scholarly journals Treatment of Recurrent Glioblastoma by Chronic Convection-Enhanced Delivery of Topotecan

2021 ◽  
Author(s):  
Eleonora F. Spinazzi ◽  
Michael G. Argenziano ◽  
Pavan S. Upadhyayula ◽  
Matei A. Banu ◽  
Justin A. Neira ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Drug Distribution ◽  
Response Assessment ◽  
Recurrent Glioblastoma ◽  
Normal Brain ◽  
Convection Enhanced Delivery ◽  
Before And After ◽  
Treatment Response Assessment ◽  
Slow Cycling ◽  
Novel Drug

ABSTRACTGlioblastoma, the most common primary brain malignancy, is invariably fatal. Systemic chemotherapy is ineffective mostly because of drug delivery limitations. To overcome this, we devised an internalized pump-catheter system for direct chronic convection-enhanced delivery (CED) into peritumoral brain tissue. Topotecan (TPT) by chronic CED in 5 patients with refractory glioblastoma selectively eliminated tumor cells without toxicity to normal brain. Large, stable drug distribution volumes were non-invasively monitored with MRI of co-infused gadolinium. Analysis of multiple radiographically localized biopsies taken before and after treatment showed a decreased proliferative tumor signature resulting in a shift to a slow-cycling mesenchymal/astrocytic-like population. Tumor microenvironment analysis showed an inflammatory response and preservation of neurons. This novel drug delivery strategy and innovative clinical trial paradigm overcomes current limitations in delivery and treatment response assessment as shown here for glioblastoma and is potentially applicable for other anti-glioma agents as well as other CNS diseases.

scholarly journals CTNI-25. PHASE IB CLINICAL TRIAL OF CHRONIC CONVECTION-ENHANCED DELIVERY OF TOPOTECAN FOR RECURRENT GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii47-ii48
Author(s):  
Jeffrey Bruce ◽  
Eleonora Spinazzi ◽  
Andrew Lassman ◽  
Fabio Iwamoto ◽  
Mary Welch ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Drug Distribution ◽  
Recurrent Glioblastoma ◽  
Post Treatment ◽  
Large Animal ◽  
Normal Brain ◽  
Convection Enhanced Delivery ◽  
Phase Ib ◽  
Non Invasive ◽  
Cellular Analysis

Abstract OBJECTIVES Convection-enhanced delivery (CED) provides pharmacokinetic advantages over systemic delivery for achieving cytotoxic drug levels into targeted regions of the brain. A major shortcoming of CED has been the need to limit treatment duration because of infection risks associated with external pumps. We engineered a subcutaneously implanted catheter-pump construct for prolonged CED which was successfully tested in a large animal model and then approved by the FDA for a Phase Ib clinical trial with topotecan in patients with refractory glioblastoma (IND 131889). METHODS Five patients with recurrent glioblastoma underwent surgical implantation of a subcutaneous pump and catheter that infused intracerebral topotecan over 30 days. Gadolinium was co-infused as a surrogate tracer and advanced non-invasive radiographic imaging was used to monitor drug distribution and pharmacological effects. Tissue from multiple radiographically-localized regions of each tumor and surrounding brain was procured pre-treatment at the time of catheter implantation and then post-treatment when tumors were surgically resected. Tissue was used for drug level measurements and advanced molecular, genomic and cellular analysis of treatment effects. RESULTS Treatments were successfully completed in all five patients without significant complications. The safety and tolerability of treatment was validated by quality-of-life measures and neurological assessments. Noninvasive imaging demonstrated large and stable drug distribution volumes. Comprehensive tissue analysis demonstrated effective targeting of mitotically active tumor cells while sparing neurons. CONCLUSIONS We engineered a subcutaneously implanted catheter-pump construct for chronic CED that was successfully tested in a Phase Ib clinical trial with topotecan in recurrent glioblastoma patients. Analysis of pre- and post-treatment tissue showed significant anti-tumor activity from topotecan that was not harmful to normal brain. Chronic CED combined with non-invasive real time drug distribution monitoring provides a safe and effective glioma strategy suitable for clinical use.

Novel Drug Delivery System of Phytopharmaceuticals: A Review

2021 ◽  
Vol 07 ◽  
Author(s):  
Sumit Aroraa ◽  
Veerendra Dhoke ◽  
Keshav Moharir ◽  
Subhash Yende ◽  
Sapan Shah
Keyword(s):  
Drug Delivery ◽  
Drug Delivery Systems ◽  
Drug Distribution ◽  
Delivery Systems ◽  
Research Activity ◽  
Innovative Drug ◽  
Preparation Methods ◽  
Conventional Drug ◽  
Sites Of Action ◽  
Novel Drug

: Herbal extracts and isolated bioactives from plants have proven their therapeutic activities as evidenced by preclinical and clinical research. However, there seems some disconnect in their clinical utility as marked by lack of proper delivery mechanism at desired sites of action. This glitch nowadays is a task for global research activity and being addressed in the form of novel drug delivery systems. A steady progress is observed in integrating novel techniques of drug delivery with successful incorporation of phytochemicals marked by scores of advantages. Limitations of conventional drug delivery systems are overcome to considerable extent by innovative drug delivery methods which show improvement in targeted drug delivery, drug distribution, and protection of active substance, prolonged action and stability. The perspective of this review thus focuses on the progress in novel drug delivery systems with spotlight on nanocarriers for herbal active agents, their preparation methods with types, examples of active ingredients incorporated and biomedical applications.

Distribution kinetics of targeted cytotoxin in glioma by bolus or convection-enhanced delivery in a murine model

2004 ◽  
Vol 101 (6) ◽  
pp. 1004-1011 ◽  
Author(s):  
Koji Kawakami ◽  
Mariko Kawakami ◽  
Mitomu Kioi ◽  
Syed R. Husain ◽  
Raj K. Puri
Keyword(s):  
Nude Mice ◽  
Bolus Injection ◽  
Drug Distribution ◽  
Normal Brain ◽  
Convection Enhanced Delivery ◽  
Content Type ◽  
Interleukin 13 ◽  
Distribution Kinetics ◽  
Kinetics Of ◽  
Fine Print

Object. Interleukin-13 receptor (IL-13R)—targeted cytotoxin (IL-13—PE38) displays a potent antitumor activity against a variety of human tumors including glioblastoma multiforme (GBM) and, thus, this agent is being tested in the clinical trial for the treatment of recurrent GBM. In this study, the authors determined the safety and distribution kinetics of IL-13 cytotoxin when infused intracranially by a bolus injection and by convection-enhanced delivery (CED) in an athymic nude mouse model of GBM. Methods. For the safety studies, athymic nude mice were given intracranial infusions of IL-13 cytotoxin into normal parenchyma by either a bolus injection or a 7-day-long CED. Toxicity was assessed by performing a histological examination of the mouse brains. For the drug distribution studies, nude mice with intracranially implanted U251 GBM tumors were given an intratumor bolus or a CED infusion of IL-13 cytotoxin. Brain tumor samples obtained between 0.25 and 72 hours after the infusion were assessed for drug distribution kinetics by performing immunohistochemical and Western blot analyses. Based on the histological changes in the tumor and brain, the maximum tolerated dose of intracranial IL-13 cytotoxin infusion in nude mice was determined to be 4 µg when delivered by a bolus injection and 10 mg when CED was used. Drug distribution reached the maximum level 1 hour after the bolus injection and the volume of distribution was determined to be 19.3 ± 5.8 mm3. Interleukin-13 cytotoxin was barely detectable 6 hours after the injection. Interestingly, when delivered by bolus injections IL-13 cytotoxin exhibited superior distribution in larger rather than smaller tumors. Convection-enhanced delivery was superior for drug distribution in the U251 tumors because when CED was used the drug remained in the tumors 6 hours after the infusion. Conclusions. These studies provide confirmation of a previous hypothesis that CED of IL-13 cytotoxin is superior to bolus injections not only for the safety of the normal brain but also for maintaining drug levels for a prolonged period in infused brain tumors. These findings are highly relevant and important for the optimal clinical development of IL-13 cytotoxin or any other targeted antitumor agent for GBM therapy, in which multiple routes of delivery of an agent are being contemplated.

NIMG-75. ANALYZING THE INTERFACE BETWEEN MRI AND DRUG DISTRIBUTION USING ORTHOTOPIC GBM-DERIVED XENOGRAFT (PDX) MODELS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi146-vi146
Author(s):  
Sameer Channar ◽  
Sara Ranjbar ◽  
Pamela Jackson ◽  
Leland Hu ◽  
Michael Regan ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Cell Lines ◽  
Mean Squared Error ◽  
Drug Distribution ◽  
Normal Brain ◽  
Imaging Features ◽  
Visible Image ◽  
Drug Levels ◽  
Mri Features ◽  
Pdx Models

Abstract INTRODUCTION Glioblastoma (GBM) is a diffusely invasive primary brain tumor with significant spread of tumor cells to the periphery of visible image abnormality. Enhancement of Gadolinium (Gd) contrast agent on magnetic resonance imaging (MRI) has historically been considered a confirmation of local breakdown of the blood brain barrier (BBB) and sufficient drug delivery to the bulk of tumors. In this work, we used GBM-derived xenograft (PDX) models to compare drug delivery in GBM brain for high and low BBB-permeable drugs. MATERIALS AND METHODS Five patient-derived orthotopic xenograft models from two GBM cell lines (GBM39 and GBM12) were co-dosed with erlotinib and osimertinib, two drugs with low and high BBB-permeability, respectively. T1Gd and T2-weighted MRIs were acquired from all animals prior to model sacrifice. Tumors were manually segmented on denoised and standardized MRIs and intensity patterns were captured using first and second order statistical features in the moving 3x3 kernel. We compared drug levels found in Matrix Assisted Laser Desorption Ionization (MALDI) in T1Gd enhancement, T2 enhancement, and normal brain. We also performed linear regression modeling to predict drug levels using MRI features. Model performance was measured using root mean squared error (RMSE). RESULTS Our analysis showed correlations between imaging features and MALDI drug levels. Osimertinib had a uniform distribution across the brain for all animals and all cell lines, consistent with our expectation for a high BBB-penetrant drug. Erlotinib showed the highest drug levels in T2 for GBM39 and in T1Gd for GBM12. Regression models showed promising results for predicting Erlotinib with a low RMSE of 0.037. CONCLUSION Our preliminary results suggest MRI can be predictive of drug levels for low-BBB penetrant drugs. Understanding the relationship between MRIs and drug distribution in diffuse tumors can be beneficial to developing effective treatment.

scholarly journals Intraparenchymal ultrasound application and improved distribution of infusate with convection-enhanced delivery in rodent and nonhuman primate brain

2016 ◽  
Vol 124 (5) ◽  
pp. 1490-1500 ◽  
Author(s):  
Yui Mano ◽  
Ryuta Saito ◽  
Yoichi Haga ◽  
Tadao Matsunaga ◽  
Rong Zhang ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Nonhuman Primate ◽  
Drug Distribution ◽  
Gadopentetate Dimeglumine ◽  
Volume Of Distribution ◽  
T Test ◽  
Control Group ◽  
Blue Dye ◽  
Convection Enhanced Delivery ◽  
Resonance Frequencies

OBJECT Convection-enhanced delivery (CED) is an effective drug delivery method that delivers high concentrations of drugs directly into the targeted lesion beyond the blood-brain barrier. However, the drug distribution attained using CED has not satisfactorily covered the entire targeted lesion in tumors such as glioma. Recently, the efficacy of ultrasound assistance was reported for various drug delivery applications. The authors developed a new ultrasound-facilitated drug delivery (UFD) system that enables the application of ultrasound at the infusion site. The purpose of this study was to demonstrate the efficacy of the UFD system and to examine effective ultrasound profiles. METHODS The authors fabricated a steel bar-based device that generates ultrasound and enables infusion of the aqueous drug from one end of the bar. The volume of distribution (Vd) after infusion of 10 ml of 2% Evans blue dye (EBD) into rodent brain was tested with different frequencies and applied voltages: 252 kHz/30 V; 252 kHz/60 V; 524 kHz/13 V; 524 kHz/30 V; and 524 kHz/60 V. In addition, infusion of 5 mM gadopentetate dimeglumine (Gd-DTPA) was tested with 260 kHz/60 V, the distribution of which was evaluated using a 7-T MRI unit. In a nonhuman primate (Macaca fascicularis) study, 300 μl of 1 mM Gd-DTPA/EBD was infused. The final distribution was evaluated using MRI. Two-sample comparisons were made by Student t-test, and 1-way ANOVA was used for multiple comparisons. Significance was set at p < 0.05. RESULTS After infusion of 10 μl of EBD into the rat brain using the UFD system, the Vds of EBD in the UFD groups were significantly larger than those of the control group. When a frequency of 252 kHz was applied, the Vd of the group in which 60 V was applied was significantly larger than that of the group in which 30 V was used. When a frequency of 524 kHz was applied, the Vd tended to increase with application of a higher voltage; however, the differences were not significant (1-way ANOVA). The Vd of Gd-DTPA was also significantly larger in the UFD group than in the control group (p < 0.05, Student t-test). The volume of Gd-DTPA in the nonhuman primate used in this study was 1209.8 ± 193.6 mm3. This volume was much larger than that achieved by conventional CED (568.6 ± 141.0 mm3). CONCLUSIONS The UFD system facilitated the distribution of EBD and Gd-DTPA more effectively than conventional CED. Lower frequency and higher applied voltage using resonance frequencies might be more effective to enlarge the Vd. The UFD system may provide a new treatment approach for CNS disorders.

scholarly journals The distribution, clearance, and brainstem toxicity of panobinostat administered by convection-enhanced delivery

2018 ◽  
Vol 22 (3) ◽  
pp. 288-296 ◽  
Author(s):  
William G. B. Singleton ◽  
Alison S. Bienemann ◽  
Max Woolley ◽  
David Johnson ◽  
Owen Lewis ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Blood Brain Barrier ◽  
Gray Matter ◽  
Water Soluble ◽  
Brain Barrier ◽  
Large Animal ◽  
Normal Brain ◽  
Convection Enhanced Delivery ◽  
Blood Brain ◽  
Delivery Technique

OBJECTIVEThe pan–histone deacetylase inhibitor panobinostat has preclinical efficacy against diffuse intrinsic pontine glioma (DIPG), and the oral formulation has entered a Phase I clinical trial. However, panobinostat does not cross the blood-brain barrier in humans. Convection-enhanced delivery (CED) is a novel neurosurgical drug delivery technique that bypasses the blood-brain barrier and is of considerable clinical interest in the treatment of DIPG.METHODSThe authors investigated the toxicity, distribution, and clearance of a water-soluble formulation of panobinostat (MTX110) in a small- and large-animal model of CED. Juvenile male Wistar rats (n = 24) received panobinostat administered to the pons by CED at increasing concentrations and findings were compared to those in animals that received vehicle alone (n = 12). Clinical observation continued for 2 weeks. Animals were sacrificed at 72 hours or 2 weeks following treatment, and the brains were subjected to neuropathological analysis. A further 8 animals received panobinostat by CED to the striatum and were sacrificed 0, 2, 6, or 24 hours after infusion, and their brains explanted and snap-frozen. Tissue-drug concentration was determined by liquid chromatography tandem mass spectrometry (LC-MS/MS). Large-animal toxicity was investigated using a clinically relevant MRI-guided translational porcine model of CED in which a drug delivery system designed for humans was used. Panobinostat was administered at 30 μM to the ventral pons of 2 juvenile Large White–Landrace cross pigs. The animals were subjected to clinical and neuropathological analysis, and findings were compared to those obtained in controls after either 1 or 2 weeks. Drug distribution was determined by LC-MS/MS in porcine white and gray matter immediately after CED.RESULTSThere were no clinical or neuropathological signs of toxicity up to an infused concentration of 30 μM in both small- and large-animal models. The half-life of panobinostat in rat brain after CED was 2.9 hours, and the drug was observed to be distributed in porcine white and gray matter with a volume infusion/distribution ratio of 2 and 3, respectively.CONCLUSIONSCED of water-soluble panobinostat, up to a concentration of 30 μM, was not toxic and was distributed effectively in normal brain. CED of panobinostat warrants clinical investigation in patients with DIPG.

Poor drug distribution as a possible explanation for the results of the PRECISE trial

2010 ◽  
Vol 113 (2) ◽  
pp. 301-309 ◽  
Author(s):  
John H. Sampson ◽  
Gary Archer ◽  
Christoph Pedain ◽  
Eva Wembacher-Schröder ◽  
Manfred Westphal ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Drug Targets ◽  
Drug Distribution ◽  
Hazard Ratio ◽  
Phase Iii ◽  
Karnofsky Performance Scale ◽  
Convection Enhanced Delivery ◽  
Resection Cavity ◽  
Delivery Technique ◽  
Target Volumes

Object Convection-enhanced delivery (CED) is a novel intracerebral drug delivery technique with considerable promise for delivering therapeutic agents throughout the CNS. Despite this promise, Phase III clinical trials employing CED have failed to meet clinical end points. Although this may be due to inactive agents or a failure to rigorously validate drug targets, the authors have previously demonstrated that catheter positioning plays a major role in drug distribution using this technique. The purpose of the present work was to retrospectively analyze the expected drug distribution based on catheter positioning data available from the CED arm of the PRECISE trial. Methods Data on catheter positioning from all patients randomized to the CED arm of the PRECISE trial were available for analyses. BrainLAB iPlan Flow software was used to estimate the expected drug distribution. Results Only 49.8% of catheters met all positioning criteria. Still, catheter positioning score (hazard ratio 0.93, p = 0.043) and the number of optimally positioned catheters (hazard ratio 0.72, p = 0.038) had a significant effect on progression-free survival. Estimated coverage of relevant target volumes was low, however, with only 20.1% of the 2-cm penumbra surrounding the resection cavity covered on average. Although tumor location and resection cavity volume had no effect on coverage volume, estimations of drug delivery to relevant target volumes did correlate well with catheter score (p < 0.003), and optimally positioned catheters had larger coverage volumes (p < 0.002). Only overall survival (p = 0.006) was higher for investigators considered experienced after adjusting for patient age and Karnofsky Performance Scale score. Conclusions The potential efficacy of drugs delivered by CED may be severely constrained by ineffective delivery in many patients. Routine use of software algorithms and alternative catheter designs and infusion parameters may improve the efficacy of drugs delivered by CED.

scholarly journals NIMG-28. VALIDATION OF MODIFIED RESPONSE ASSESSMENT IN NEURO ONCOLOGY (mRANO) DETERMINED PFS AS A STRONG PREDICTOR OF OVERALL SURVIVAL IN RECURRENT GLIOBLASTOMA TREATED WITH A TARGETED IMMUNOTOXIN

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii153-ii153
Author(s):  
Benjamin Ellingson ◽  
Chandtip Chandhasin ◽  
Melissa Coello ◽  
Nina Merchant ◽  
Fahar Merchant
Keyword(s):  
Overall Survival ◽  
Strong Correlation ◽  
Strong Predictor ◽  
Response Assessment ◽  
Recurrent Glioblastoma ◽  
Convection Enhanced Delivery ◽  
Local Site ◽  
Weak Association ◽  
Immunotherapy Trial ◽  
Tumor Measurements

Abstract INTRODUCTION The current study compared the modified response assessment in neuro-oncology (mRANO)(1), iRANO (2), and standard RANO criteria (3) as well as quantified the association between progression-free (PFS) and overall survival (OS) in an immunotherapy trial in recurrent glioblastoma (rGBM). METHODS A total of 47 patients with rGBM were enrolled in a phase II convection-enhanced delivery of an IL4R-targeted immunotoxin (MDNA55-05, NCT02858895). Bidirectional tumor measurements were created by local sites and an independent radiologic faculty (IRF), then standard RANO, iRANO, and mRANO criteria were applied. Differences of PFS and the association between PFS and OS were evaluated. RESULTS 41 of 47 patients were evaluable for response. Both local site and IRF-determined PFS was significantly shorter using standard RANO compared to iRANO (log-rank, P&lt; 0.0001; HR=0.3) and mRANO (P&lt; 0.0001; HR=0.3). No difference in PFS was observed between iRANO and mRANO (Local, P=0.67; IRF, P=0.59). In patients who died and had confirmed progression on standard RANO, no correlation was observed between PFS and OS (Local, P=0.47; IRF, P=0.34). Using the iRANO, a weak association driven by a few outliers was observed between confirmed PFS and OS via local site measurements (P=0.017), but not central IRF measurements (P=0.18). Importantly, 24 of 41 patients (59%) were censored using iRANO and not included because they did not have confirmation of progression 3 months after initial progression. A strong correlation was observed between mRANO PFS and OS for both local (R2=0.66, P&lt; 0.0001) and IRF-determined reads (R2=0.57, P=0.0007). CONCLUSION No correlation between PFS and OS was observed for standard RANO or iRANO, but a strong correlation was identified between both locally-determined and centrally-determined PFS and OS using the mRANO criteria. Also, the iRANO criteria was difficult to implement due to need to confirm progression 3 months after initial progression, censoring more than half the patients.

scholarly journals PREPARATION AND EVALUATION OF CLARITHROMYCIN LOADED BISMUTH SULFIDE (Bi2S3) NANOPARTICLES UTILIZING NANOTECHNOLOGY AS A NOVEL DRUG DELIVERY SYSTEM

2017 ◽  
Vol 9 (9) ◽  
pp. 115 ◽  
Author(s):  
Mustafa R. Abdulbaqi
Keyword(s):  
Drug Delivery ◽  
Antibacterial Activity ◽  
In Vitro Release ◽  
Bismuth Sulfide ◽  
Particle Size Reduction ◽  
Before And After ◽  
Release Study ◽  
Novel Drug ◽  
Vitro Release

Objective: This study was designed to improve the solubility and biological activity of class II drug clarithromycin (CLA) by utilizing the nanotechnology as a novel drug delivery system.Methods: Bismuth sulfide (Bi2S3) nanoparticles were synthesized using chemical co-precipitation technique, while the loading of clarithromycin (CLA) with bismuth sulfide (Bi2S3) nanoparticles was achieved using incorporation method. The loading process, as well as particle size reduction, were evaluated using x-ray diffraction (XRD), furrier transformed infrared (FTIR) and atomic force microscopy (AFM). In vitro release study was performed using USP paddle apparatus type II in phosphate buffer solution pH 7.4. Disc diffusion method was the technique used to test the antibacterial activity of CLA before and after loading process.Results: Loading of CLA with Bi2S3 nanoparticles was accomplished successfully accompanied with particle size reduction within nano range as measured by AFM. In vitro release study showed a significant* increase in solubility and dissolution profile of CLA after loading process, which was also proven using XRD that indicate transformation from crystalline into more soluble amorphous structure. Susceptibility test displayed significant* potentiation of antibacterial activity at all tested concentrations against gram+ve bacteria Staphylococcus aureus and Bacillus subtilis after loading of CLA with Bi2S3 nanoparticles, while gram –ve bacteria E. coli showed no response for CLA before and after loading process.Conclusion: The solubility, as well as the antibacterial activity of CLA, were improved significantly* after preparation of nanotechnology based drug delivery system through the utilization of metal nanoparticles, Bi2S3, as nanocarriers for CLA.

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