EXTH-25. A MECHANICALLY-ENGINEERED SPRAY TO INCREASE BRAIN PENETRATION OF CHEMOTHERAPEUTIC NANOPARTICLES IN THE TREATMENT OF HIGH GRADE GLIOMAS

Abstract Design and implementation of innovative local drug delivery systems (DDS) may overcome current limitations in GBM treatment, such as the lack of therapeutic drug concentrations reaching residual GBM cells following surgery. Here we describe a novel DDS which utilises a bespoke mechanically engineered spray device, designed for safe surgical use, to deliver a mucoadhesive hydrogel containing chemotherapeutic nanoparticles (NPs) into the tumour resection margins. The overall aim is to spray a NP and polymer solution onto the resection cavity and potentially increase penetration of anti-cancer drugs within the 2 cm reoccurrence zone beyond the infiltrative margin. The mucoadhesive gel of choice, pectin, is currently used in other in vivo applications; however we have repurposed this for the brain. Pectin is biocompatible with GBM and human astrocyte cells in vitro and showed neither toxicity nor inflammation for up to 2 weeks upon orthotopic brain injection. Pectin is biodegradable in artificial CSF and is capable of being sprayed from the engineered device. A panel of polymeric, oil-based and polymer-coated NPs have been developed and optimised to maximise drug encapsulation of etoposide and olaparib as proof-of-concept for combination drug delivery. Etoposide/olaparib were chosen due to cytotoxicity from 5 GBM cell lines, including primary lines isolated from the invasive tumour margin (Mean IC50 of 1.1 µM and 8.3 µM respectively). The optimal NP/drug formulation (based on drug encapsulation, spray capability and bio-adhesiveness) will ultimately be assessed for tolerability and efficacy using orthotopic allograft and xenograft high-grade glioma models, including measurement of penetration of drug/nanoparticle in ex vivo murine and porcine brain using novel hybrid time-of-flight/Orbitrap TM secondary ion mass spectrometer (orbiSIMS) technology.

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A mechanically-engineered spray to increase brain penetration of chemotherapeutic nanoparticles in the treatment of high-grade gliomas

Neuro-Oncology ◽

10.1093/neuonc/noz167.002 ◽

2019 ◽

Vol 21 (Supplement_4) ◽

pp. iv1-iv1

Author(s):

Phoebe McCrorie ◽

Vincenco Taresco ◽

Zeyuan Xu ◽

Alison Ritchie ◽

Phillip Clarke ◽

...

Keyword(s):

Drug Delivery ◽

Drug Formulation ◽

Local Drug Delivery ◽

Resection Margins ◽

Therapeutic Drug ◽

Tumour Resection ◽

High Grade ◽

Combination Drug ◽

Drug Encapsulation ◽

Drug Concentrations

Abstract Design and implementation of innovative local drug delivery systems (DDS) may overcome current limitations in GBM treatment, such as the lack of therapeutic drug concentrations reaching residual GBM cells following surgery. Here we describe a novel DDS which utilises a bespoke mechanically engineered spray device, designed for safe surgical use, to deliver a mucoadhesive hydrogel containing chemotherapeutic nanoparticles (NPs) into the tumour resection margins. The overall aim is to spray a NP and polymer solution onto the resection cavity and potentially increase penetration of anti-cancer drugs within the 2 cm reoccurrence zone beyond the infiltrative margin. The mucoadhesive gel of choice, pectin, is currently used in other in vivo applications; however we have repurposed this for the brain. Pectin is biocompatible with GBM and human astrocyte cells in vitro and showed neither toxicity nor inflammation for up to 2 weeks upon orthotopic brain injection. Pectin is biodegradable in artificial CSF and is capable of being sprayed from the engineered device. A panel of polymeric, oil-based and polymer-coated NPs have been developed and optimised to maximise drug encapsulation of etoposide and olaparib as proof-of-concept for combination drug delivery. Etoposide/olaparib was chosen due to cytotoxicity from 5 GBM cell lines, including primary lines isolated from the invasive tumour margin (Mean IC50 of 1.1 µM and 8.3 µM respectively). The optimal NP/drug formulation (based on drug encapsulation, spray capability and bio-adhesiveness) will ultimately be assessed for tolerability and efficacy using orthotopic allograft and xenograft high-grade glioma models.

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SCIDOT-19. A MECHANICALLY-ENGINEERED SPRAY TO INCREASE BRAIN PENETRATION OF CHEMOTHERAPEUTIC NANOPARTICLES IN THE TREATMENT OF HIGH-GRADE GLIOMAS

Neuro-Oncology ◽

10.1093/neuonc/noz175.1155 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi275-vi275

Author(s):

Phoebe McCrorie ◽

Vincenzo Taresco ◽

Zeyuan Xu ◽

Alison Ritchie ◽

Philip A Clarke ◽

...

Keyword(s):

Drug Delivery ◽

Drug Formulation ◽

Local Drug Delivery ◽

Resection Margins ◽

Therapeutic Drug ◽

Tumour Resection ◽

High Grade ◽

Combination Drug ◽

Drug Encapsulation ◽

Drug Concentrations

Abstract Design and implementation of innovative local drug delivery systems (DDS) may overcome current limitations in GBM treatment, such as the lack of therapeutic drug concentrations reaching residual GBM cells following surgery. Here we describe a novel DDS which utilises a bespoke mechanically engineered spray device, designed for safe surgical use, to deliver a mucoadhesive hydrogel containing chemotherapeutic nanoparticles (NPs) into the tumour resection margins. The overall aim is to spray a NP and polymer solution onto the resection cavity and potentially increase penetration of anti-cancer drugs within the 2 cm reoccurrence zone beyond the infiltrative margin. The mucoadhesive gel of choice, pectin, is currently used in other in vivo applications; however we have repurposed this for the brain. Pectin is biocompatible with GBM and human astrocyte cells in vitro and showed neither toxicity nor inflammation for up to 2 weeks upon orthotopic brain injection. Pectin is biodegradable in artificial CSF and is capable of being sprayed from the engineered device. A panel of polymeric, oil-based and polymer-coated NPs have been developed and optimised to maximise drug encapsulation of etoposide and olaparib as proof-of-concept for combination drug delivery. Etoposide/olaparib was chosen due to cytotoxicity from 5 GBM cell lines, including primary lines isolated from the invasive tumour margin (Mean IC50 of 1.1 µM and 8.3 µM respectively). The optimal NP/drug formulation (based on drug encapsulation, spray capability and bio-adhesiveness) will ultimately be assessed for tolerability and efficacy using orthotopic allograft and xenograft high-grade glioma models, including measurement of penetration of drug/nanoparticle in ex vivo murine and porcine brain using novel hybrid time-of-flight/Orbitrap TM secondary ion mass spectrometer (orbiSIMS) technology.

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SCIDOT-18. NANOTHERAPEUTICS FOR NEUROSURGICALLY-APPLIED DRUG DELIVERY

Neuro-Oncology ◽

10.1093/neuonc/noz175.1154 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi275-vi275

Author(s):

Catherine Vasey ◽

Vincenzo Taresco ◽

Stuart Smith ◽

Cameron Alexander ◽

Ruman Rahman

Keyword(s):

Drug Delivery ◽

Ex Vivo ◽

Drug Formulation ◽

Local Drug Delivery ◽

Resection Margins ◽

Therapeutic Drug ◽

Tumour Resection ◽

Combination Drug ◽

Drug Encapsulation ◽

Drug Concentrations

Abstract Design and implementation of innovative local drug delivery systems (DDS) may overcome current limitations in GBM treatment, such as the lack of therapeutic drug concentrations reaching residual GBM cells following surgery. Here we describe a novel DDS which utilises a bespoke mechanically engineered spray device, designed for safe surgical use, to deliver a mucoadhesive hydrogel containing chemotherapeutic nanoparticles (NPs) into the tumour resection margins. The overall aim is to spray a NP and polymer solution onto the resection cavity and potentially increase penetration of anti-cancer drugs within the 2 cm reoccurrence zone beyond the infiltrative margin. The mucoadhesive gel of choice, pectin, is currently used in other in vivo applications; however we have repurposed this for the brain. Pectin is biocompatible with GBM and human astrocyte cells in vitro and showed neither toxicity nor inflammation for up to 2 weeks upon orthotopic brain injection. Pectin is biodegradable in artificial CSF and is capable of being sprayed from the engineered device. A panel of polymeric, oil-based and polymer-coated NPs have been developed and optimised to maximise drug encapsulation of etoposide and olaparib as proof-of-concept for combination drug delivery. Etoposide/olaparib was chosen due to cytotoxicity from 5 GBM cell lines, including primary lines isolated from the invasive tumour margin (Mean IC50 of 1.1 µM and 8.3 µM respectively). The optimal NP/drug formulation (based on drug encapsulation, spray capability and bio-adhesiveness) will ultimately be assessed for tolerability and efficacy using orthotopic allograft and xenograft high-grade glioma models, including measurement of penetration of drug/nanoparticle in ex vivo murine and porcine brain using novel hybrid time-of-flight/Orbitrap TM secondary ion mass spectrometer (orbiSIMS) technology.

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Development of Microneedle Devices for Drug Delivery

10.23889/suthesis.58289 ◽

2021 ◽

Author(s):

◽

Olivia Howells

Keyword(s):

Drug Delivery ◽

Stratum Corneum ◽

Drug Formulation ◽

Therapeutic Drug ◽

Hydrophobic Barrier ◽

First Pass Metabolism ◽

First Pass ◽

Out Of Plane ◽

Pass Metabolism ◽

Hollow Microneedles

There are numerous modes of therapeutic administration, of which oral delivery is the most convenient and conventional as it involves administration of therapeutics in the form of liquids or solid capsules and tablets. However, this mode encounters several challenges, such as chemical processes within the gastrointestinal track and first pass metabolism which subsequently reduce the efficacy of the therapeutic drugs. To overcome these issues, transdermal drug administration in the form of hypodermic needles, topical creams, and transdermal patches have been employed. However, the effect of transdermal administration is limited due the stratum corneum layer of the skin, which acts as a lipophilic and hydrophobic barrier preventing external molecules from entering the skin. Therefore, hypodermic needles are used due to their sharp tip facilitating penetration through the stratum corneum to deposit the drug formulation into the skin, subcutaneous fat, or muscles layers. However, these needles induce needle-phobia and reduce patient compliance due to the complexity with administration and pain associated with injection. Microneedle devices have been developed to avoid these issues and provide enhanced transdermal therapeutic drug delivery in a minimally invasive manner to eliminate the first-pass metabolism and provide a sustained release. Unlike hypodermic needles injection, they do not cause pain and related fear or phobia in individuals, thereby improving compliance to the prescribed dosage regime. Till now different types of microneedles have been fabricated. These include, solid, coated, hollow and dissolvable, where each type has its own advantages and unique properties and designs. In this thesis, two novel methods utilising silicon etching processes, for the fabrication of both out-of-plane and in-plane silicon microneedles are presented. Hollow out-of-plane microneedles are manufactured through deep reactive-ion etching (DRIE) technology. The patented three-step process flow has been developed to produce multiple arrays of sharp bevelled tipped, hollow microneedles which facilitate easy insertion and controlled fluid injection into excised skin samples. The in-plane microneedles have been fabricated from simultaneous wet KOH etching of the front and reverse of (100) orientated silicon wafers. The characteristic 54.7˚ sidewall etch angle was utilised to form a sharp six-sided microneedle tip and hexagonal shaped shaft. Employing this method allowed fabrication of both solid and hollow microneedles with different geometries i.e., widths and heights of several µm, to determine the optimal MN height and width for effective penetration and transdermal drug delivery. All microneedles fabricated during the PhD studentship tenure have been characterised through histology, fluorescent studies, and delivery into ex-vivo porcine and human skin tissue (research ethics committee reference 08/WSE03/55) to demonstrate effective microneedle based transdermal therapeutic drug delivery. The transdermal delivery of insulin and hyaluronic acid has been successfully demonstrated by employing a simple poke and patch application technique, presenting a clinical improvement over traditional application such as creams and ointments.

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An Integrated Multiscale Mechanistic Model for Cancer Drug Therapy

ISRN Biomathematics ◽

10.5402/2012/818492 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 6

Author(s):

Lei Tang ◽

Jing Su ◽

De-Shuang Huang ◽

Daniel Y. Lee ◽

King C. Li ◽

...

Keyword(s):

Drug Delivery ◽

Drug Therapy ◽

Mechanistic Model ◽

Scale Model ◽

Distribution Model ◽

Cancer Drug ◽

Therapeutic Effects ◽

Antitumor Effects ◽

Combination Drug ◽

Drug Concentrations

In this paper, we established a multiscale mechanistic model for studying drug delivery, biodistribution, and therapeutic effects of cancer drug therapy in order to identify optimal treatment strategies. Due to the specific characteristics of cancer, our proposed model focuses on drug effects on malignant solid tumor and specific internal organs as well as the intratumoral and regional extracellular microenvironments. At the organ level, we quantified drug delivery based on a multicompartmental model. This model will facilitate the analysis and prediction of organ toxicity and provide important pharmacokinetic information with regard to drug clearance rates. For the analysis of intratumoral microenvironment which is directly related to blood drug concentrations and tumor properties, we constructed a drug distribution model using diffusion-convection solute transport to study temporal/spatial variations of drug concentration. With this information, our model incorporates signaling pathways for the analysis of antitumor response with drug combinations at the extracellular level. Moreover, changes in tumor size, cellular proliferation, and apoptosis induced by different drug treatment conditions are studied. Therefore, the proposed multi-scale model could be used to understand drug clinical actions, study drug therapy-antitumor effects, and potentially identify optimal combination drug therapy. Numerical simulations demonstrate the proposed system's effectiveness.

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A first-in-human study of neural stem cells (NSCs) expressing cytosine deaminase (CD) in combination with 5-fluorocytosine (5-FC) in patients with recurrent high-grade glioma.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.2018 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 2018-2018 ◽

Cited By ~ 1

Author(s):

Jana Portnow ◽

Behnam Badie ◽

Timothy W. Synold ◽

Alexander Annala ◽

Bihong Chen ◽

...

Keyword(s):

Drug Delivery ◽

Human Study ◽

Tumor Resection ◽

Cytosine Deaminase ◽

High Grade Glioma ◽

Intracerebral Microdialysis ◽

High Grade ◽

Drug Concentrations ◽

Average Maximum ◽

The Brain

2018 Background: Human NSCs are inherently tumor-tropic, making them attractive drug delivery vehicles. This pilot-feasibility study assessed the safety of using genetically-modified NSCs for tumor selective enzyme/prodrug therapy. An immortalized, clonal NSC line was retrovirally-transduced to stably express CD, which converts the prodrug 5-FC to 5-fluorouracil (5-FU), producing chemotherapy locally at sites of tumor in the brain. Methods: Patients 18 years or older with recurrent high-grade glioma underwent intracranial administration of NSCs during tumor resection or biopsy. Four days later, 5-FC was administered orally every 6 hours for 7 days. Study treatment was given only once. A standard 3+3 dose escalation schema was used to increase doses of NSCs from 1 x 107 to 5 x 107 and 5-FC from 75 to 150 mg/kg/day. Intracerebral microdialysis was performed to measure brain levels of 5-FC and 5-FU; serial blood samples were obtained to assess systemic drug concentrations. Three patients received iron-labeled NSCs for MRI tracking. Brain autopsies were done on 2 patients. Results: Fifteen patients received study treatment. Three were inevaluable for toxicity and replaced. All patients tolerated the NSCs well. There was 1 dose-limiting toxicity (grade 3 transaminitis) possibly related to 5-FC. At the highest dose level of NSCs, the average steady-state concentration of 5-FU in the brain was 63.9±7.9 nM. The average maximum 5-FU level in brain was 104±88 nM compared to 24±36 nM in plasma, indicating local production of 5-FU in the brain by the NSCs. MR imaging of iron-labeled NSCs showed preliminary evidence of NSC migration. Autopsy data documented (by IHC, FISH, and PCR) NSCs at distant sites of tumor in the brain and no development of secondary tumors. Conclusions: This first-in-human study has demonstrated safety and proof-of-concept regarding NSC-mediated conversion of 5-FC to 5-FU and NSC tumor-tropism. NSCs have the potential to overcome obstacles of drug delivery that limit current gene therapy strategies. Results of this pilot study will serve as the foundation for future NSC studies. (Supported by NCI 1R21 CA137639-01A1, CIRM DR-01421). Clinical trial information: NCT01172964.

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Controlled Release of Therapeutics from Thermoresponsive Nanogels: A Thermal Magnetic Resonance Feasibility Study

Cancers ◽

10.3390/cancers12061380 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1380

Author(s):

Yiyi Ji ◽

Lukas Winter ◽

Lucila Navarro ◽

Min-Chi Ku ◽

João S. Periquito ◽

...

Keyword(s):

Drug Delivery ◽

Controlled Release ◽

Magnetic Resonance ◽

Release Kinetics ◽

Temperature Response ◽

Local Drug Delivery ◽

Whole Body ◽

Therapeutic Drug ◽

Temperature Modulation ◽

Thermoresponsive Polymers

Thermal magnetic resonance (ThermalMR) accommodates radio frequency (RF)-induced temperature modulation, thermometry, anatomic and functional imaging, and (nano)molecular probing in an integrated RF applicator. This study examines the feasibility of ThermalMR for the controlled release of a model therapeutics from thermoresponsive nanogels using a 7.0-tesla whole-body MR scanner en route to local drug-delivery-based anticancer treatments. The capacity of ThermalMR is demonstrated in a model system involving the release of fluorescein-labeled bovine serum albumin (BSA-FITC, a model therapeutic) from nanometer-scale polymeric networks. These networks contain thermoresponsive polymers that bestow environmental responsiveness to physiologically relevant changes in temperature. The release profile obtained for the reference data derived from a water bath setup used for temperature stimulation is in accordance with the release kinetics deduced from the ThermalMR setup. In conclusion, ThermalMR adds a thermal intervention dimension to an MRI device and provides an ideal testbed for the study of the temperature-induced release of drugs, magnetic resonance (MR) probes, and other agents from thermoresponsive carriers. Integrating diagnostic imaging, temperature intervention, and temperature response control, ThermalMR is conceptually appealing for the study of the role of temperature in biology and disease and for the pursuit of personalized therapeutic drug delivery approaches for better patient care.

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Chrono Modulated Therapy-A Review

International Journal of Research in Pharmaceutical Sciences ◽

10.26452/ijrps.v11ispl4.4575 ◽

2020 ◽

Vol 11 (SPL4) ◽

pp. 2884-2890

Author(s):

Mallamma T ◽

Prakash Goudanavar ◽

Nagaraja Sreeharsha ◽

Santosh Fattepur

Keyword(s):

Drug Delivery ◽

Circadian Rhythm ◽

Circadian Rhythms ◽

Rational Approach ◽

Therapeutic Drug ◽

Systemic Delivery ◽

Many Body ◽

Hormone Production ◽

Drug Concentrations ◽

Controlled Drug Delivery System

Chrono therapeutic drug delivery systems stay attaining prominence in the area of pharmaceuticals. It decreases dosing incidence, toxicity, and distributes a drug that matches the circadian rhythm of that definite disease when the signs are exciting to sorrier.ChrDDS is the essentially time-controlled drug delivery system. It offers a patient with a staggered profile of the therapeutic agent. It makes some consecutive changes in the ADME process. This mechanism is lag time independent of environmental variables including pH, enzymes, gastrointestinal motility. The circadian rhythm regulates many body functions in humans, such as metabolism, behaviour, sleep patterns, and hormone production. Chronotherapy has gained attention as a novel and rational approach to exploit the best. Presently, drugs are delivered in a controlled release like an IR, ER, & PR. Certain conditions that follow circadian rhythms include hypertension, diabetes, cardiovascular, asthma, neurological disorders, ulcer conditions, etc. Various technologies such as time-controlled, pulsed, triggered and programmed drug delivery devices have been developed and extensively studied in recent years for chronopharmaceutical drug delivery are Diffucaps, OROS, Codas, 3D printing, Egalet, Port, etc. this system is designed according to body-clock. Special drug delivery technology must be relied upon to synchronize drug concentrations to rhythms in disease activity with the body’s 24-hour rhythms to extend therapeutic effectiveness and reduce/avoid side effects. In this article, the various concepts like a mechanism of circadian rhythms, current obstacles to the production of chronopharmaceutical drug, circadian chronotherapy in various diseases, a profile of launched Chronopharmaceutical dosage forms, various technologies for systemic delivery,chronopathalogy have been reviewed.

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Malignant Intracranial High Grade Glioma and Current Treatment Strategy

Current Cancer Drug Targets ◽

10.2174/1568009618666180530090922 ◽

2019 ◽

Vol 19 (2) ◽

pp. 101-108

Author(s):

Xiang Zhang ◽

Wei Zhang ◽

Xing-Gang Mao ◽

Wei-Dong Cao ◽

Hai-Ning Zhen ◽

...

Keyword(s):

Drug Delivery ◽

Tumor Resection ◽

High Grade Glioma ◽

Pharmacokinetic Profile ◽

Vascular Supply ◽

Chemotherapeutic Agents ◽

Local Drug Delivery ◽

High Grade ◽

Targeting Therapy ◽

Molecular Features

Malignant high-grade glioma (HGG) is the most common and extremely fatal type of primary intracranial tumor. These tumors recurred within 2 to 3 cm of the primary region of tumor resection in the majority of cases. Furthermore, the blood-brain barrier significantly limited the access of many systemically administered chemotherapeutics to the tumor, pointing towards a stringent need for new therapeutic patterns. Therefore, targeting therapy using local drug delivery for HGG becomes a priority for the development of novel therapeutic strategies. The main objectives to the effective use of chemotherapy for HGG include the drug delivery to the tumor region and the infusion of chemotherapeutic agents into the vascular supply of a tumor directly, which could improve the pharmacokinetic profile by enhancing drug delivery to the neoplasm tissue. Herein, we reviewed clinical and molecular features, different methods of chemotherapy application in HGGs, especially the existing and promising targeting therapies using local drug delivery for HGG which could effectively inhibit tumor invasion, proliferation and recurrence of HGG to combat the deadly disease. Undoubtedly, novel chemical medicines targeting these HGG may represent one of the most important directions in the Neuro-oncology.

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