Persistent GDNF Expression 45 Months after Putaminal Infusion of AAV2-GDNF in a Patient with Parkinson's Disease.

OBJECTIVE: Gene therapy by convection-enhanced delivery of type 2 adeno-associated virus-glial cell derived neurotrophic factor (AAV2-GDNF) to the bilateral putamina seeks to increase GDNF gene expression and treat Parkinson's disease (PD). METHODS: A 63-year-old man with advanced PD received AAV2-GDNF in a clinical trial. He died from pneumonia after anterior cervical discectomy and fusion 45 months later. An autopsy included brain examination for GDNF transgene expression. Putaminal catecholamine concentrations were compared to in vivo 18F-Fluorodopa (18F-FDOPA) positron emission tomography (PET) scanning results before and 18 months after AAV2-GDNF infusion. RESULTS: Parkinsonian progression stabilized clinically. Postmortem neuropathology confirmed PD. Bilateral putaminal regions previously infused with AAV2-GDNF expressed the GDNF gene. Total putaminal dopamine was 1% of control, confirming the striatal dopaminergic deficiency suggested by baseline 18F-DOPA-PET scanning. Putaminal regions responded as expected to AAV2-GDNF. CONCLUSION: After AAV2-GDNF infusion, infused putaminal regions showed increased GDNF gene expression, tyrosine hydroxylase immunoreactive sprouting, catechol levels, and 18F-FDOPA-PET signal, suggesting the regenerative potential of AAV2-GDNF in PD.

Adjuvant convection-enhanced delivery for the treatment of brain tumors.

BACKGROUND: Malignant gliomas are a therapeutic challenge and remain nearly uniformly fatal. While new targeted chemotherapeutic agentsagainst malignant glioma have been developed in vitro, these putative therapeutics have not been translated into successful clinical treatments. The lack of clinical effectiveness can be the result of ineffective biologic strategies, heterogeneous tumor targets and/or the result of poortherapeutic distribution to malignant glioma cells using conventional nervous system delivery modalities (intravascular, cerebrospinal fluid and/orpolymer implantation), and/or ineffective biologic strategies. METHODS: The authors performed a review of the literature for the terms "convection enhanced delivery", "glioblastoma", and "glioma". Selectclinical trials were summarized based on their various biological mechanisms and technological innovation, focusing on more recently publisheddata when possible. RESULTS: We describe the properties, features and landmark clinical trials associated with convection-enhanced delivery for malignant gliomas.We also discuss future trends that will be vital to CED innovation and improvement. CONCLUSION: Efficacy of CED for malignant glioma to date has been mixed, but improvements in technology and therapeutic agents arepromising.

Strategies to Improve Drug Delivery Across the Blood-Brain Barrier for Glioblastoma.

PURPOSE OF REVIEW: Glioblastoma remains resistant to most conventional treatments. Despite scientific advances in the past three decades, there has been a dearth of effective new treatments. New approaches to drug delivery and clinical trial design are needed. RECENT FINDINGS: We discuss how the blood-brain barrier and tumor microenvironment pose challenges for development of effective therapies for glioblastoma. Next, we discuss treatments in development that aim to overcome these barriers, including novel drug designs such as nanoparticles and antibody-drug conjugates, novel methods of drug delivery, including convection-enhanced and intra-arterial delivery, and novel methods to enhance drug penetration, such as blood-brain barrier disruption by focused ultrasound and laser interstitial thermal therapy. Lastly, we address future opportunities, positing combination therapy as the best strategy for effective treatment, neoadjuvant and window-of-opportunity approaches to simultaneously enhance therapeutic effectiveness with interrogation of on-treatment biologic endpoints, and adaptive platform and basket trials as imperative for future trial design. New approaches to GBM treatment should account for the blood-brain barrier and immunosuppression by improving drug delivery, combining treatments, and integrating novel clinical trial designs.

A Spatial Interpolation Approach to Assign Magnetic Resonance Imaging-Derived Material Properties for Finite Element Models of Adeno-Associated Virus Infusion Into a Recurrent Brain Tumor.

Adeno-associated virus (AAV) is a clinically useful gene delivery vehicle for treating neurological diseases. To deliver AAV to focal targets, direct infusion into brain tissue by convection-enhanced delivery (CED) is often needed due to AAV's limited penetration across the blood-brain-barrier and its low diffusivity in tissue. In this study, computational models that predict the spatial distribution of AAV in brain tissue during CED were developed to guide future placement of infusion catheters in recurrent brain tumors following primary tumor resection. The brain was modeled as a porous medium, and material property fields that account for magnetic resonance imaging (MRI)-derived anatomical regions were interpolated and directly assigned to an unstructured finite element mesh. By eliminating the need to mesh complex surfaces between fluid regions and tissue, mesh preparation was expedited, increasing the model's clinical feasibility. The infusion model predicted preferential fluid diversion into open fluid regions such as the ventricles and subarachnoid space (SAS). Additionally, a sensitivity analysis of AAV delivery demonstrated that improved AAV distribution in the tumor was achieved at higher tumor hydraulic conductivity or lower tumor porosity. Depending on the tumor infusion site, the AAV distribution covered 3.67-70.25% of the tumor volume (using a 10% AAV concentration threshold), demonstrating the model's potential to inform the selection of infusion sites for maximal tumor coverage.

On the microstructural origin of brain white matter hydraulic permeability.

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.

Intraparenchymal convection enhanced delivery of AAV in sheep to treat Mucopolysaccharidosis IIIC.

BACKGROUND: Mucopolysaccharidosis IIIC (MPSIIIC) is one of four Sanfilippo diseases sharing clinical symptoms of severe cognitive decline and shortened lifespan. The missing enzyme, heparan sulfate acetyl-CoA: α-glucosaminide-N-acetyltransferase (HGSNAT), is bound to the lysosomal membrane, therefore cannot cross the blood-brain barrier or diffuse between cells. We previously demonstrated disease correction in MPSIIIC mice using an Adeno-Associated Vector (AAV) delivering HGSNAT via intraparenchymal brain injections using an AAV2 derived AAV-truetype (AAV-TT) serotype with improved distribution over AAV9. METHODS: Here, intraparenchymal AAV was delivered in sheep using catheters or Hamilton syringes, placed using Brainlab cranial navigation for convection enhanced delivery, to reduce proximal vector expression and improve spread. RESULTS: Hamilton syringes gave improved AAV-GFP distribution, despite lower vector doses and titres. AAV-TT-GFP displayed moderately better transduction compared to AAV9-GFP but both serotypes almost exclusively transduced neurons. Functional HGSNAT enzyme was detected in 24-37% of a 140g gyrencephalic sheep brain using AAV9-HGSNAT with three injections in one hemisphere. CONCLUSIONS: Despite variabilities in volume and titre, catheter design may be critical for efficient brain delivery. These data help inform a clinical trial for MPSIIIC.

Intraputamenal Cerebral Dopamine Neurotrophic Factor in Parkinson's Disease: A Randomized, Double-Blind, Multicenter Phase 1 Trial.

BACKGROUND: Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor that protects dopamine neurons and improves motor function in animal models of Parkinson's disease (PD). OBJECTIVE: The primary objectives of this study were to assess the safety and tolerability of both CDNF and the drug delivery system (DDS) in patients with PD of moderate severity. METHODS: We assessed the safety and tolerability of monthly intraputamenal CDNF infusions in patients with PD using an investigational DDS, a bone-anchored transcutaneous port connected to four catheters. This phase 1 trial was divided into a placebo-controlled, double-blind, 6-month main study followed by an active-treatment 6-month extension. Eligible patients, aged 35 to 75 years, had moderate idiopathic PD for 5 to 15 years and Hoehn and Yahr score ≤ 3 (off state). Seventeen patients were randomized to placebo (n = 6), 0.4 mg CDNF (n = 6), or 1.2 mg CDNF (n = 5). The primary endpoints were safety and tolerability of CDNF and DDS and catheter implantation accuracy. Secondary endpoints were measures of PD symptoms, including Unified Parkinson's Disease Rating Scale, and DDS patency and port stability. Exploratory endpoints included motor symptom assessment (PKG, Global Kinetics Pty Ltd, Melbourne, Australia) and positron emission tomography using dopamine transporter radioligand [18 F]FE-PE2I. RESULTS: Drug-related adverse events were mild to moderate with no difference between placebo and treatment groups. No severe adverse events were associated with the drug, and device delivery accuracy met specification. The severe adverse events recorded were associated with the infusion procedure and did not reoccur after procedural modification. There were no significant changes between placebo and CDNF treatment groups in secondary endpoints between baseline and the end of the main and extension studies. CONCLUSIONS: Intraputamenally administered CDNF was safe and well tolerated, and possible signs of biological response to the drug were observed in individual patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Treatment of Orthotopic U251 Human Glioblastoma Multiforme Tumors in NRG Mice by Convection-Enhanced Delivery of Gold Nanoparticles Labeled with the ß-Particle-Emitting Radionuclide, 177Lu.

In this study, we investigated convection-enhanced delivery (CED) of 23 ± 3 nm gold nanoparticles (AuNPs) labeled with the ß-particle-emitting radionuclide 177Lu (177Lu-AuNPs) for treatment of orthotopic U251-Luc human glioblastoma multiforme (GBM) tumors in NRG mice. The cytotoxicity in vitro of 177Lu-AuNPs (0.0-2.0 MBq, 4 × 1011 AuNPs) on U251-Luc cells was also studied by a clonogenic survival assay, and DNA double-strand breaks (DSBs) caused by ß-particle emissions of 177Lu were measured by confocal immunofluorescence microscopy for γH2AX. NRG mice with U251-Luc tumors in the right cerebral hemisphere of the brain were treated by CED of 1.1 ± 0.2 MBq of 177Lu-AuNPs (4 × 1011 AuNPs). Control mice received unlabeled AuNPs or normal saline. Tumor retention of 177Lu-AuNPs was assessed by single-photon emission computed tomography/computed tomography (SPECT/CT) imaging and biodistribution studies. Radiation doses were estimated for the tumor, brain, and other organs. The effectiveness for treating GBM tumors was determined by bioluminescence imaging (BLI) and T2-weighted magnetic resonance imaging (MRI) and by Kaplan-Meier median survival. Normal tissue toxicity was assessed by monitoring body weight and hematology and blood biochemistry analyses at 14 d post-treatment. 177Lu-AuNPs (2.0 MBq, 4 × 1011 AuNPs) decreased the clonogenic survival of U251-Luc cells to 0.005 ± 0.002 and increased DNA DSBs by 14.3-fold compared to cells treated with unlabeled AuNPs or normal saline. A high proportion of 177Lu-AuNPs was retained in the U251-Luc tumor in NRG mice up to 21 d with minimal re-distribution to the brain or other organs. The radiation dose in the tumor was high (599 Gy). The dose in the normal right cerebral hemisphere of the brain excluding the tumor was 93-fold lower (6.4 Gy), and 2000-3000-fold lower doses were calculated for the contralateral left cerebral hemisphere (0.3 Gy) or cerebellum (0.2 Gy). The doses in peripheral organs were <0.1 Gy. BLI revealed almost complete tumor growth arrest in mice treated with 177Lu-AuNPs, while tumors grew rapidly in control mice. MRI at 28 d post-treatment and histological staining showed no visible tumor in mice treated with 177Lu-AuNPs but large GBM tumors in control mice. All control mice reached a humane endpoint requiring sacrifice within 39 d (normal saline) or 45 d post-treatment (unlabeled AuNPs), while 5/8 mice treated with 177Lu-AuNPs survived up to 150 d. No normal tissue toxicity was observed in mice treated with 177Lu-AuNPs. We conclude that CED of 177Lu-AuNPs was highly effective for treating U251-Luc human GBM tumors in the brain in NRG mice at amounts that were non-toxic to normal tissues. These 177Lu-AuNPs administered by CED hold promise for treating patients with GBM to prevent recurrence and improve long-term outcome.

Long-term safety of MRI-guided administration of AAV2-GDNF and gadoteridol in the putamen of individuals with Parkinson's disease.

Direct putaminal infusion of adeno-associated virus vector (serotype 2) (AAV2) containing the human glial cell line-derived neurotrophic factor (GDNF) transgene was studied in a phase I clinical trial of participants with advanced Parkinson's disease (PD). Convection-enhanced delivery of AAV2-GDNF with a surrogate imaging tracer (gadoteridol) was used to track infusate distribution during real-time intraoperative magnetic resonance imaging (iMRI). Pre-, intra-, and serial postoperative (up to 5 years after infusion) MRI were analyzed in 13 participants with PD treated with bilateral putaminal co-infusions (52 infusions in total) of AAV2-GDNF and gadoteridol (infusion volume, 450 mL per putamen). Real-time iMRI confirmed infusion cannula placement, anatomic quantification of volumetric perfusion within the putamen, and direct visualization of off-target leakage or cannula reflux (which permitted corresponding infusion rate/cannula adjustments). Serial post-treatment MRI assessment (n = 13) demonstrated no evidence of cerebral parenchyma toxicity in the corresponding regions of AAV2-GDNF and gadoteridol co-infusion or surrounding regions over long-term follow-up. Direct confirmation of key intraoperative safety and efficacy parameters underscores the safety and tissue targeting value of real-time imaging with co-infused gadoteridol and putative therapeutic agents (i.e., AAV2-GDNF). This delivery-imaging platform enhances safety, permits delivery personalization, improves therapeutic distribution, and facilitates assessment of efficacy and dosing effect.

Stereotactic and Functional Neurosurgery Convection-Enhanced Delivery of Autologous Cerebrospinal Fluid Enhances Basal Ganglia Visualization during MRI-Guided Deep Brain Stimulation Surgery.

INTRODUCTION: The aim of this study was to determine the safety and feasibility of convection-enhanced delivery of autologous cerebrospinal fluid (CSF) for enhancing intraoperative magnetic resonance imaging (MRI) of the basal ganglia during stereotactic neurosurgery. METHODS: This pilot study was conducted in 4 patients with Parkinson's disease (PD) who underwent MRI-guided deep brain stimulation of the globus pallidus internus (GPi). CSF was obtained via lumbar puncture after general anesthesia and prior to incision. A frameless stereotaxy system was installed, and an infusion catheter was inserted to the GPi using intraoperative MRI. Infusion of autologous CSF was performed at a convective rate of 5 µL/min with a maximum volume of infusion (Vi) of 500 mL. T2-weighted MRI scans were obtained every 15 min up to a maximum of 105 min in order to calculate the volume of distribution (Vd). Safety was assessed with adverse event monitoring, and clinical outcomes were measured with changes in unmedicated UPDRS part III and PDQ-39 scores from baseline to 6 months postoperatively. RESULTS: All four infusions were safe and without adverse events. The mean unmedicated UPDRS part III and PDQ-39 scores improved by 24% and 26%, respectively. The Vd:Vi ratio ranged from 2.2 to 2.8 and peaked 45 min from the onset of infusion, which is when the borders of the GPi could generally be visualized based on T2-weighted MRI. Two patients underwent refinement of the stereotactic targeting based on infusion-enhanced images. CONCLUSIONS: The convective administration of autologous CSF to deep brain structures appears safe and feasible for enhancing intraoperative MRI during stereotactic procedures. Infusion-enhanced imaging with target-specific infusates could be developed to visualize neurochemical circuits or cellular regions that currently are not seen with anatomic/structural MRI.

Malignant Glioma.

This chapter provides a comprehensive overview of malignant gliomas, the most common primary brain tumor in adults. These tumors are varied in their cellular origin, genetic profile, and morphology under the microscope, but together they share some of the most dismal prognoses of all neoplasms in the body. Although there is currently no cure for malignant glioma, persistent efforts to improve outcomes in patients with these tumors have led to modest increases in survival, and researchers worldwide continue to strive toward a deeper understanding of the factors that influence glioma development and response to treatment. In addition to well-established epidemiology, clinical manifestations, and common histopathologic and radiologic features of malignant gliomas, this section considers recent advances in molecular biology that have led to a more nuanced understanding of the genetic changes that characterize the different types of malignant glioma, as well as their implications for treatment. Beyond the traditional classification of malignant gliomas based on histopathological features, this chapter incorporates the World Health Organization's 2016 criteria for the classification of brain tumors, with special focus on disease-defining genetic alterations and newly established subcategories of malignant glioma that were previously unidentifiable based on microscopic examination alone. Traditional therapeutic modalities that form the cornerstone of treatment for malignant glioma, such as aggressive surgical resection followed by adjuvant chemotherapy and radiation therapy, and the studies that support their efficacy are reviewed in detail. This provides a foundation for additional discussion of novel therapeutic methods such as immunotherapy and convection-enhanced delivery, as well as new techniques for enhancing extent of resection such as fluorescence-guided surgery.

Local Delivery of Nimustine Hydrochloride against Brain Tumors: Basic Characterization Study.

Convection-enhanced delivery (CED) delivers agents directly into tumors and the surrounding parenchyma. Although a promising concept, clinical applications are often hampered by insufficient treatment efficacy. Toward developing an effective CED-based strategy for delivering drugs with proven clinical efficacy, we performed a basic characterization study to explore the locally delivered characteristics of the water soluble nitrosourea nimustine hydrochloride (ACNU). First, ACNU distribution after CED in rodent brain was studied using mass spectrometry imaging. Clearance of 14C-labeled ACNU after CED in striatum was also studied. ACNU was robustly distributed in rodent brain similar to the distribution of the hydrophilic dye Evans blue after CED, and locally delivered ACNU was observed for over 24 h at the delivery site. Subsequently, to investigate the potential of ACNU to induce an immunostimulative microenvironment, Fas and transforming growth factor-ß1 (TGF-ß1) was assessed in vitro. We found that ACNU significantly inhibited TGF-ß1 secretion and reduced Fas expression. Further, after CED of ACNU in 9L-derived intracranial tumors, the infiltration of CD4/CD8 lymphocytes in tumors was evaluated by immunofluorescence.CED of ACNU in xenografted intracranial tumors induced tumor infiltration of CD4/CD8 lymphocytes. ACNU has a robust distribution in rodent brain by CED, and delayed clearance of the drug was observed at the local infusion site. Further, local delivery of ACNU affects the tumor microenvironment and induces immune cell migration in tumor. These characteristics make ACNU a promising agent for CED.

Advances and Clinical Trials Update in the Treatment of Diffuse Intrinsic Pontine Gliomas.

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPGs) are high-grade gliomas (HGGs) that occur primarily in children, and represent a leading cause of death in pediatric patients with brain tumors with a median overall survival of only 8-11 months. SUMMARY: While these lesions were previously thought to behave similarly to adult HGG, emerging data have demonstrated that DIPG is a biologically distinct entity from adult HGG frequently driven by mutations in the histone genes H3.3 and H3.1 not found in adult glioma. While biopsy of DIPG was historically felt to confer unacceptable risk of morbidity and mortality, multiple studies have demonstrated that stereotactic biopsy of DIPG is safe, allowing not only for improved understanding of DIPG but also forming the basis for protocols for personalized medicine in DIPG. However, current options for personalized medicine in DIPG are limited by the lack of efficacious targeted therapies for the mutations commonly found in DIPG. Multiple treatment modalities including targeted therapies, immunotherapy, convection-enhanced delivery, and focused ultrasound are in various stages of investigation. KEY MESSAGE: Increasing frequency of biopsy for DIPG has identified distinct driving mutations that may serve as therapeutic targets. Novel treatment modalities are under investigation.

Infusion-related side-effects during convection enhanced delivery for brainstem-diffuse midline glioma/diffuse intrinsic pontine glioma.

INTRODUCTION: Side-effects during convection enhanced delivery (CED) are poorly understood. We intended to determine the frequency of side-effects during brain stem infusion and determine risk factors for side-effects persisting longer than 24 h. METHODS: Children with a radiological diagnosis of brain stem diffuse midline glioma/Diffuse Intrinsic Pontine Glioma were treated on compassionate grounds with awake infusion of carboplatin and sodium valproate into the brain stem using the 4-catheter (2 trans-cerebellar 2 trans-frontal) chronic, intermittent Renishaw Drug Delivery System. We used change in the Pontine Neurological Observation Score (PONScore), a standardised neurological assessment tool, to identify side-effects during infusion. Recovery was determined by retrospective chart review. RESULTS: 55 infusions were performed in 8 children (3-11 years). Mean PONScore increased during infusion from 3.3 to 5.7 (p-value > 0.001). One hundred and fifty-seven infusion-related side-effects were identified including headache (33/157) and limb weakness (49/157). Fifty-four side-effects persisted > 24 h. Side-effects that had occurred during a previous infusion and those that occurred during infusion via trans-cerebellar catheters were more likely to be persistent with OR 2.333 (95% CI 1.094-4.976; p-value = 0.028) and 2.155 (1.029-4.513; p-value = 0.042) respectively. If infusion was stopped or titrated at onset rather than continued, the side-effect was less likely to persist > 24 h, OR 0.473 (95% CI 0.177-0.948; p-value = 0.037). Most side-effects developed within the first three millilitre of infusion. CONCLUSIONS: Side-effects during brainstem infusion are common, can be transient or persist longer than 24 h. Neurological injury during infusion may be time dependent and accumulative rather than volume dependent.

Role of Tissue Hydraulic Permeability in Convection-Enhanced Delivery of Nanoparticle-Encapsulated Chemotherapy Drugs to Brain Tumour.

PURPOSE: Tissue hydraulic permeability of brain tumours can vary considerably depending on the tissue microstructure, compositions in interstitium and tumour cells. Its effects on drug transport and accumulation remain poorly understood. METHODS: Mathematical modelling is applied to predict the drug delivery outcomes in tumours with different tissue permeability upon convection-enhanced delivery. The modelling is based on a 3-D realistic tumour model that is extracted from patient magnetic resonance images. RESULTS: Modelling results show that infusing drugs into a permeable tumour can facilitate a more favourable hydraulic environment for drug transport. The infused drugs will exhibit a relatively uniform distribution and cover a larger tumour volume for effective cell killing. Cross-comparisons show the delivery outcomes are more sensitive to the changes in tissue hydraulic permeability and blood pressure than the fluid flow from the brain ventricle. Quantitative analyses demonstrate that increasing the fluid gain from both the blood and brain ventricle can further improve the interstitial fluid flow, and thereby enhance the delivery outcomes. Furthermore, similar responses to the changes in tissue hydraulic permeability can be found for different types of drugs. CONCLUSIONS: Tissue hydraulic permeability as an intrinsic property can influence drug accumulation and distribution. Results from this study can deepen the understanding of the interplays between drug and tissues that are involved in the drug delivery processes in chemotherapy.

Polymer nanocarriers for targeted local delivery of agents in treating brain tumors.

Glioblastoma (GBM), the deadliest brain cancer, presents a multitude of challenges to the development of new therapies. The standard of care has only changed marginally in the past 17 years, and few new chemotherapies have emerged to supplant or effectively combine with temozolomide. Concurrently, new technologies and techniques are being investigated to overcome the pharmacokinetic challenges associated with brain delivery, such as the blood brain barrier (BBB), tissue penetration, diffusion, and clearance in order to allow for potent agents to successful engage in tumor killing. Alternative delivery modalities such as focused ultrasound and convection enhanced delivery allow for the local disruption of the BBB, and the latter in particular has shown promise in achieving broad distribution of agents in the brain. Furthermore, the development of polymeric nanocarriers to encapsulate a variety of cargo, including small molecules, proteins, and nucleic acids, have allowed for formulations that protect and control the release of said cargo to extend its half-life. The combination of local delivery and nanocarriers presents an exciting opportunity to address the limitations of current chemotherapies for GBM toward the goal of improving safety and efficacy of treatment. However, much work remains to establish standard criteria for selection and implementation of these modalities before they can be widely implemented in the clinic. Ultimately, engineering principles and nanotechnology have opened the door to a new wave of research that may soon advance the stagnant state of GBM treatment development.

Convection-Enhanced Delivery in Children: Techniques and Applications.

Since its first description in 1994, convection-enhanced delivery (CED) has become a reliable method of administering drugs directly into the brain parenchyma. More predictable and effective than simple diffusion, CED bypasses the challenging boundary of the blood brain barrier, which has frustrated many attempts at delivering large molecules or polymers into the brain parenchyma. Although most of the clinical work with CED has been carried out on adults with incurable neoplasms, principally glioblastoma multiforme, an increasing number of studies have recognized its potential for paediatric applications, which now include treatment of currently incurable brain tumours such as diffuse intrinsic pontine glioma (DIPG), as well as metabolic and neurotransmitter diseases. The roadmap for the development of hardware and use of pharmacological agents in CED has been well-established, and some neurosurgical centres throughout the world have successfully undertaken clinical trials, admittedly mostly early phase, on the basis of in vitro, small animal and large animal pre-clinical foundations. However, the clinical efficacy of CED, although theoretically logical, has yet to be unequivocally demonstrated in a clinical trial; this applies particularly to neuro-oncology.This review aims to provide a broad description of the current knowledge of CED as applied to children. It reviews published studies of paediatric CED in the context of its wider history and developments and underlines the challenges related to the development of hardware, the selection of pharmacological agents, and gene therapy. It also reviews the difficulties related to the development of clinical trials involving CED and looks towards its potential disease-modifying opportunities in the future.

Constant Pressure Convection-Enhanced Delivery Increases Volume Dispersed With Catheter Movement in Agarose.

Convection-enhanced delivery (CED) has been extensively studied for drug delivery to the brain due to its inherent ability to bypass the blood-brain barrier. Unfortunately, CED has also been shown to inadequately distribute therapeutic agents over a large enough targeted tissue volume to be clinically beneficial. In this study, we explore the use of constant pressure infusions in addition to controlled catheter movement as a means to increase volume dispersed (Vd) in an agarose gel brain tissue phantom. Constant flow rate and constant pressure infusions were conducted with a stationary catheter, a catheter retracting at a rate of 0.25 mm/min, and a catheter retracting at a rate of 0.5 mm/min. The 0.25 mm/min and 0.5 mm/min retracting constant pressure catheters resulted in significantly larger Vd compared to any other group, with a 105% increase and a 155% increase compared to the stationary constant flow rate catheter, respectively. These same constant pressure retracting infusions resulted in a 42% and 45% increase in Vd compared to their constant flow rate counterparts. Using constant pressure infusions coupled with controlled catheter movement appears to have a beneficial effect on Vd in agarose gel. Furthermore, constant pressure infusions reveal the fundamental limitation of flow-driven infusions in both controlled catheter movement protocols as well as in stationary protocols where maximum infusion volume can never be reliably obtained.

Insights into Infusion-Based Targeted Drug Delivery in the Brain: Perspectives, Challenges and Opportunities.

Targeted drug delivery in the brain is instrumental in the treatment of lethal brain diseases, such as glioblastoma multiforme, the most aggressive primary central nervous system tumour in adults. Infusion-based drug delivery techniques, which directly administer to the tissue for local treatment, as in convection-enhanced delivery (CED), provide an important opportunity; however, poor understanding of the pressure-driven drug transport mechanisms in the brain has hindered its ultimate success in clinical applications. In this review, we focus on the biomechanical and biochemical aspects of infusion-based targeted drug delivery in the brain and look into the underlying molecular level mechanisms. We discuss recent advances and challenges in the complementary field of medical robotics and its use in targeted drug delivery in the brain. A critical overview of current research in these areas and their clinical implications is provided. This review delivers new ideas and perspectives for further studies of targeted drug delivery in the brain.

Convection-enhanced drug delivery for glioblastoma: a review.

INTRODUCTION: Convection-enhanced delivery (CED) is a method of targeted, local drug delivery to the central nervous system (CNS) that bypasses the blood-brain barrier (BBB) and permits the delivery of high-dose therapeutics to large volumes of interest while limiting associated systemic toxicities. Since its inception, CED has undergone considerable preclinical and clinical study as a safe method for treating glioblastoma (GBM). However, the heterogeneity of both, the surgical procedure and the mechanisms of action of the agents studied-combined with the additional costs of performing a trial evaluating CED-has limited the field's ability to adequately assess the durability of any potential anti-tumor responses. As a result, the long-term efficacy of the agents studied to date remains difficult to assess. MATERIALS AND METHODS: We searched PubMed using the phrase "convection-enhanced delivery and glioblastoma". The references of significant systematic reviews were also reviewed for additional sources. Articles focusing on physiological and physical mechanisms of CED were included as well as technological CED advances. RESULTS: We review the history and principles of CED, procedural advancements and characteristics, and outcomes from key clinical trials, as well as discuss the potential future of this promising technique for the treatment of GBM. CONCLUSION: While the long-term efficacy of the agents studied to date remains difficult to assess, CED remains a promising technique for the treatment of GBM.