Convection-enhanced Drug Delivery Research Articles

Effect of infusion direction on convection-enhanced drug delivery to anisotropic tissue.

Convection-enhanced delivery (CED) can effectively overcome the blood-brain barrier by infusing drugs directly into diseased sites in the brain using a catheter, but its clinical performance still needs to be improved. This is strongly related to the highly anisotropic characteristics of brain white matter, which results in difficulties in controlling drug transport and distribution in space. In this study, the potential to improve the delivery of six drugs by adjusting the placement of the infusion catheter is examined using a mathematical model and accurate numerical simulations that account simultaneously for the interstitial fluid (ISF) flow and drug transport processes in CED. The results demonstrate the ability of this direct infusion to enhance ISF flow and therefore facilitate drug transport. However, this enhancement is highly anisotropic, subject to the orientation of local axon bundles and is limited within a small region close to the infusion site. Drugs respond in different ways to infusion direction: the results of our simulations show that while some drugs are almost insensitive to infusion direction, this strongly affects other compounds in terms of isotropy of drug distribution from the catheter. These findings can serve as a reference for planning treatments using CED.

Convection-Enhanced Drug Delivery: Experimental and Analytical Studies of Infusion Behavior in an In Vitro Brain Surrogate.

Convection-enhanced drug delivery (CED) directly infuses drugs with a large molecular weight toward target cells as a therapeutic strategy for neurodegenerative diseases and brain cancers. Despite the success of many previous in vitro experiments on CED, challenges still remain. In particular, a theoretical predictive model is needed to form a basis for treatment planning, and developing such a model requires well-controlled injection tests that can rigorously capture the convective (advective) and diffusive transport of an infusate. For this purpose, we investigated the advection-diffusion transport of an infusate (bromophenol blue solution) in the brain surrogate (0.2% w/w agarose gel) at different injection rates, ranging from 0.25 to 4 μL/min, by closely monitoring changes in the color intensity, propagation distance, and injection pressures. One dimensional closed-form solution was examined with two variable sets, such as the mathematically calculated coefficient of molecular diffusion and average velocity, and the hydraulic dispersion coefficient and seepage velocity by the least squared method. As a result, the seepage velocity was greater than the average velocity to some extent, particularly for the later infusion times. The poroelastic deformation in the brain surrogate might lead to changes in porosity, and consequently, slight increases in the actual flow velocity as infusion continues. The limitation of efficiency of the single catheter was analyzed by dimensionless analysis. Lastly, this study suggests a simple but robust approach that can properly capture the convective (advective) and diffusive transport of an infusate in an in vitro brain surrogate via well-controlled injection tests.

Segmentation and structural connectivity of the Putamen for targeted Convection Enhanced Drug Delivery in Parkinson's Disease: A tractography-based approach

Segmentation and structural connectivity of the Putamen for targeted Convection Enhanced Drug Delivery in Parkinson's Disease: A tractography-based approach

Evaluating drug distribution in children and young adults with diffuse midline glioma of the pons (DIPG) treated with convection-enhanced drug delivery.

To determine an imaging protocol that can be used to assess the distribution of infusate in children with DIPG treated with CED. 13 children diagnosed with DIPG received between 3.8 and 5.7 ml of infusate, through two pairs of catheters to encompass tumor volume on day 1 of cycle one of treatment. Volumetric T2-weighted (T2W) and diffusion-weighted MRI imaging (DWI) were performed before and after day 1 of CED. Apparent diffusion coefficient (ADC) maps were calculated. The tumor volume pre and post CED was automatically segmented on T2W and ADC on the basis of signal intensity. The ADC maps pre and post infusion were aligned and subtracted to visualize the infusate distribution. There was a significant increase (p < 0.001) in mean ADC and T2W signal intensity (SI) ratio and a significant (p < 0.001) increase in mean tumor volume defined by ADC and T2W SI post infusion (mean ADC volume pre: 19.8 ml, post: 24.4 ml; mean T2W volume pre: 19.4 ml, post: 23.4 ml). A significant correlation (p < 0.001) between infusate volume and difference in ADC/T2W SI defined tumor volume was observed (ADC, r = 0.76; T2W, r = 0.70). Finally, pixel-by-pixel subtraction of the ADC maps pre and post infusion demonstrated a volume of high signal intensity, presumed infusate distribution. ADC and T2W MRI are proposed as a combined parameter method for evaluation of CED infusate distribution in brainstem tumors in future clinical trials.

Pore-scale experimental study on fluid injection into two-dimensional deformable porous media

Fluid injection into a deformable (or soft) porous medium often results in the deformation and/or displacement of hosting solids, which in return, influences the transport of injected fluid. This study presents a summary of recent pore-scale experimental efforts that attempted to advance our understanding on the hydro-mechanical coupling at the pore scale. Our experimental study examines the effects of various fluid flow conditions, including miscibility, viscosity, injection rate, as well as mechanical stiffness/compression on the fluid-driven deformation and concurrent fluid transport more comprehensively. We also introduce four particle-level pressure terms, the yield (Py), fracture (Pf), capillary entry (Pc), and viscous drag (Pv) pressures, as primary indicators to properly capture the observed regimes of fluid-driven deformation and fluid transport, in addition to the traditional capillary and mobility numbers. The collected test results reveal that the single-phase fluid flow causes the fluid-driven solid deformation only when Pv/max(Py, Pf) ≥ 10−2, and its prevalent shape is volumetric deformation around the injection port. The two-phase fluid flow renders a volumetric deformation pattern when 10−5 < Pv/max(Py, Pf) < 10−2 and 10−2 < Pc/max(Py, Pf). Whereas, it causes fracture-like solid deformation when Pv/max(Py, Pf) ≥ 10−2 and Pc/max(Py, Pf) ≥ 10−2. A complex transition from the volumetric to fracture-like deformation, and then to pore invasion (without any noticeable solid deformation) may occur in a single porous medium if the injected fluid is low viscous and the local effective stress is relatively small. Furthermore, the results reveal a good correlation between the maximum inlet pressure and the magnitude of fluid-driven deformation. Lastly, a comparison of fluid injection energy is provided for those different regimes of fluid-driven deformation and fluid transport. This study provides unique pore-scale experiment results on flow-induced deformation and suggests criteria based on dimensionless parameters with the particle-level pressures, which advances our understanding and prediction capability on hydro-mechanical behavior associated with fluid injection. The observations from this study have implications for many geological and biological systems that are associated with porous materials and fluid injection, including geologic carbon sequestration and convection-enhanced drug delivery.

Brain-Targeted Drug Delivery System: A Novel Approach

A targeted drug delivery system is based on a technique that continuously administers a predetermined dosage of a therapeutic agent to a sick location of the body. The targeted drug delivery goal is to raise the relative amount of the treatment in the target tissues while lowering it in the non-target tissues. This technique's intrinsic benefit has been reduced drug dose and adverse effects. Drug targeting in the brain is one of the most challenging issues in pharmaceutical research because the blood-brain barrier acts as an impermeable barrier for systemically delivered therapeutics and the brain extracellular matrix contributes to the poor distribution of locally delivered drugs. In the treatment of various Central nervous system (CNS) diseases, general approaches that can improve drug delivery to the brain are of great interest. Drugs are less harmful and more effective when they are administered close to where they would be most effective. Extreme research studies have recently concentrated on the development of fresh strategies for more successfully delivering medications to the brain in response to the shortcomings of the traditional delivery mechanism. This study thoroughly explains the obstacles involved in brain-targeted drug delivery, the process of drug transfer through Blood Brain Barrier, different techniques for brain-targeted drug delivery, and some recent breakthroughs in brain-targeted drug delivery.&#x0D; Keywords: Blood-brain barrier, Brain-targeted, Cerebrospinal fluid, Nanoparticles, Liposomes, Convection-enhanced drug delivery.

Intrinsically Disordered Protein Micelles as Vehicles for Convection-Enhanced Drug Delivery to Glioblastoma Multiforme.

Lipid and micelle-based nanocarriers have been explored for anticancer drug delivery to improve accumulation and uptake in tumor tissue. As an experimental opportunity in this area, our lab has developed a protein-based micelle nanocarrier consisting of a hydrophilic intrinsically disordered protein (IDP) domain bound to a hydrophobic tail, termed IDP-2Yx2A. This construct can be used to encapsulate hydrophobic chemotherapeutics that would otherwise be too insoluble in water to be administered. In this study, we evaluate the in vivo efficacy of IDP-2Yx2A by delivering a highly potent but water-insoluble cancer drug, SN38, into glioblastoma multiforme (GBM) tumors via convection-enhanced delivery (CED). The protein carriers alone are shown to elicit minimal toxicity effects in mice; furthermore, they can encapsulate and deliver concentrations of SN38 that would otherwise be lethal without the carriers. CED administration of these drug-loaded micelles into mice bearing U251-MG GBM xenografts resulted in slowed tumor growth and significant increases in median survival times compared to nonencapsulated SN38 and PBS controls.

DIPG-18. Evaluating drug distribution in children with diffuse intrinsic pontine glioma (DIPG) treated with convection-enhanced drug delivery

BACKGROUND: There is currently no method for evaluating drug distribution and tumour coverage using the convection-enhanced drug delivery (CED) technique in diffuse midline glioma of the pons (previous DIPG). AIMS: To determine an imaging protocol that can be used to assess the distribution of infusate in children with DIPG treated with CED of carboplatin and sodium valproate. METHODS: 12 children with DIPG received between 4–18ml of infusate, through 2 pairs of catheters to encompass tumour volume on 2 days. Volumetric T2W and Diffusion Weighted Imaging (DWI) MRI sequences were performed before and after the first cycle of CED therapy and Apparent Diffusion Coefficient (ADC) maps were calculated. The tumour volume pre and post CED was automatically segmented (ITKSnap) on T2W and ADC on the basis of signal intensity. The ADC maps pre and post infusion were registered and subtracted (FSL) to visualize the infusate distribution. RESULTS: ADC and T2W demonstrated a significant (<0.001) change in mean tumour volume post-infusion (mean ADC volume pre: 19.8ml, post 24.4ml; mean T2W volume pre 19.4ml, post 23.4ml). A significant correlation (p<0.001) was observed for the difference in tumour volume and the actual infused volume (ADC, r=0.76, T2W, r=0.70). There was a significant increase (p<0.001) in mean ADC and mean T2W signal intensity ratio post-infusion, no significant correlation with infusion volume. Finally, pixel-by-pixel subtraction of the ADC maps pre and post infusion visually demonstrated high signal intensity, presumed infusate coverage of the tumour. CONCLUSIONS: Our study provides the preliminary evidence that measurement of change in tumour ADC and T2W MR sequences, has a potential value for quantifying the distribution of infusate delivered by the intermittent CED, which will facilitate the use of CED in future clinical trials.

Cheyne–Stokes respiration in two sheep during recovery from general anaesthesia for experimental convection enhanced drug delivery

AbstractTwo 8‐month‐old Suffolk sheep, weighing 45 and 55 kg, respectively, were anaesthetised for an intrathalamic injection of an experimental drug. After an uneventful procedure and general anaesthesia using controlled mechanical ventilation, the sheep were weaned off the ventilator and allowed to breathe spontaneously with end‐tidal carbon dioxide (PE′CO2) levels remaining within normal limits. During recovery, intermittent apnoeic phases were observed with increasing PE′CO2 (&gt;70 mmHg) and decreasing oxygen saturation of haemoglobin (SpO2) levels (90%–91%). The sheep appeared unresponsive, and reflexes were absent. This alternated with phases of normal mentation, normal reflexes and regular spontaneous ventilation, where ventilatory parameters improved. Tentative treatment to reduce intracranial pressure and administration of the opioid receptor antagonist naloxone were unsuccessful. Definite diagnosis of Cheyne–Stokes respiration is difficult but was suspected in these two cases; cerebral cortex damage, intracranial haemorrhage or opioid mediated respiratory rhythm disturbances are possible causes.

CTNI-56. EVALUATING DRUG DISTRIBUTION IN CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) TREATED WITH CONVECTION ENHANCED DRUG DELIVERY

Abstract BACKGROUND There is currently no method for evaluating drug distribution and tumour coverage using the convection-enhanced drug delivery (CED) technique in Diffuse Intrinsic Pontine Glioma (DIPG). AIMS To determine an imaging protocol that can be used to assess the distribution of infusate in children with DIPG treated with CED of carboplatin and sodium valproate. METHODS 12 children with DIPG received between 4–18ml of infusate, through 2 pairs of catheters to encompass tumour volume on 2 days. Volumetric T2W and Diffusion Weighted Imaging (DWI) MRI sequences were performed before and after the first cycle of CED therapy and Apparent Diffusion Coefficient (ADC) maps were calculated. The tumour volume pre and post CED was automatically segmented (ITKSnap) on T2W and ADC on the basis of signal intensity. The ADC maps pre and post infusion were registered and subtracted (FSL) to visualize the infusate distribution. RESULTS ADC and T2W demonstrated a significant (&amp;lt; 0.001) change in mean tumour volume post-infusion (mean ADC volume pre: 19.8ml, post 24.4ml; mean T2W volume pre 19.4ml, post 23.4ml). A significant correlation (p&amp;lt; 0.001) was observed for the difference in tumour volume and the actual infused volume (ADC, r=0.76, T2W, r=0.70). There was a significant increase (p&amp;lt; 0.001) in mean ADC and mean T2W signal intensity ratio post-infusion, no significant correlation with infusion volume. Finally, pixel-by-pixel subtraction of the ADC maps pre and post infusion visually demonstrated high signal intensity, presumed infusate coverage of the tumour. CONCLUSIONS ADC and T2W MR sequences could potentially be used to evaluate the volume of distribution of infusate delivered by CED, paramount to ensure tumour coverage and leading to more effective therapy evaluation. This will facilitate the use of CED in future clinical trials.

Numerical analysis of a porous–elastic model for convection enhanced drug delivery

Convection enhanced drug delivery (CED) is a technique used to make therapeutic agents reach, through a catheter, sites of difficult access. The name of this technique comes from the convective flow originated by a pressure gradient induced at the tip of the catheter. This flow enhances passive diffusion and allows a more efficient spread of the agents by the target site. CED is particularly useful in the treatment of diseases that affect the central nervous system, where the blood–brain barrier prevents the diffusion of most therapeutic agents from the cerebral blood vessels to the brain interstitial space.In this work we deal with the numerical analysis of a coupled system of partial differential equations that can be used to simulate CED in an elastic medium like brain tissue. The model variables are the fluid velocity, the pressure, the tissue deformation, and the agents concentration. We prove the stability of the coupled problem and from the numerical point of view we propose a fully discrete piecewise linear finite element method (FEM). The convergence analysis shows that the method has second order convergence for the pressure, displacement, and concentration. Numerical experiments illustrating the theoretical convergence rates and the behavior of the system are also given.

Evaluation of a patient-specific algorithm for predicting distribution for convection-enhanced drug delivery into the brainstem of patients with diffuse intrinsic pontine glioma.

With increasing use of convection-enhanced delivery (CED) of drugs, the need for software that can predict infusion distribution has grown. In the context of a phase I clinical trial for pediatric diffuse intrinsic pontine glioma (DIPG), CED was used to administer an anti-B7H3 radiolabeled monoclonal antibody, iodine-124-labeled omburtamab. In this study, the authors retrospectively evaluated a software algorithm (iPlan Flow) for the estimation of infusate distribution based on the planned catheter trajectory, infusion parameters, and patient-specific MRI. The actual infusate distribution, as determined on MRI and PET imaging, was compared to the distribution estimated by the software algorithm. Similarity metrics were used to quantify the agreement between predicted and actual distributions. Ten pediatric patients treated at the same dose level in the NCT01502917 trial conducted at Memorial Sloan Kettering Cancer Center were considered for this retrospective analysis. T2-weighted MRI in combination with PET imaging was used to determine the distribution of infusate in this study. The software algorithm was applied for the generation of estimated fluid distribution maps. Similarity measures included object volumes, intersection volume, union volume, Dice coefficient, volume difference, and the center and average surface distances. Acceptable similarity was defined as a simulated distribution volume (Vd Sim) object that had a Dice coefficient higher than or equal to 0.7, a false-negative rate (FNR) lower than 50%, and a positive predictive value (PPV) higher than 50% compared to the actual Vd (Vd PET). Data for 10 patients with a mean infusion volume of 4.29 ml (range 3.84-4.48 ml) were available for software evaluation. The mean Vd Sim found to be covered by the actual PET distribution (PPV) was 77% ± 8%. The mean percentage of PET volume found to be outside the simulated volume (FNR) was 34% ± 10%. The mean Dice coefficient was 0.7 ± 0.05. In 8 out of 10 patients, the simulation algorithm fulfilled the combined acceptance criteria for similarity. iPlan Flow software can be useful to support planning of trajectories that produce intraparenchymal convection. The simulation algorithm is able to model the likely infusate distribution for a CED treatment in DIPG patients. The combination of trajectory planning guidelines and infusion simulation in the software can be used prospectively to optimize personalized CED treatment.

Convection-enhanced drug delivery for glioblastoma: a review

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. 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. 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. 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.

Successful Clinical Trial of Chronic Convection-Enhanced Drug Delivery Via an Implanted Pump

Successful Clinical Trial of Chronic Convection-Enhanced Drug Delivery Via an Implanted Pump

Adapting to Space Limitations During Prone Real-Time Magnetic Resonance Imaging-Guided Stereotaxic Laser Ablation: Technical Pearls.

New techniques of intraoperative magnetic resonance imaging (MRI)-guided stereotaxy enable minimally invasive approaches to intracranial pathology. Laser interstitial thermal therapy (LITT), convection-enhanced drug delivery, and stereotactic biopsy can be performed with a real-time confirmation of location and the ability to adjust for intracranial shift during the procedure. However, these procedures are constrained by patient positioning and the need for trajectories that avoid collision between stereotactic elements and the small MRI bore. To our knowledge, this is the first report to outline the technical details of safe intraoperative MRI (iMRI)-guided stereotaxy, performed with prone positioning. To present technical pearls to guide the safe conduction of iMRI-guided stereotaxy and LITT while in the prone position. The details of the positioning and trajectories for a series of patients who underwent Clearpoint® (MRI Interventions Inc) frameless real-time MRI-guided stereotaxis using a posterior approach were reviewed. In this series, 5 patients underwent selective amygdalohippocampectomy, and 2 underwent tumor biopsy/ablation while in the prone position without any complications. Prone iMRI procedures can be performed safely even in a 60-cm MRI bore.

New trial of convection enhanced drug delivery (CED) in DIPG- applying the SIOPe DIPG survival prediction model for power calculation.

Abstract Background In diffuse intrinsic pontine glioma (DIPG) drug resistance is in part due to inadequate penetration of blood-brain barrier (BBB) by systemically administered drugs. Convection-enhanced drug delivery (CED) techniques have been established to bypass BBB. Trial design to measure efficacy requires evidence to justify power calculation. Aims To apply SIOPe DIPG registry survival prediction tool to pilot cohort of children with DIPG treated with CED of carboplatin and sodium valproate. Methods Case note and imaging review of 9 children with typical DIPG on imaging who were treated on compassionate basis with CED intra-tumoural infusions of carboplatin (0.12 mg/ml) and sodium valproate (14.4 mg/ml), after radiotherapy (n=9) and chemotherapy (n=4). Each had Renishaw device placed with 4 micro-catheters located within tumour mass. Up to 8 treatment cycles of CED infusions delivered through 2 pairs of catheters on 2 days to encompass pontine tumour volume. Survival prediction was performed using clinical criteria: age, sex, duration of symptoms, prior chemotherapy; and radiological criteria: absence of distant metastases; disease involving more than 50% of, and confined to, pons, ring enhancement at diagnosis. Results Cases were categorized as intermediate or high-risk using SIOPe risk scoring with predicted median overall survival (OS) of 9.7, and 7.0 months, respectively. Four patients, categorized as high-risk, had median overall survival (OS) of 14.2 months. Five children, categorized as standard-risk, had median OS of 16.0 months. Conclusions Results justify a phase 2 trial of CED carboplatin and sodium valproate powered to detect at least 4-month prolongation of survival.

Convection-enhanced Drug Delivery for Glioblastoma: A Systematic Review Focused on Methodological Differences in the Use of the Convection-enhanced Delivery Method.

Glioblastoma (GBM) is a leading cause of brain cancer-related death. The blood–brain barrier (BBB) prevents the transport of most systemic delivered molecules to the brain. This constitutes a major problem in the therapy of brain tumors. In the last decade, numerous different drug-delivery approaches have been developed to overcome the BBB. The objective of this study is to provide an overview of the methodological aspects used in all preclinical and clinical studies published from 2011 to 2016 where convection-enhanced delivery (CED) was used for drug delivery in the treatment of GBM. A systematic review of English articles published in the past 5 years was undertaken using PubMed and Embase. The search terms (brain tumor [MeSH Terms]) AND (CED OR convection enhanced delivery) were used in PubMed and a similar search was carried out in Embase using their “multi-field search.” All studies using CED on an intracranial GBM model were included. The search resulted in 151 hits after duplicates were removed. In total, 30 studies were included in the review. Of these, two publications studied the technical aspects of the CED method. Furthermore, only one study was a clinical study. The research field is focused on preclinical drug development trials and less emphasis is placed on the CED technique itself. However, it is important that future studies focus on establishing optimal protocols for the use of CED in rodents as well as for big brain models to be able to use the CED method in patients with GBM.

Improving the Predictions of Computational Models of Convection-Enhanced Drug Delivery by Accounting for Diffusion Non-gaussianity.

Convection-enhanced delivery (CED) is an innovative method of drug delivery to the human brain, that bypasses the blood-brain barrier by injecting the drug directly into the brain. CED aims to target pathological tissue for central nervous system conditions such as Parkinson's and Huntington's disease, epilepsy, brain tumors, and ischemic stroke. Computational fluid dynamics models have been constructed to predict the drug distribution in CED, allowing clinicians advance planning of the procedure. These models require patient-specific information about the microstructure of the brain tissue, which can be collected non-invasively using magnetic resonance imaging (MRI) pre-infusion. Existing models employ the diffusion tensor, which represents Gaussian diffusion in brain tissue, to provide predictions for the drug concentration. However, those predictions are not always in agreement with experimental observations. In this work we present a novel computational fluid dynamics model for CED that does not use the diffusion tensor, but rather the diffusion probability that is experimentally measured through diffusion MRI, at an individual-participant level. Our model takes into account effects of the brain microstructure on the motion of drug molecules not taken into account in previous approaches, namely the restriction and hindrance that those molecules experience when moving in the brain tissue, and can improve the drug concentration predictions. The duration of the associated MRI protocol is 19 min, and therefore feasible for clinical populations. We first prove theoretically that the two models predict different drug distributions. Then, using in vivo high-resolution diffusion MRI data from a healthy participant, we derive and compare predictions using both models, in order to identify the impact of including the effects of restriction and hindrance. Including those effects results in different drug distributions, and the observed differences exhibit statistically significant correlations with measures of diffusion non-Gaussianity in brain tissue. The differences are more pronounced for infusion in white-matter areas of the brain. Using experimental results from the literature along with our simulation results, we show that the inclusion of the effects of diffusion non-Gaussianity in models of CED is necessary, if reliable predictions that can be used in the clinic are to be generated by CED models.

Evaluation of Three Morphologically Distinct Virus-Like Particles as Nanocarriers for Convection-Enhanced Drug Delivery to Glioblastoma.

Glioblastoma is a particularly challenging cancer, as there are currently limited options for treatment. New delivery routes are being explored, including direct intratumoral injection via convection-enhanced delivery (CED). While promising, convection-enhanced delivery of traditional chemotherapeutics such as doxorubicin (DOX) has seen limited success. Several studies have demonstrated that attaching a drug to polymeric nanoscale materials can improve drug delivery efficacy via CED. We therefore set out to evaluate a panel of morphologically distinct protein nanoparticles for their potential as CED drug delivery vehicles for glioblastoma treatment. The panel consisted of three different virus-like particles (VLPs), MS2 spheres, tobacco mosaic virus (TMV) disks and nanophage filamentous rods modified with DOX. While all three VLPs displayed adequate drug delivery and cell uptake in vitro, increased survival rates were only observed for glioma-bearing mice that were treated via CED with TMV disks and MS2 spheres conjugated to doxorubicin, with TMV-treated mice showing the best response. Importantly, these improved survival rates were observed after only a single VLP–DOX CED injection several orders of magnitude smaller than traditional IV doses. Overall, this study underscores the potential of nanoscale chemotherapeutic CED using virus-like particles and illustrates the need for further studies into how the overall morphology of VLPs influences their drug delivery properties.

340 Convection-Enhanced Delivery of Macromolecules to the Brain Using Electrokinetic Transport

Electrokinetic transport in brain tissue represents the movement of molecules due to an applied electric field and the interplay between the electrophoretic and electroosmotic velocities that are developed. This dissertation provides a framework for understanding electrokinetic transport and how it may be utilized for short-distance ejections, relevant to capillary iontophoresis, and long-distance infusions, for the clinical management of malignant brain tumors as a novel convection-enhanced drug delivery system.In particular, electrokinetic transport was first analyzed in a series of poly(acrylamide-co-acrylic acid) hydrogels that demonstrated varying electroosmotic velocities. Moreover, a hydrogel was synthesized to mimic the electrokinetic properties of organotypic hippocampal slice cultures (OHSC), as a surrogate for brain tissue. Short- and long-distance capillary infusions of molecules into the hydrogels and OHSC provided a framework to understand the relevant phenomena, such as the effect of varying the capillary tip size, applied electrical current, ζ-potential of the capillary or the outside matrix, infusion time, tortuosity, and properties of the solute (including molecular weight and electrophoretic mobility). Control of the directional transport of molecules was also demonstrated over a distance of several hundred micrometers to millimeters. Finally, electrokinetic infusions were conducted in vivo in the adult rat brain, with results compared to those of pressure-driven infusions.The experiments and results described in this dissertation provide a foundation for further development, by presenting a methodical means to increase the ejection profile and attain clinically relevant penetration distances while minimizing adverse effects to the brain tissue, including from the electric field itself. The rate of electrokinetic transport is greater than the rate of diffusion, and therefore it represents a novel form of convection-enhanced drug delivery system.