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Dive into the research topics where Anitha Thomas is active.

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Featured researches published by Anitha Thomas.


Journal of Controlled Release | 2011

Development of a liposomal nanoparticle formulation of 5-fluorouracil for parenteral administration: formulation design, pharmacokinetics and efficacy.

Anitha Thomas; Anita I. Kapanen; Jennifer I Hare; Euan Ramsay; Katarina Edwards; Göran Karlsson; Marcel B. Bally

5-Fluorouracil (5-FU) is a small, very membrane permeable drug that is poorly retained within the aqueous compartment of liposomal nanoparticles (LNP). To address this problem a novel method relying on formation of a ternary complex comprising copper, low molecular weight polyethylenimine (PEI) and 5-FU has been developed. More specifically, in the presence of entrapped copper and PEI, externally added 5-FU can be efficiently encapsulated (>95%) in DSPC/Chol (1,2-Distearoyl-sn-Glycero-3-Phosphocholine/cholesterol; 55:45 mol%) liposomes (130-170 nm) to achieve drug-to-lipid ratios of 0.1 (mol:mol). Drug release studies completed using this LNP formulation of 5-FU demonstrated significant improvements in drug retention in vitro and in vivo. Plasma concentrations of 5-FU were 7- to 23-fold higher when the drug was administered intravenously to mice as the LNP 5-FU formulation compared to free 5-FU. Further, the therapeutic effects of the LNP 5-FU formulation, as determined in a HT-29 subcutaneous colorectal cancer model where treatment was given QDx5, was greater than that which could be achieved with free 5-FU when compared at equivalent doses. This is the first time an active loading method has been described for 5-FU. The use of ternary metal complexation strategy to encapsulate therapeutic agents may define a unique platform for preparation of LNP drug formulations.


Journal of Cancer | 2013

The Autophagy Inhibitor Verteporfin Moderately Enhances the Antitumor Activity of Gemcitabine in a Pancreatic Ductal Adenocarcinoma Model

Elizabeth Donohue; Anitha Thomas; Norbert Maurer; Irina Manisali; Magali Zeisser-Labouebe; Natalia Zisman; Hilary J. Anderson; Sylvia S.W. Ng; Murray S. Webb; Marcel B. Bally; Michel Roberge

Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to chemotherapy. It has been described as requiring elevated autophagy for growth and inhibiting autophagy has been proposed as a treatment strategy. To date, all preclinical reports and clinical trials investigating pharmacological inhibition of autophagy have used chloroquine or hydroxychloroquine, which interfere with lysosomal function and block autophagy at a late stage. Verteporfin is a newly discovered autophagy inhibitor that blocks autophagy at an early stage by inhibiting autophagosome formation. Here we report that PDAC cell lines show variable sensitivity to verteporfin in vitro, suggesting cell-line specific autophagy dependence. Using image-based and molecular analyses, we show that verteporfin inhibits autophagy stimulated by gemcitabine, the current standard treatment for PDAC. Pharmacokinetic and efficacy studies in a BxPC-3 xenograft mouse model demonstrated that verteporfin accumulated in tumors at autophagy-inhibiting levels and inhibited autophagy in vivo, but did not reduce tumor volume or increase survival as a single agent. In combination with gemcitabine verteporfin moderately reduced tumor growth and enhanced survival compared to gemcitabine alone. While our results do not uphold the premise that autophagy inhibition might be widely effective against PDAC as a single-modality treatment, they do support autophagy inhibition as an approach to sensitize PDAC to gemcitabine.


Proceedings of the 3rd World Congress on Recent Advances in Nanotechnology | 2018

A Scalable Microfluidic Platform for the Development of LipidNanoparticles for Gene Delivery

Jagbir Singh; Kevin Ou; Anitha Thomas; Shyam Garg; Mark Ma; Ben Versteeg; R. Broadhead; Shell Ip; Tim Leaver; Andre Wild; James Taylor; Euan Ramsay

Extended Abstract Microfluidic devices have been broadly used to produce nucleic acid-delivery nanoparticles for genetic medicine because they offer control, reproducibility and scalability of the nanoparticle precipitation process to overcome a significant challenge in the translation of these therapeutics [1-5]. Control over process parameters afforded by microfluidics, allows optimization of nanoparticle quality and encapsulation efficiency [2]. Automation improves the reproducibility and optimization of formulations. The continuous nature of the microfluidic process is inherently scalable, allowing optimization at low volumes to conserve scarce or costly materials, and seamless scale-up of optimized formulations by employing multiple microfluidic mixers performing identical unit operations in parallel. In this study, we present a scalable microfluidic platform for producing nanomedicines. The platform includes a system designed for production under cGMP conditions employing 8 parallel microfluidic mixers capable of producing a 25 L formulation of RNA lipid nanoparticles (LNP) in ~4 h. Seamless scale up of production was demonstrated by producing test batches of siRNA-LNPs against the blood clotting protein Factor VII (FVII) on each of 3 systems designed for different stages of nanomedicine development. The physico-chemical characteristics were determined by DLS, and HPLC, and in vivo efficacy was measured by assaying serum FVII levels in murine models. With a system designed for bench-scale formulation development we produced 10 mL batches of siRNA LNPs of avg. diameter ~60 nm (PDI <0.1) with encapsulation efficiency >95 %. No differences were observed in physicochemical properties of these particles when batch sizes were scaled-up by 10x on a pre-clinical scale-up system or by 100x with a system employing 8 microfluidic chips arrayed in parallel. The particles exhibited consistent lipid composition and N/P ratio within the target specifications. In addition, nanoparticles manufactured across the microfluidic platform showed a similar dose-dependent gene knockdown achieving >90 % reduction in protein levels at a dose of 1 mg/kg. These studies demonstrated the seamless scale-up of nanoparticle formulations across the platform with the potential for producing large scale, clinically relevant volumes, of lipid nanoparticles. The system employing 8 parallel mixers can prepare up to 25 L of product under 4.5 hours at 12 mL/min per mixer and incorporates a disposable fluid path that eliminates the need for costly and time consuming cleaning validation.


Archive | 2018

Microfluidic Production and Application of Lipid Nanoparticles for Nucleic Acid Transfection

Anitha Thomas; Shyam Garg; Rebecca Anne Grace De Souza; Eric Ouellet; Grace Tharmarajah; Dave Reichert; Mina Ordobadi; Shell Ip; Euan Ramsay

Lipid nanoparticles (LNPs) are established in the biopharmaceutical industry for efficient encapsulation and cytosolic delivery of nucleic acids for potential therapeutics, with several formulations in clinical trials. The advantages of LNPs can also be applied in basic research and discovery with a microfluidic method of preparation now commercially available that allows preparations to be scaled down to quantities appropriate for cell culture. These preparations conserve expensive nucleic acids while maintaining the particle characteristics that have made LNPs successful in later stages of genetic medicine development. Additionally, this method and the resulting LNPs are seamlessly scalable to quantities appropriate for in vivo models and development of nucleic acid therapeutics.The present work describes the methodology for preparing LNPs loaded with siRNA, mRNA or plasmids using a commercially available microfluidic instrument and an accompanying transfection kit. Guidelines for application to cultured cells in a well-plate format are also provided.


Molecular Therapy | 2016

614. Microfluidic Manufacture of RNA-Lipid Nanoparticles Leads to Highly Efficient Delivery of Potent Nucleic Acid Therapeutics for Controlling Gene Expression

Grace Tharmarajah; Eric Ouellet; Oscar Seira; Jie Liu; Anitha Thomas; Timothy Leaver; Andre Wild; Yuping Li; Yu Tian Wang; Wolfram Tetzlaff; Carl Hansen; Pieter R. Cullis; James Taylor; Euan Ramsay

Lipid nanoparticles (LNPs) have demonstrated efficient nucleic acid delivery in vitro and in vivo, as well as in clinical development. They exploit endogenous delivery pathways, by co-opting apolipoprotein E (apoE), to mediate effective delivery of the encapsulated nucleic acids into cells via the low-density lipoprotein receptor (LDLR). However, use of LNPs from the bench to the clinic has been considerably limited by challenges in manufacturing at both small and large scales. Here, we bridge that gap by describing the robust manufacture and use of clinical-grade lipid-based nanoparticles for highly efficient delivery of nucleic acids at scales suitable for both in vitro screening and in vivo applications.RNA-LNPs manufactured using an optimized microfluidic platform enables efficient encapsulation of nucleic acids (e.g. siRNA, mRNA, pDNA) into biocompatible “solid-core” nanoparticles (~50 nm). The resultant nanoparticles can then be applied to cell cultures in vitro or administered in vivo. The following reports a comprehensive set of studies conducted to evaluate the merits of the technology and further provide insights for delivering short interfering RNA (siRNA) and mRNA in difficult-to-transfect cells both in vitro and in vivo.RNA-LNPs were formulated to encapsulate a potent siRNA directed against PTEN - a clinically relevant gene associated with neural regeneration. Exceptional cellular uptake (>98%) with minimal toxicity was observed in both primary rat hippocampal and mixed cortical cell cultures. High transfection efficency (>95%) of the encapsulated material resulted in concomitant high-level (>85%) PTEN knockdown within the first 4 hours of a low dose (100 ng/ml) treatment; that level of knockdown was further sustained for 21 days. Similarly, RNA-LNPs encapsulating mRNA were also found to mediate early ( 75% for 7 days) following a single (500 ng/ml) treatment in primary rat mixed cortical cultures.Strategies for locally administering RNA-LNPs into the brain and spinal cord of adult Sprague Dawley rats were also investigated. Controlled localized injections of PTEN-encaspulated siRNA into the motorcortex resulted in significant and sustained (7 days) knockdown. Similarly, local administration at the site of a cervical spinal cord injury significantly reduced target PTEN expression, 10 days later. Visible uptake of RNA-LNPs characterized by their presence in the soma of neurons found in the red nucleus provides further insights into a regtrograde transport mechanism involving the axons.Collectively, these studies reflect the simplicity and efficacy of this commercially available technology in presenting a cost-effective and advantageous avenue for screening and validating new targeted nucleic acid therapies.


Journal of Controlled Release | 2006

Copper-topotecan complexation mediates drug accumulation into liposomes.

Amandeep S. Taggar; Jehan Alnajim; Malathi Anantha; Anitha Thomas; Murray S. Webb; Euan Ramsay; Marcel B. Bally


Archive | 2018

COMPOSITIONS POUR LA TRANSFECTION DE TYPES DE CELLULES RÉSISTANTES

Anitha Thomas; Rebecca Anne Grace De Souza; Eric Ouellet; Grace Tharmarajah; Jagbir Singh; Shyam Garg


Archive | 2016

DISPOSABLE MICROFLUIDIC CARTRIDGE

Andre Wild; Timothy Leaver; Colin Walsh; Gesine Heuck; Anitha Thomas; Aysha Ansari; Kevin Ou; R. James Taylor; Euan Ramsay


Archive | 2016

CARTOUCHE MICROFLUIDIQUE JETABLE

Andre Wild; Timothy Leaver; Colin Walsh; Gesine Heuck; Anitha Thomas; Aysha Ansari; Kevin Ou; Taylor, R., James; Euan Ramsay


Blood | 2015

Effective Treatment of Human CML By RNAi In Vivo in a Xenotransplantation Mouse Model

Nidhi Jyotsana; Amit Sharma; Anuhar Chaturvedi; Colin Walsh; Anitha Thomas; Michaela Scherr; Matthias Eder; Karin Battmer; Florian Kuchenbauer; Sajti Laszlo; Annette Barchanski; Kerstin Goerlich; Robert Lindner; Fatih Noyan; Suehs.Kurt Wolfram; Denis Grote-Koska; Korbinian Brand; Hans-Peter Vornlocher; Arnold Ganser; Euan Ramsay; Pieter R. Cullis; Michael Heuser

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Andre Wild

University of British Columbia

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Colin Walsh

University of British Columbia

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Marcel B. Bally

University of British Columbia

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Timothy Leaver

University of British Columbia

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Aysha Ansari

University of British Columbia

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James Taylor

University of British Columbia

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Kevin Ou

University of British Columbia

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Pieter R. Cullis

University of British Columbia

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Shell Ip

University of Toronto

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