Convection enhanced delivery of chemotherapeutic drugs into brain tumour

Zhan, Wenbo; Wang, Chi-Hwa

doi:10.1016/j.jconrel.2017.12.020

Cited by 69 publications

(41 citation statements)

References 70 publications

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“…Therefore, intratumoral drug delivery is a valid option for clinical therapy. CED circumvents the blood-brain barrier by providing direct access into the tumor while decreasing the risk of potential systemic side effects [28][29][30]. For this purpose, we use Alzet® mini-osmotic pumps which deliver the drug directly into the tumor using positive pressure, thus reaching the desired intratumoral dose.…”

Section: Discussionmentioning

confidence: 99%

Convection-enhanced delivery of temozolomide and whole cell tumor immunizations in GL261 and KR158 experimental mouse gliomas

et al. 2020

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Background: Glioblastomas (GBM) are therapy-resistant tumors with a profoundly immunosuppressive tumor microenvironment. Chemotherapy has shown limited efficacy against GBM. Systemic delivery of chemotherapeutic drugs is hampered by the difficulty of achieving intratumoral levels as systemic toxicity is a dose-limiting factor. Although some of its effects might be mediated by immune reactivity, systemic chemotherapy can also inhibit induced or spontaneous antitumor immune reactivity. Convection-enhanced delivery of temozolomide (CED-TMZ) can tentatively increase intratumoral drug concentration while reducing systemic side effects. The objective of this study was to evaluate the therapeutic effect of intratumorally delivered temozolomide in combination with immunotherapy and whether such therapy can generate a cellular antitumor immune response. Methods: Single bolus intratumoral injection and 3-day mini-osmotic pumps (Alzet®) were used to deliver intratumoral TMZ in C57BL6 mice bearing orthotopic gliomas. Immunotherapy consisted of subcutaneous injections of irradiated GL261 or KR158 glioma cells. Tumor size and intratumoral immune cell populations were analyzed by immunohistochemistry.Results: Combined CED-TMZ and immunotherapy had a synergistic antitumor effect in the GL261 model, compared to CED-TMZ or immunotherapy as monotherapies. In the KR158 model, immunization cured a small proportion of the mice whereas addition of CED-TMZ did not have a synergistic effect. However, CED-TMZ as monotherapy prolonged the median survival. Moreover, TMZ bolus injection in the GL261 model induced neurotoxicity and lower cure rate than its equivalent dose delivered by CED. In addition, we found that T-cells were the predominant cells responsible for the TMZ antitumor effect in the GL261 model. Finally, CED-TMZ combined with immunotherapy significantly reduced tumor volume and increased the intratumoral influx of T-cells in both models. Conclusions: We show that immunotherapy synergized with CED-TMZ in the GL261 model and cured animals in the KR158 model. Single bolus administration of TMZ was effective with a narrower therapeutic window than CED-TMZ. Combined CED-TMZ and immunotherapy led to an increase in the intratumoral influx of T-cells. These results form part of the basis for the translation of the therapy to patients with GBM but the dosing and timing of delivery will have to be explored in depth both experimentally and clinically.

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Section: Discussionmentioning

confidence: 99%

Convection-enhanced delivery of temozolomide and whole cell tumor immunizations in GL261 and KR158 experimental mouse gliomas

et al. 2020

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“…Both the brain tumour and its surrounding tissue can be briefly divided into the intracellular space (ICS), cell membrane (CM), and extracellular space (ECS). Governed by the mass conservation equation, the free doxorubicin concentration in the entire tissue (C F ) can be expressed in the form of [16,23]…”

Section: Direct Delivery Of Free Doxorubicinmentioning

confidence: 99%

Effects of Focused-Ultrasound-and-Microbubble-Induced Blood-Brain Barrier Disruption on Drug Transport under Liposome-Mediated Delivery in Brain Tumour: A Pilot Numerical Simulation Study

Zhan

2020

Pharmaceutics

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Focused ultrasound (FUS) coupled with microbubbles (MB) has been found to be a promising approach to disrupt the blood-brain barrier (BBB). However, how this disruption affects drug transport remains unclear. In this study, drug transport in combination therapy of liposomes and FUS-MB-induced BBB disruption (BBBD) was investigated based on a multiphysics model. A realistic 3D brain tumour model extracted from MR images was applied. The results demonstrated the advantage of liposomes compared to free doxorubicin injection in further improving treatment when the BBB is opened under the same delivery conditions using burst sonication. This improvement was mainly due to the BBBD-enhanced transvascular transport of free doxorubicin and the sustainable supply of the drug by long-circulating liposomes. Treatment efficacy can be improved in different ways. Disrupting the BBB simultaneously with liposome bolus injection enables more free drug molecules to cross the vessel wall, while prolonging the BBBD duration could accelerate liposome transvascular transport for more effective drug release. However, the drug release rate needs to be well controlled to balance the trade-off among drug release, transvascular exchange and elimination. The results obtained in this study could provide suggestions for the future optimisation of this FUS-MB–liposome combination therapy against brain cancer.

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“…These could provide a step change in the delivery of diagnostic sensors and therapies to the brain via flexible surgical access, with the potential for advancements in cancer therapy. In this context, the EDEN2020 project, which is supported by the European Commission Horizon 2020 programme (www.eden2020.eu), is developing a biologically inspired, nonholonomic steerable needle [15, 19], for application to Convection Enhanced drug Delivery (CED, [20, 23]). While the clinical efficacy of the system has yet to be established, full 3D steering without spin [2, 13, 16] during insertion, has already been demonstrated under laboratory conditions.…”

Section: Introductionmentioning

confidence: 99%

The Adaptive Hermite Fractal Tree (AHFT): a novel surgical 3D path planning approach with curvature and heading constraints

2019

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PurposeIn the context of minimally invasive neurosurgery, steerable needles such as the one developed within the Horizon2020-funded EDEN2020 project (Frasson et al. in Proc Inst Mech Eng Part H J Eng Med 224(6):775–88, 2010. 10.1243/09544119JEIM663; Secoli and y Baena in IEEE international conference on robotics and automation, 2013) aspire to address the clinical challenge of better treatment for cancer patients. The direct, precise infusion of drugs in the proximity of a tumor has been shown to enhance its effectiveness and diffusion in the surrounding tissue (Vogelbaum and Aghi in Neuro-Oncology 17(suppl 2):ii3–ii8, 2015. 10.1093/neuonc/nou354). However, planning for an appropriate insertion trajectory for needles such as the one proposed by EDEN2020 is challenging due to factors like kinematic constraints, the presence of complex anatomical structures such as brain vessels, and constraints on the required start and target poses.MethodsWe propose a new parallelizable three-dimensional (3D) path planning approach called Adaptive Hermite Fractal Tree (AHFT), which is able to generate 3D obstacle-free trajectories that satisfy curvature constraints given a specified start and target pose. The AHFT combines the Adaptive Fractal Tree algorithm’s efficiency (Liu et al. in IEEE Robot Autom Lett 1(2):601–608, 2016. 10.1109/LRA.2016.2528292) with optimized geometric Hermite (Yong and Cheng in Comput Aided Geom Des 21(3):281–301, 2004. 10.1016/j.cagd.2003.08.003) curves, which are able to handle heading constraints.ResultsSimulated results demonstrate the robustness of the AHFT to perturbations of the target position and target heading. Additionally, a simulated preoperative environment, where the surgeon is able to select a desired entry pose on the patient’s skull, confirms the ability of the method to generate multiple feasible trajectories for a patient-specific case.ConclusionsThe AHFT method can be adopted in any field of application where a 3D path planner with kinematic and heading constraints on both start and end poses is required.

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Convection enhanced delivery of chemotherapeutic drugs into brain tumour

Cited by 69 publications

References 70 publications

Convection-enhanced delivery of temozolomide and whole cell tumor immunizations in GL261 and KR158 experimental mouse gliomas

Convection-enhanced delivery of temozolomide and whole cell tumor immunizations in GL261 and KR158 experimental mouse gliomas

Effects of Focused-Ultrasound-and-Microbubble-Induced Blood-Brain Barrier Disruption on Drug Transport under Liposome-Mediated Delivery in Brain Tumour: A Pilot Numerical Simulation Study

The Adaptive Hermite Fractal Tree (AHFT): a novel surgical 3D path planning approach with curvature and heading constraints

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