Brain Kinetics after Ultrasound-Mediated Blood–Brain Barrier Permeability

by Andrei Molotkov, Patrick Carberry, Martin A. Dolan, Simon Joseph, Sidney Idumonyi, Shunichi Oya, John Castrillon, Elisa E. Konofagou, Mikhail Doubrovin, Glenn J. Lesser, Francesca Zanderigo and Akiva Mintz

Pharmaceutics 2021, 13(3), 405; https://doi.org/10.3390/pharmaceutics13030405 - 18 Mar 2021

Cited by 7 | Viewed by 2581

Abstract

Glioblastoma (GBM) is the most common primary adult brain malignancy with an extremely poor prognosis and a median survival of fewer than two years. A key reason for this high mortality is that the blood–brain barrier (BBB) significantly restricts systemically delivered therapeutics to [...] Read more.

Glioblastoma (GBM) is the most common primary adult brain malignancy with an extremely poor prognosis and a median survival of fewer than two years. A key reason for this high mortality is that the blood–brain barrier (BBB) significantly restricts systemically delivered therapeutics to brain tumors. High-intensity focused ultrasound (HIFU) with microbubbles is a methodology being used in clinical trials to noninvasively permeabilize the BBB for systemic therapeutic delivery to GBM. Topotecan is a topoisomerase inhibitor used as a chemotherapeutic agent to treat ovarian and small cell lung cancer. Studies have suggested that topotecan can cross the BBB and can be used to treat brain metastases. However, pharmacokinetic data demonstrated that topotecan peak concentration in the brain extracellular fluid after systemic injection was ten times lower than in the blood, suggesting less than optimal BBB penetration by topotecan. We hypothesize that HIFU with microbubbles treatment can open the BBB and significantly increase topotecan concentration in the brain. We radiolabeled topotecan with ¹¹C and acquired static and dynamic positron emission tomography (PET) scans to quantify [¹¹C] topotecan uptake in the brains of normal mice and mice after HIFU treatment. We found that HIFU treatments significantly increased [¹¹C] topotecan brain uptake. Moreover, kinetic analysis of the [¹¹C] topotecan dynamic PET data demonstrated a substantial increase in [¹¹C] topotecan volume of distribution in the brain. Furthermore, we found a decrease in [¹¹C] topotecan brain clearance, confirming the potential of HIFU to aid in the delivery of topotecan through the BBB. This opens the potential clinical application of [¹¹C] topotecan as a tool to predict topotecan loco-regional brain concentration in patients with GBMs undergoing experimental HIFU treatments. Full article

(This article belongs to the Special Issue Drug Delivery to Brain Tumors)

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11 pages, 8426 KiB

Open AccessArticle

Utilizing Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) to Analyze Interstitial Fluid Flow and Transport in Glioblastoma and the Surrounding Parenchyma in Human Patients

by Krishnashis Chatterjee, Naciye Atay, Daniel Abler, Saloni Bhargava, Prativa Sahoo, Russell C. Rockne and Jennifer M. Munson

Pharmaceutics 2021, 13(2), 212; https://doi.org/10.3390/pharmaceutics13020212 - 04 Feb 2021

Cited by 11 | Viewed by 2897

Abstract

Background: Glioblastoma (GBM) is the deadliest and most common brain tumor in adults, with poor survival and response to aggressive therapy. Limited access of drugs to tumor cells is one reason for such grim clinical outcomes. A driving force for therapeutic delivery is [...] Read more.

Background: Glioblastoma (GBM) is the deadliest and most common brain tumor in adults, with poor survival and response to aggressive therapy. Limited access of drugs to tumor cells is one reason for such grim clinical outcomes. A driving force for therapeutic delivery is interstitial fluid flow (IFF), both within the tumor and in the surrounding brain parenchyma. However, convective and diffusive transport mechanisms are understudied. In this study, we examined the application of a novel image analysis method to measure fluid flow and diffusion in GBM patients. Methods: Here, we applied an imaging methodology that had been previously tested and validated in vitro, in silico, and in preclinical models of disease to archival patient data from the Ivy Glioblastoma Atlas Project (GAP) dataset. The analysis required the use of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), which is readily available in the database. The analysis results, which consisted of IFF flow velocity and diffusion coefficients, were then compared to patient outcomes such as survival. Results: We characterized IFF and diffusion patterns in patients. We found strong correlations between flow rates measured within tumors and in the surrounding parenchymal space, where we hypothesized that velocities would be higher. Analyzing overall magnitudes indicated a significant correlation with both age and survival in this patient cohort. Additionally, we found that neither tumor size nor resection significantly altered the velocity magnitude. Lastly, we mapped the flow pathways in patient tumors and found a variability in the degree of directionality that we hypothesize may lead to information concerning treatment, invasive spread, and progression in future studies. Conclusions: An analysis of standard DCE-MRI in patients with GBM offers more information regarding IFF and transport within and around the tumor, shows that IFF is still detected post-resection, and indicates that velocity magnitudes correlate with patient prognosis. Full article

(This article belongs to the Special Issue Drug Delivery to Brain Tumors)

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14 pages, 2691 KiB

Open AccessArticle

Non-Invasive Low Pulsed Electrical Fields for Inducing BBB Disruption in Mice—Feasibility Demonstration

by Shirley Sharabi, David Last, Dianne Daniels, Ido Didi Fabian, Dana Atrakchi, Yael Bresler, Sigal Liraz-Zaltsman, Itzik Cooper and Yael Mardor

Pharmaceutics 2021, 13(2), 169; https://doi.org/10.3390/pharmaceutics13020169 - 27 Jan 2021

Cited by 12 | Viewed by 1638

Abstract

The blood–brain barrier (BBB) is a major hurdle for the treatment of central nervous system disorders, limiting passage of both small and large therapeutic agents from the blood stream into the brain. Thus, means for inducing BBB disruption (BBBd) are urgently needed. Here, [...] Read more.

The blood–brain barrier (BBB) is a major hurdle for the treatment of central nervous system disorders, limiting passage of both small and large therapeutic agents from the blood stream into the brain. Thus, means for inducing BBB disruption (BBBd) are urgently needed. Here, we studied the application of low pulsed electrical fields (PEFs) for inducing BBBd in mice. Mice were treated by low PEFs using electrodes pressed against both sides of the skull (100–400 square 50 µs pulses at 4 Hz with different voltages). BBBd as a function of treatment parameters was evaluated using MRI-based treatment response assessment maps (TRAMs) and Evans blue extravasation. A 3D numerical model of the mouse brain and electrodes was constructed using finite element software, simulating the electric fields distribution in the brain and ensuring no significant temperature elevation. BBBd was demonstrated immediately after treatment and significant linear regressions were found between treatment parameters and the extent of BBBd. The maximal induced electric field in the mice brains, calculated by the numerical model, ranged between 62.4 and 187.2 V/cm for the minimal and maximal applied voltages. These results demonstrate the feasibility of inducing significant BBBd using non-invasive low PEFs, well below the threshold for electroporation. Full article

(This article belongs to the Special Issue Drug Delivery to Brain Tumors)

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15 pages, 2008 KiB

Open AccessArticle

Convection-Enhanced Delivery of a First-in-Class Anti-β1 Integrin Antibody for the Treatment of High-Grade Glioma Utilizing Real-Time Imaging

by Chibueze D. Nwagwu, Amanda V. Immidisetti, Gabriela Bukanowska, Michael A. Vogelbaum and Anne-Marie Carbonell

Pharmaceutics 2021, 13(1), 40; https://doi.org/10.3390/pharmaceutics13010040 - 30 Dec 2020

Cited by 21 | Viewed by 3088

Abstract

Introduction: OS2966 is a first-in-class, humanized and de-immunized monoclonal antibody which targets the adhesion receptor subunit, CD29/β1 integrin. CD29 expression is highly upregulated in glioblastoma and has been shown to drive tumor progression, invasion, and resistance to multiple modalities of therapy. Here, we [...] Read more.

Introduction: OS2966 is a first-in-class, humanized and de-immunized monoclonal antibody which targets the adhesion receptor subunit, CD29/β1 integrin. CD29 expression is highly upregulated in glioblastoma and has been shown to drive tumor progression, invasion, and resistance to multiple modalities of therapy. Here, we present a novel Phase I clinical trial design addressing several factors plaguing effective treatment of high-grade gliomas (HGG). Study Design: This 2-part, ascending-dose, Phase I clinical trial will enroll patients with recurrent/progressive HGG requiring a clinically indicated resection. In Study Part 1, patients will undergo stereotactic tumor biopsy followed by placement of a purpose-built catheter which will be used for the intratumoral, convection-enhanced delivery (CED) of OS2966. Gadolinium contrast will be added to OS2966 before each infusion, enabling the real-time visualization of therapeutic distribution via MRI. Subsequently, patients will undergo their clinically indicated tumor resection followed by CED of OS2966 to the surrounding tumor-infiltrated brain. Matched pre- and post-infusion tumor specimens will be utilized for biomarker development and validation of target engagement by receptor occupancy. Dose escalation will be achieved using a unique concentration-based accelerated titration design. Discussion: The present study design leverages multiple innovations including: (1) the latest CED technology, (2) 2-part design including neoadjuvant intratumoral administration, (3) a first-in-class investigational therapeutic, and (4) concentration-based dosing. Trial registration: A U.S. Food and Drug Administration (FDA) Investigational New Drug application (IND) for the above protocol is now active. Full article

(This article belongs to the Special Issue Drug Delivery to Brain Tumors)

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37 pages, 11998 KiB

Open AccessArticle

Determinants of Intraparenchymal Infusion Distributions: Modeling and Analyses of Human Glioblastoma Trials

by Martin Brady, Raghu Raghavan and John Sampson

Pharmaceutics 2020, 12(9), 895; https://doi.org/10.3390/pharmaceutics12090895 - 21 Sep 2020

Cited by 10 | Viewed by 2645

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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13 pages, 1272 KiB

Open AccessArticle

Controlled Catheter Movement Affects Dye Dispersal Volume in Agarose Gel Brain Phantoms

by Jason N. Mehta, Gabrielle R. McRoberts and Christopher G. Rylander

Pharmaceutics 2020, 12(8), 753; https://doi.org/10.3390/pharmaceutics12080753 - 11 Aug 2020

Cited by 8 | Viewed by 2889

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 (V_d), forward dispersal volume (V_df), infusion radius, backflow distance, and forward flow distance were quantified for each catheter movement protocol using optical images recorded throughout the experiment. V_d and V_df 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 V_d 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 V_d and shape of the infusion. Full article

(This article belongs to the Special Issue Drug Delivery to Brain Tumors)

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Review

Jump to: Research

16 pages, 1326 KiB

Open AccessReview

Convection Enhanced Delivery of Topotecan for Gliomas: A Single-Center Experience

by Pavan S. Upadhyayula, Eleonora F. Spinazzi, Michael G. Argenziano, Peter Canoll and Jeffrey N. Bruce

Pharmaceutics 2021, 13(1), 39; https://doi.org/10.3390/pharmaceutics13010039 - 30 Dec 2020

Cited by 9 | Viewed by 2879

Abstract

A key limitation to glioma treatment involves the blood brain barrier (BBB). Convection enhanced delivery (CED) is a technique that uses a catheter placed directly into the brain parenchyma to infuse treatments using a pressure gradient. In this manuscript, we describe the physical [...] Read more.

A key limitation to glioma treatment involves the blood brain barrier (BBB). Convection enhanced delivery (CED) is a technique that uses a catheter placed directly into the brain parenchyma to infuse treatments using a pressure gradient. In this manuscript, we describe the physical principles behind CED along with the common pitfalls and methods for optimizing convection. Finally, we highlight our institutional experience using topotecan CED for the treatment of malignant glioma. Full article

(This article belongs to the Special Issue Drug Delivery to Brain Tumors)

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15 pages, 2217 KiB

Open AccessReview

Focused Ultrasound and Microbubbles-Mediated Drug Delivery to Brain Tumor

by Sheng-Kai Wu, Chia-Lin Tsai, Yuexi Huang and Kullervo Hynynen

Pharmaceutics 2021, 13(1), 15; https://doi.org/10.3390/pharmaceutics13010015 - 24 Dec 2020

Cited by 43 | Viewed by 5362

Abstract

The presence of blood–brain barrier (BBB) and/or blood–brain–tumor barriers (BBTB) is one of the main obstacles to effectively deliver therapeutics to our central nervous system (CNS); hence, the outcomes following treatment of malignant brain tumors remain unsatisfactory. Although some approaches regarding BBB disruption [...] Read more.

The presence of blood–brain barrier (BBB) and/or blood–brain–tumor barriers (BBTB) is one of the main obstacles to effectively deliver therapeutics to our central nervous system (CNS); hence, the outcomes following treatment of malignant brain tumors remain unsatisfactory. Although some approaches regarding BBB disruption or drug modifications have been explored, none of them reach the criteria of success. Convention-enhanced delivery (CED) directly infuses drugs to the brain tumor and surrounding tumor infiltrating area over a long period of time using special catheters. Focused ultrasound (FUS) now provides a non-invasive method to achieve this goal via combining with systemically circulating microbubbles to locally enhance the vascular permeability. In this review, different approaches of delivering therapeutic agents to the brain tumors will be discussed as well as the characterization of BBB and BBTB. We also highlight the mechanism of FUS-induced BBB modulation and the current progress of this technology in both pre-clinical and clinical studies. Full article

(This article belongs to the Special Issue Drug Delivery to Brain Tumors)

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38 pages, 2626 KiB

Open AccessReview

Addressing BBB Heterogeneity: A New Paradigm for Drug Delivery to Brain Tumors

by Jessica I. Griffith, Sneha Rathi, Wenqiu Zhang, Wenjuan Zhang, Lester R. Drewes, Jann N. Sarkaria and William F. Elmquist

Pharmaceutics 2020, 12(12), 1205; https://doi.org/10.3390/pharmaceutics12121205 - 11 Dec 2020

Cited by 30 | Viewed by 5230

Abstract

Effective treatments for brain tumors remain one of the most urgent and unmet needs in modern oncology. This is due not only to the presence of the neurovascular unit/blood–brain barrier (NVU/BBB) but also to the heterogeneity of barrier alteration in the case of [...] Read more.

Effective treatments for brain tumors remain one of the most urgent and unmet needs in modern oncology. This is due not only to the presence of the neurovascular unit/blood–brain barrier (NVU/BBB) but also to the heterogeneity of barrier alteration in the case of brain tumors, which results in what is referred to as the blood–tumor barrier (BTB). Herein, we discuss this heterogeneity, how it contributes to the failure of novel pharmaceutical treatment strategies, and why a “whole brain” approach to the treatment of brain tumors might be beneficial. We discuss various methods by which these obstacles might be overcome and assess how these strategies are progressing in the clinic. We believe that by approaching brain tumor treatment from this perspective, a new paradigm for drug delivery to brain tumors might be established. Full article

(This article belongs to the Special Issue Drug Delivery to Brain Tumors)

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14 pages, 879 KiB

Open AccessReview

Pharmacokinetic Principles and Their Application to Central Nervous System Tumors

by Joelle P. Straehla and Katherine E. Warren

Pharmaceutics 2020, 12(10), 948; https://doi.org/10.3390/pharmaceutics12100948 - 06 Oct 2020

Cited by 10 | Viewed by 3464

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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15 pages, 1198 KiB

Open AccessReview

Convection Enhanced Delivery for Diffuse Intrinsic Pontine Glioma: Review of a Single Institution Experience

by Umberto Tosi and Mark Souweidane

Pharmaceutics 2020, 12(7), 660; https://doi.org/10.3390/pharmaceutics12070660 - 14 Jul 2020

Cited by 13 | Viewed by 7085

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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