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University of Toronto
1.
Parker, James.
Affinity Release of Insulin-like Growth Factor-1 Increases the Viability of Retinal Pigment Epithelium Cells In Vitro.
Degree: 2015, University of Toronto
URL: http://hdl.handle.net/1807/70518 
► Poor cell survival in vitro and in vivo is a key challenge in tissue engineering. Pro-survival therapeutic proteins such as insulin-like growth factor-1 (IGF-1) can…
(more)
▼ Poor cell survival in vitro and in vivo is a key challenge in tissue engineering. Pro-survival therapeutic proteins such as insulin-like growth factor-1 (IGF-1) can promote cell viability but require controlled delivery systems due to their brief half-lives. Biocompatible materials are commonly used for drug-delivery platforms or to encapsulate cells for increased viability but no material exists for simultaneous use in both applications. A blend of hyaluronan and methylcellulose known to promote cell survival was modified with Src homology 3 (SH3)-binding peptides and demonstrated tunable, affinity-based release of the pro-survival fusion protein SH3-IGF-1. The material was also shown to significantly increase the viability of retinal pigment epithelium cells (RPE) in anchorage-independent conditions. This novel system is applicable to a broad range of cells and protein therapeutics and is a promising strategy for a drug-delivery/cell transplantation strategy to increase the viability of both exogenous and endogenous cells in tissue engineering applications.
M.Sc.
Advisors/Committee Members: Shoichet, Molly S, Chemistry.
Subjects/Keywords: Affinity release; Cell viability; Hydrogel; Insulin-like growth factor-1; Retinal pigment epithelium; Tunable release; 0541
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APA (6th Edition):
Parker, J. (2015). Affinity Release of Insulin-like Growth Factor-1 Increases the Viability of Retinal Pigment Epithelium Cells In Vitro. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/70518
Chicago Manual of Style (16th Edition):
Parker, James. “Affinity Release of Insulin-like Growth Factor-1 Increases the Viability of Retinal Pigment Epithelium Cells In Vitro.” 2015. Masters Thesis, University of Toronto. Accessed March 08, 2021.
http://hdl.handle.net/1807/70518.
MLA Handbook (7th Edition):
Parker, James. “Affinity Release of Insulin-like Growth Factor-1 Increases the Viability of Retinal Pigment Epithelium Cells In Vitro.” 2015. Web. 08 Mar 2021.
Vancouver:
Parker J. Affinity Release of Insulin-like Growth Factor-1 Increases the Viability of Retinal Pigment Epithelium Cells In Vitro. [Internet] [Masters thesis]. University of Toronto; 2015. [cited 2021 Mar 08].
Available from: http://hdl.handle.net/1807/70518.
Council of Science Editors:
Parker J. Affinity Release of Insulin-like Growth Factor-1 Increases the Viability of Retinal Pigment Epithelium Cells In Vitro. [Masters Thesis]. University of Toronto; 2015. Available from: http://hdl.handle.net/1807/70518
University of Toronto
2.
Arnold, Amy Elizabeth.
Bioconjugate Strategies for Antisense Therapeutic Delivery to Glioblastoma Stem Cells.
Degree: PhD, 2020, University of Toronto
URL: http://hdl.handle.net/1807/100910
► Antisense therapeutics, including antisense oligonucleotides (AONs) and small interfering ribonucleic acids (siRNAs), are powerful tools for regulating genes, making them a promising therapy for diseases…
(more)
▼ Antisense therapeutics, including antisense oligonucleotides (AONs) and small interfering ribonucleic acids (siRNAs), are powerful tools for regulating genes, making them a promising therapy for diseases such as cancer where oncogenic genes are over-expressed. The delivery of antisense therapeutics to target cells presents a significant challenge due to the many barriers a nucleic acid must face in order to reach the cytoplasm where it exerts its effects. In this thesis, I explored multiple strategies for delivery of AONs and siRNAs, focusing on targeting the desired cell population, inducing endocytosis, and facilitating endosomal escape. This was done within the context of glioblastoma (GBM), and specifically the glioblastoma stem cells (GSCs), an aggressive subpopulation of GBM cells that are involved in resistance, migration, and recurrence. Antisense oligonucleotides against a relevant GBM gene were conjugated to an antibody engineered to target CD44, a cell surface receptor which is highly expressed on GSCs. Using this system, we demonstrated functional targeting, endocytosis, and gene knockdown in the GSCs, leading to a morphological change in the cells. This represented the first time an antibody-oligonucleotide conjugate was used to target the GSC population. We were challenged with a lack of endosomal escape when using the antibody delivery platform, so we next looked at using a protein with a native endosomal escape mechanism to facilitate oligonucleotide delivery. For the second strategy, I conjugated attenuated diphtheria toxin (aDT), a protein which escapes the endolysosomal pathway, to siRNAs against relevant gene targets involved in GSC proliferation and invasion. Using this aDT-siRNA conjugate, we could downregulate genes of interest in the glioblastoma stem cells, leading to significant changes in cell viability and the invasive capacity of these cells. This is the first diphtheria toxin-based siRNA delivery vehicle and represents a platform technology for siRNA- and AON-based therapies.
Advisors/Committee Members: Shoichet, Molly S, Chemistry.
Subjects/Keywords: Drug Delivery; Glioblastoma; Nucleic Acids; 0485
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APA (6th Edition):
Arnold, A. E. (2020). Bioconjugate Strategies for Antisense Therapeutic Delivery to Glioblastoma Stem Cells. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/100910
Chicago Manual of Style (16th Edition):
Arnold, Amy Elizabeth. “Bioconjugate Strategies for Antisense Therapeutic Delivery to Glioblastoma Stem Cells.” 2020. Doctoral Dissertation, University of Toronto. Accessed March 08, 2021.
http://hdl.handle.net/1807/100910.
MLA Handbook (7th Edition):
Arnold, Amy Elizabeth. “Bioconjugate Strategies for Antisense Therapeutic Delivery to Glioblastoma Stem Cells.” 2020. Web. 08 Mar 2021.
Vancouver:
Arnold AE. Bioconjugate Strategies for Antisense Therapeutic Delivery to Glioblastoma Stem Cells. [Internet] [Doctoral dissertation]. University of Toronto; 2020. [cited 2021 Mar 08].
Available from: http://hdl.handle.net/1807/100910.
Council of Science Editors:
Arnold AE. Bioconjugate Strategies for Antisense Therapeutic Delivery to Glioblastoma Stem Cells. [Doctoral Dissertation]. University of Toronto; 2020. Available from: http://hdl.handle.net/1807/100910
University of Toronto
3.
Anandakumaran, Priya Nivashini.
Co-delivery of Chondroitinase ABC and Pre-differentiated Progeny of Human Neuroepithelial Cells in Hydrogels to the Injured Spinal Cord.
Degree: 2016, University of Toronto
URL: http://hdl.handle.net/1807/97273
► The inability of injured axons to regenerate across the lesion that forms following a spinal cord injury is largely attributed to their reduced growth capacity,…
(more)
▼ The inability of injured axons to regenerate across the lesion that forms following a spinal cord injury is largely attributed to their reduced growth capacity, and the inhibitory microenvironment surrounding the lesion. To overcome these obstacles, a combinatorial strategy was designed involving the delivery of the enzyme chondroitinase ABC (chABC), from a methylcellulose hydrogel to degrade inhibitory molecules, and the transplantation of neuronal precursor cells in a hyaluronan-methylcellulose hydrogel to bridge the lesion. Although motor and sensory functionality was not recovered through this strategy in rat models of spinal cord injury, high levels of transplanted cells remained 8 weeks after transplantation, the cells retained a neuronal phenotype and migrated toward the lesion, despite being injected 1 mm away from the injury site. Future work involves determining the effect that chABC had in this system, and what modifications can be made to achieve functional recovery through this type of combinatorial strategy.
M.A.S.
2019-11-10 00:00:00
Advisors/Committee Members: Shoichet, Molly S, Biomedical Engineering.
Subjects/Keywords: Biomaterials; Cell Transplantation; Chondroitinase ABC; Hydrogels; Neuronal Precursor Cells; Spinal Cord Injury; 0541
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APA (6th Edition):
Anandakumaran, P. N. (2016). Co-delivery of Chondroitinase ABC and Pre-differentiated Progeny of Human Neuroepithelial Cells in Hydrogels to the Injured Spinal Cord. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/97273
Chicago Manual of Style (16th Edition):
Anandakumaran, Priya Nivashini. “Co-delivery of Chondroitinase ABC and Pre-differentiated Progeny of Human Neuroepithelial Cells in Hydrogels to the Injured Spinal Cord.” 2016. Masters Thesis, University of Toronto. Accessed March 08, 2021.
http://hdl.handle.net/1807/97273.
MLA Handbook (7th Edition):
Anandakumaran, Priya Nivashini. “Co-delivery of Chondroitinase ABC and Pre-differentiated Progeny of Human Neuroepithelial Cells in Hydrogels to the Injured Spinal Cord.” 2016. Web. 08 Mar 2021.
Vancouver:
Anandakumaran PN. Co-delivery of Chondroitinase ABC and Pre-differentiated Progeny of Human Neuroepithelial Cells in Hydrogels to the Injured Spinal Cord. [Internet] [Masters thesis]. University of Toronto; 2016. [cited 2021 Mar 08].
Available from: http://hdl.handle.net/1807/97273.
Council of Science Editors:
Anandakumaran PN. Co-delivery of Chondroitinase ABC and Pre-differentiated Progeny of Human Neuroepithelial Cells in Hydrogels to the Injured Spinal Cord. [Masters Thesis]. University of Toronto; 2016. Available from: http://hdl.handle.net/1807/97273
University of Toronto
4.
Ing, Sonja Tasia.
Sustained Regional Anesthesia for Post-operative Pain Management.
Degree: 2018, University of Toronto
URL: http://hdl.handle.net/1807/97671
► Acute post-operative pain is inevitable, yet current treatment strategies do not provide sufficient pain relief. While local anesthetics are widely used to achieve a regional…
(more)
▼ Acute post-operative pain is inevitable, yet current treatment strategies do not provide sufficient pain relief. While local anesthetics are widely used to achieve a regional block, they are currently delivered as a bolus liquid injection and, thus, quickly clear the injection site. Subsequently, pain relief is short-lived, and quick distribution of the drug throughout the body leads to systemic side effects. Post-operative pain management can be improved by a local, controlled and sustained drug delivery system that increases the duration of local anesthetic efficacy while minimizing side effects. Herein, a hyaluronan-methylcellulose hydrogel (HAMC) was investigated as a drug delivery vehicle to locally deliver pain medication over an extended period. By distributing particulates of a local anesthetic within HAMC, the hydrogel serves as a local drug depot and prevents fast clearance of the drug. The anesthetic-loaded HAMC system was optimized in vitro and then evaluated in rat models of nerve block.
M.A.S.
2019-11-15 00:00:00
Advisors/Committee Members: Shoichet, Molly S, Biomedical Engineering.
Subjects/Keywords: Drug delivery; HAMC; Hydrogel; Local anesthetic; Pain; Sustained release; 0541
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APA (6th Edition):
Ing, S. T. (2018). Sustained Regional Anesthesia for Post-operative Pain Management. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/97671
Chicago Manual of Style (16th Edition):
Ing, Sonja Tasia. “Sustained Regional Anesthesia for Post-operative Pain Management.” 2018. Masters Thesis, University of Toronto. Accessed March 08, 2021.
http://hdl.handle.net/1807/97671.
MLA Handbook (7th Edition):
Ing, Sonja Tasia. “Sustained Regional Anesthesia for Post-operative Pain Management.” 2018. Web. 08 Mar 2021.
Vancouver:
Ing ST. Sustained Regional Anesthesia for Post-operative Pain Management. [Internet] [Masters thesis]. University of Toronto; 2018. [cited 2021 Mar 08].
Available from: http://hdl.handle.net/1807/97671.
Council of Science Editors:
Ing ST. Sustained Regional Anesthesia for Post-operative Pain Management. [Masters Thesis]. University of Toronto; 2018. Available from: http://hdl.handle.net/1807/97671
University of Toronto
5.
Tuladhar, Anup.
Local delivery of cyclosporine and erythropoietin promote functional recovery in a rodent model of stroke injury by endogenous tissue repair.
Degree: PhD, 2018, University of Toronto
URL: http://hdl.handle.net/1807/91957
► In the adult brain, endogenous neural stem and progenitor cells (NSPCs) can be stimulated to promote tissue and functional repair after traumatic injury, such as…
(more)
▼ In the adult brain, endogenous neural stem and progenitor cells (NSPCs) can be stimulated to promote tissue and functional repair after traumatic injury, such as stroke. Cyclosporine (CsA) stimulates endogenous neural stem cells and erythropoietin (EPO) promotes neurogenesis, making their dual delivery compelling for investigation. However, the blood brain barrier poses a significant challenge for drug-based neural repair strategies. To overcome this barrier, a minimally invasive polymer system was developed for local drug delivery to the brain. The polymer system is composed of a hyaluronan and methylcellulose (HAMC) hydrogel depot carrying drug-loaded poly(lactic-co-glycolic) acid microparticles. The hydrogel depot was delivered epi-cortically, onto the surface of the brain, in a rat model of transient ischemic stroke.
Local delivery with the polymer system was compared to systemic delivery using osmotic minipumps, with CsA serving as a model compound. With local delivery, higher tissue concentrations of CsA were achieved in the brain and significantly reduced concentrations were observed in non-targeted organs, compared to systemic delivery. The system was expanded to co-release CsA and EPO and the effects on post-stroke motor recovery and chronic tissue repair were evaluated. Both drugs were released for 4 weeks post-implantation and diffused to the sub-cortical NSPC niche located along the lateral walls of the ventricles. Only co-delivery of CsA and EPO (relative to all other controls, including delivery of each drug alone) increased and accelerated recovery in two different forelimb motor tasks: cylinder and staircase. Differential effects of the two drugs were seen on NSPC stimulation and synaptic plasticity: EPO increased the number of NSPCs found in the ventricles while CsA increased the number of proliferating NSPCs and synaptic plasticity in the striatum. Only the combination of CsA and EPO decreased the stroke lesion volume.
Combined, this work demonstrates that local drug delivery with the polymer system can stimulate endogenous brain repair. This approach is amenable to a wide range of drugs that can target different aspects of tissue repair and can be combined with other reparative approaches, such as cell delivery or rehabilitation therapy, to enhance recovery after stroke.
Στον ενήλικο εγκέφαλο, ενδογενή νευρικά βλαστοκύτταρα και προγονικά κύτταρα (NSPCs) μπορούν να διεγερθούν για να προωθήσουν ιστούς και λειτουργική αποκατάσταση μετά από τραυματικές βλάβες, όπως εγκεφαλικό επεισόδιο. Η κυκλοσπορίνη (CsA) διεγείρει τα ενδογενή νευρικά βλαστικά κύτταρα και η ερυθροποιητίνη (ΕΡΟ) προάγει τη νευρογένεση, καθιστώντας τη διπλή απεικόνισή τους επιτακτική για τη διερεύνηση. Ωστόσο, το φράγμα αίματος εγκεφάλου αποτελεί σημαντική πρόκληση για τις στρατηγικές νευρικής αποκατάστασης που βασίζονται σε φάρμακα. Για να ξεπεραστεί αυτός ο φραγμός, αναπτύχθηκε ένα ελάχιστα επεμβατικό σύστημα πολυμερούς για την τοπική χορήγηση φαρμάκου στον εγκέφαλο. Το σύστημα πολυμερούς αποτελείται από ένα υδραυλικό πήκτωμα…
Advisors/Committee Members: Shoichet, Molly S, Biomedical Engineering.
Subjects/Keywords: Brain repair; Drug delivery; Regenerative medicine; Stem cells; Stroke; Tissue engineering; 0541
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APA (6th Edition):
Tuladhar, A. (2018). Local delivery of cyclosporine and erythropoietin promote functional recovery in a rodent model of stroke injury by endogenous tissue repair. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/91957
Chicago Manual of Style (16th Edition):
Tuladhar, Anup. “Local delivery of cyclosporine and erythropoietin promote functional recovery in a rodent model of stroke injury by endogenous tissue repair.” 2018. Doctoral Dissertation, University of Toronto. Accessed March 08, 2021.
http://hdl.handle.net/1807/91957.
MLA Handbook (7th Edition):
Tuladhar, Anup. “Local delivery of cyclosporine and erythropoietin promote functional recovery in a rodent model of stroke injury by endogenous tissue repair.” 2018. Web. 08 Mar 2021.
Vancouver:
Tuladhar A. Local delivery of cyclosporine and erythropoietin promote functional recovery in a rodent model of stroke injury by endogenous tissue repair. [Internet] [Doctoral dissertation]. University of Toronto; 2018. [cited 2021 Mar 08].
Available from: http://hdl.handle.net/1807/91957.
Council of Science Editors:
Tuladhar A. Local delivery of cyclosporine and erythropoietin promote functional recovery in a rodent model of stroke injury by endogenous tissue repair. [Doctoral Dissertation]. University of Toronto; 2018. Available from: http://hdl.handle.net/1807/91957
University of Toronto
6.
Mitrousis, Nikolaos.
A Bioengineering Approach Towards Retina Regeneration.
Degree: PhD, 2018, University of Toronto
URL: http://hdl.handle.net/1807/91970
► Currently, there is no cure for blindness. Pharmacology can only slow down the progression of a blinding disease, aiming at minimizing the symptoms. Stem cell…
(more)
▼ Currently, there is no cure for blindness. Pharmacology can only slow down the progression of a blinding disease, aiming at minimizing the symptoms. Stem cell regenerative therapy is a novel and very promising approach to overcome blindness. It has shown some potential in the eye but there remain major obstacles to be overcome before it can turn into a clinical reality, namely, the integration and survival of transplanted cells. In this work, we follow a two-pronged approach to address these challenges.
Studies of photoreceptor development and degeneration could previously only be performed in vivo, due to the extremely poor survival of isolated photoreceptors in culture. Here, we describe a three-dimensional culture platform that enables isolated mouse postnatal day 11 rod photoreceptor survival and maturation in vitro and investigate its mechanism of action. We show that material stiffness does not affect photoreceptor survival and instead identify hyaluronic acid (HA) as its bioactive component. We investigate the molecular pathways activated by HA on photoreceptors and find that the Wnt, RhoA and mTOR pathways are its downstream effectors.
The photoreceptors and the retinal pigmented epithelium (RPE) of the retina have a well-established mutual relationship in development, homeostasis and degeneration. In the second part of this work, we assess whether co-transplanting human embryonic stem cell-derived RPE and mouse postnatal day 11 rod photoreceptors in an HA hydrogel can improve behavioral recovery and cell survival compared to transplanting each cell type alone. We first validate the NaIO3 mouse model, which recapitulates advanced retinal degeneration. We next demonstrate that visual recovery in this model can be achieved only when RPE and photoreceptors are co-transplanted, as evidenced by three different outcome measures. This is accompanied by superior cell survival for both cell types in the co-transplant group. Our findings will guide future research and translation for retinal degenerative diseases.
Advisors/Committee Members: Shoichet, Molly S, Biomedical Engineering.
Subjects/Keywords: Biomaterials; Blindness; Cell Therapy; Regenerative Medicine; 0541
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APA (6th Edition):
Mitrousis, N. (2018). A Bioengineering Approach Towards Retina Regeneration. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/91970
Chicago Manual of Style (16th Edition):
Mitrousis, Nikolaos. “A Bioengineering Approach Towards Retina Regeneration.” 2018. Doctoral Dissertation, University of Toronto. Accessed March 08, 2021.
http://hdl.handle.net/1807/91970.
MLA Handbook (7th Edition):
Mitrousis, Nikolaos. “A Bioengineering Approach Towards Retina Regeneration.” 2018. Web. 08 Mar 2021.
Vancouver:
Mitrousis N. A Bioengineering Approach Towards Retina Regeneration. [Internet] [Doctoral dissertation]. University of Toronto; 2018. [cited 2021 Mar 08].
Available from: http://hdl.handle.net/1807/91970.
Council of Science Editors:
Mitrousis N. A Bioengineering Approach Towards Retina Regeneration. [Doctoral Dissertation]. University of Toronto; 2018. Available from: http://hdl.handle.net/1807/91970
University of Toronto
7.
Ngai, Jessica Wan-Yan.
Local Delivery System to Reduce Pain in a Model of Back Surgery.
Degree: 2016, University of Toronto
URL: http://hdl.handle.net/1807/92623
► Lumbar disc herniation is a common cause for lower back pain and reason for spinal surgery. Inevitably, patients will feel acute post-operative pain following surgery,…
(more)
▼ Lumbar disc herniation is a common cause for lower back pain and reason for spinal surgery. Inevitably, patients will feel acute post-operative pain following surgery, thus local analgesics are given to patients after the surgery to alleviate pain. Existing drug delivery methods are limited by large doses, quick clearance rate from the injury site, short pain-relief period and multiple injections. As a result, there is an unmet need for a local, controlled and sustained drug delivery system following spine surgery. We propose to investigate a novel biomaterial to prolong the delivery of drugs to the local injury site. The drug-loaded hydrogel was characterized in terms of its release profile (where different factors were considered to prolong the release of the drug), storage modulus and swelling ratio. Behavioural tests and a pharmacokinetic study were conducted to determine the effects of the drug-loaded hydrogel in vivo.
M.A.S.
2018-11-30 00:00:00
Advisors/Committee Members: Shoichet, Molly S, Chemical Engineering Applied Chemistry.
Subjects/Keywords: Biomaterial; Drug Delivery; Pain; 0541
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APA (6th Edition):
Ngai, J. W. (2016). Local Delivery System to Reduce Pain in a Model of Back Surgery. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/92623
Chicago Manual of Style (16th Edition):
Ngai, Jessica Wan-Yan. “Local Delivery System to Reduce Pain in a Model of Back Surgery.” 2016. Masters Thesis, University of Toronto. Accessed March 08, 2021.
http://hdl.handle.net/1807/92623.
MLA Handbook (7th Edition):
Ngai, Jessica Wan-Yan. “Local Delivery System to Reduce Pain in a Model of Back Surgery.” 2016. Web. 08 Mar 2021.
Vancouver:
Ngai JW. Local Delivery System to Reduce Pain in a Model of Back Surgery. [Internet] [Masters thesis]. University of Toronto; 2016. [cited 2021 Mar 08].
Available from: http://hdl.handle.net/1807/92623.
Council of Science Editors:
Ngai JW. Local Delivery System to Reduce Pain in a Model of Back Surgery. [Masters Thesis]. University of Toronto; 2016. Available from: http://hdl.handle.net/1807/92623
University of Toronto
8.
Kesselman, Leah Ranit Baskin.
3D Hydrogels for Astrocyte/Neural Progenitor Cell Co-cultures.
Degree: 2016, University of Toronto
URL: http://hdl.handle.net/1807/72681
► This thesis explores the use of hyaluronic acid-based hydrogels as extracellular matrix mimics for growing astrocytes and neural progenitor cells in 3D. An examination of…
(more)
▼ This thesis explores the use of hyaluronic acid-based hydrogels as extracellular matrix mimics for growing astrocytes and neural progenitor cells in 3D. An examination of laminin- and fibronectin-based peptides showed that modifying gels with peptides containing the adhesive sequence RGD provided the best attachment for astrocytes. Both Diels-Alder and oxime "click" reactions were examined as gelation mechanisms, and oxime-crosslinked gels were used for cell co-cultures. It was determined that astrocytes grown on tissue culture plastic underneath the gels supported neural progenitor cell growth and differentiation better than 3D encapsulated co-cultures. These results demonstrate the importance of co-culture conditions to examine the role of astrocytes on neural progenitor cell fate. Ultimately, engineered matrices, such as those described herein, may provide useful biomimetic environments in which to probe development and/or disease progression in vitro.
M.A.S.
Advisors/Committee Members: Shoichet, Molly S, Chemical Engineering Applied Chemistry.
Subjects/Keywords: astrocyte; cell encapsulation; hydrogel; neural progenitor cell; 0542
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APA (6th Edition):
Kesselman, L. R. B. (2016). 3D Hydrogels for Astrocyte/Neural Progenitor Cell Co-cultures. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/72681
Chicago Manual of Style (16th Edition):
Kesselman, Leah Ranit Baskin. “3D Hydrogels for Astrocyte/Neural Progenitor Cell Co-cultures.” 2016. Masters Thesis, University of Toronto. Accessed March 08, 2021.
http://hdl.handle.net/1807/72681.
MLA Handbook (7th Edition):
Kesselman, Leah Ranit Baskin. “3D Hydrogels for Astrocyte/Neural Progenitor Cell Co-cultures.” 2016. Web. 08 Mar 2021.
Vancouver:
Kesselman LRB. 3D Hydrogels for Astrocyte/Neural Progenitor Cell Co-cultures. [Internet] [Masters thesis]. University of Toronto; 2016. [cited 2021 Mar 08].
Available from: http://hdl.handle.net/1807/72681.
Council of Science Editors:
Kesselman LRB. 3D Hydrogels for Astrocyte/Neural Progenitor Cell Co-cultures. [Masters Thesis]. University of Toronto; 2016. Available from: http://hdl.handle.net/1807/72681
University of Toronto
9.
Smith, Kelti Aileen.
Synthesis of a Reversible Crosslinked Hydrogel.
Degree: 2020, University of Toronto
URL: http://hdl.handle.net/1807/103122
► Detachment of fragile cell types cultured on two-dimensional (2D) surfaces detrimentally affects cell viability. Accutase treatment of neurons growing in 2D damaged fragile neuronal connections,…
(more)
▼ Detachment of fragile cell types cultured on two-dimensional (2D) surfaces detrimentally affects cell viability. Accutase treatment of neurons growing in 2D damaged fragile neuronal connections, resulting in cell death and host tissue damage in vivo. Avoiding cell detachment altogether by developing an in vitro culture system may better maintain cell viability; therefore, we present the synthesis of a reversible crosslinked three-dimensional (3D) hydrogel which would provide stability for culture/differentiation when crosslinked and injectability for transplantation following crosslink degradation. A blend of hyaluronan (HA) and methylcellulose (MC), HAMC, was chemically crosslinked with an enzyme-degradable peptide sequence using oxime click-chemistry. Specifically, HA and MC were modified with ketone and aldehyde groups, respectively, and a TEV protease-degradable peptide crosslinker was synthesized and modified with oxyamine groups. The gel components were characterized, and gels were formed that demonstrated good stability, improved injectability upon crosslink degradation, and cytocompatibility with iPSC-derived neural progenitor cells.
M.A.S.
Advisors/Committee Members: Shoichet, Molly S, Chemical Engineering Applied Chemistry.
Subjects/Keywords: degradable; dynamic; hyaluronan; hydrogel; methylcellulose; TEV protease; 0542
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APA ·
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APA (6th Edition):
Smith, K. A. (2020). Synthesis of a Reversible Crosslinked Hydrogel. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/103122
Chicago Manual of Style (16th Edition):
Smith, Kelti Aileen. “Synthesis of a Reversible Crosslinked Hydrogel.” 2020. Masters Thesis, University of Toronto. Accessed March 08, 2021.
http://hdl.handle.net/1807/103122.
MLA Handbook (7th Edition):
Smith, Kelti Aileen. “Synthesis of a Reversible Crosslinked Hydrogel.” 2020. Web. 08 Mar 2021.
Vancouver:
Smith KA. Synthesis of a Reversible Crosslinked Hydrogel. [Internet] [Masters thesis]. University of Toronto; 2020. [cited 2021 Mar 08].
Available from: http://hdl.handle.net/1807/103122.
Council of Science Editors:
Smith KA. Synthesis of a Reversible Crosslinked Hydrogel. [Masters Thesis]. University of Toronto; 2020. Available from: http://hdl.handle.net/1807/103122
University of Toronto
10.
Czupiel, Petro Pawlo.
Synergistic Nanoparticle Formulations against Multi-drug Resistant Breast Cancers.
Degree: PhD, 2019, University of Toronto
URL: http://hdl.handle.net/1807/98593
► Current breast cancer treatments lack specificity, leading to dose-limiting cardiotoxicity, which is often coupled with multi-drug resistance (MDR), and thus severely impedes efficacious cancer treatment.…
(more)
▼ Current breast cancer treatments lack specificity, leading to dose-limiting cardiotoxicity, which is often coupled with multi-drug resistance (MDR), and thus severely impedes efficacious cancer treatment. Current efforts to utilize chemotherapeutics and MDR inhibitors have failed in the clinic due to low efficacy, off-target toxicities, and altered pharmacokinetics. Synergistic nanoparticles (NPs) offer spatiotemporal control of therapeutics from the injection site to the tumor site. Synergistic NPs co-encapsulate two or more drugs, whereby the co-encapsulated drugs exhibit anti-cancer activity greater than the sum of the anti-cancer activity exhibited by the single-drug loaded NPs. This thesis demonstrates that doubly-loaded NPs are more efficacious against multi-drug resistant (MDR) breast cancer cells in vitro, relative to each drug alone or combined, singly-loaded drug NPs. The NPs, comprising poly(D,L-lactide-co-2-methyl-2-carboxytrimethylene carbonate)-graft-poly(ethylene glycol)-azide (P(LA-co-TMCC)-g-PEG-N3), were used to co-encapsulate two therapeutics and evaluate their synergistic cytotoxicity of MDR cancer cells: vitamin E succinate modified with octahistidine-octaarginine (VES-H8R8) and a pH-responsive prodrug of doxorubicin (pDox).
The mechanism of the anti-cancer activity of VES-H8R8 comprised MDR efflux inhibition, mitochondria depolarization with inhibited bioenergetics, and induction of reactive oxygen species, apoptosis and G1 cell cycle arrest. When VES-H8R8 was co-encapsulated with pDox in NPs, synergistic anti-cancer activity against MDR breast cancer cells was observed, but only when co-encapsulated NPs were administered.
Work towards NP-mediated delivery of siRNA targeted against an essential protein, eukaryotic translation initiation factor 3 subunit B (eIF3B), is also presented; however, limitations associated with endo/lysosomal accumulation terminated the use of NPs comprising P(LA-co-TMCC)-g-PEG-N3.
This thesis provides the groundwork to study synergistic anti-cancer activity against MDR breast cancer in vivo.
Advisors/Committee Members: Shoichet, Molly S., Chemical Engineering Applied Chemistry.
Subjects/Keywords: Cancer; chemotherapeutics; Mitochondria; Multi-drug resistance; Nanoparticles; Synergistic; 0541
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APA (6th Edition):
Czupiel, P. P. (2019). Synergistic Nanoparticle Formulations against Multi-drug Resistant Breast Cancers. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/98593
Chicago Manual of Style (16th Edition):
Czupiel, Petro Pawlo. “Synergistic Nanoparticle Formulations against Multi-drug Resistant Breast Cancers.” 2019. Doctoral Dissertation, University of Toronto. Accessed March 08, 2021.
http://hdl.handle.net/1807/98593.
MLA Handbook (7th Edition):
Czupiel, Petro Pawlo. “Synergistic Nanoparticle Formulations against Multi-drug Resistant Breast Cancers.” 2019. Web. 08 Mar 2021.
Vancouver:
Czupiel PP. Synergistic Nanoparticle Formulations against Multi-drug Resistant Breast Cancers. [Internet] [Doctoral dissertation]. University of Toronto; 2019. [cited 2021 Mar 08].
Available from: http://hdl.handle.net/1807/98593.
Council of Science Editors:
Czupiel PP. Synergistic Nanoparticle Formulations against Multi-drug Resistant Breast Cancers. [Doctoral Dissertation]. University of Toronto; 2019. Available from: http://hdl.handle.net/1807/98593
University of Toronto
11.
Payne, Samantha Louise.
An Investigation of the Impact of Cell Maturity on Transplantation Success for Stroke.
Degree: PhD, 2018, University of Toronto
URL: http://hdl.handle.net/1807/92016
► Stroke is a devastating disease that affects millions of people worldwide and leads to lifelong disabilities. Increasingly, transplantation of an exogenous source of cells is…
(more)
▼ Stroke is a devastating disease that affects millions of people worldwide and leads to lifelong disabilities. Increasingly, transplantation of an exogenous source of cells is becoming a feasible strategy to regain function, however preclinical studies suffer from a lack of long term cell survival. To increase transplanted cell survival and differentiation, we explored two main strategies: 1) Transplantation in a biocompatible hydrogel delivery system, and 2) Transplantation of neural progenitor cells of increasing neuronal maturation. We hypothesized that the initial neuronal maturity of the cell population will impact in vitro survival, and consequently functional recovery in a rat model of stroke following intracortical delivery in a hydrogel. To test this hypothesis, we delivered cells in a hydrogel composed of hyaluronan and methylcellulose, termed HAMC, previously shown to be beneficial for cell delivery in models of retinal degeneration, spinal cord injury and stroke. Three populations of neuronal progenitors were differentiated from human cortically-specified neural progenitor cells (cNEPs) and selected along the maturation continuum: early (day 0), mid (day 16) and late (day 32) differentiated cells. Early, mid and late differentiated cells were transplanted into the stroke-injured rat brain and cell survival and fate was investigated one and 7 weeks later. Surprisingly, at 7 weeks there was no difference in cell survival or fate between the groups tested; however early differentiated cells exhibited significant improvement in behavioural recovery. It was determined by testing in vitro post-injection cell viability that late differentiated cells experience more cell death during the transplantation process. Furthermore, we investigated the phenotype of cells following injection and found that mature cells are preferentially killed during this process, leading to the elimination of any differences in maturity once cells are injected into the brain. We also determined that this acute cell death negatively affects the host tissue, including increased lesion volume, cell death and gliosis. These findings suggest that the transplantation process can drastically alter the desired transplant population, affecting the targeted outcome of the delivery strategy, and should be taken into careful consideration when designing any transplantation therapy.
뇌졸중은 전 세계적으로 수백만 명의 사람들에게 영향을 미치며 평생 장애로 이어지는 파괴적인 질병입니다. 점차적으로, 외인성 세포원의 이식은 기능을 되 찾는 실현 가능한 전략이되고 있지만, 전임상 연구는 장기 세포 생존의 결핍으로 어려움을 겪고있다. 이식 된 세포 생존 및 분화를 증가시키기 위해, 우리는 2 가지 주요 전략, 즉 1) 생체 적합성 하이드로 겔 전달 시스템에서의 이식, 2) 증가하는 연결 성숙의 신경 전구 세포의 이식. 우리는 세포 집단의 초기의 연결 성숙이 생체 외 생존에 영향을 미치고 결과적으로 하이드로 겔 내 대뇌 피질 전달 후 뇌졸중의 쥐 모델에서 기능 회복에 영향을 미칠 것이라는 가설을 세웠다. 이 가설을 시험하기 위해, 우리는 이전에 망막 변성, 척수 손상 및 뇌졸중 모델에서 세포 전달에 유리한 것으로 나타 났던 HAMC라고 불리는 히알루 론산과 메틸 셀룰로오스로 구성된 하이드로 겔에 세포를 전달했습니다. 신경 전구 세포의 세 집단은 인간 피질 - 지정 신경 전구 세포 (cNEPs)와 차별화되어 성숙 연속체를 따라 선택되었다 : 초기 (0 일), 중간 (16 일) 및 늦은 (32 일) 분화 된 세포. 뇌졸중에 걸린 쥐의 뇌에 초기, 중기 및 후기 분화 세포를 이식하여 1 주 및 7 주 후에 세포 생존과 운명을 조사했다. 놀랍게도, 7 주에 실험 된 그룹 사이에 세포 생존이나…
Advisors/Committee Members: Shoichet, Molly S, Chemical Engineering Applied Chemistry.
Subjects/Keywords: Cell Delivery; Hydrogel; Neuroscience; Regenerative Medicine; Stem Cells; 0541
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APA (6th Edition):
Payne, S. L. (2018). An Investigation of the Impact of Cell Maturity on Transplantation Success for Stroke. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/92016
Chicago Manual of Style (16th Edition):
Payne, Samantha Louise. “An Investigation of the Impact of Cell Maturity on Transplantation Success for Stroke.” 2018. Doctoral Dissertation, University of Toronto. Accessed March 08, 2021.
http://hdl.handle.net/1807/92016.
MLA Handbook (7th Edition):
Payne, Samantha Louise. “An Investigation of the Impact of Cell Maturity on Transplantation Success for Stroke.” 2018. Web. 08 Mar 2021.
Vancouver:
Payne SL. An Investigation of the Impact of Cell Maturity on Transplantation Success for Stroke. [Internet] [Doctoral dissertation]. University of Toronto; 2018. [cited 2021 Mar 08].
Available from: http://hdl.handle.net/1807/92016.
Council of Science Editors:
Payne SL. An Investigation of the Impact of Cell Maturity on Transplantation Success for Stroke. [Doctoral Dissertation]. University of Toronto; 2018. Available from: http://hdl.handle.net/1807/92016
University of Toronto
12.
Logie, Jennifer.
Design and Synthesis of Self-Assembled Polymeric Nanoparticles for Cancer Drug Delivery.
Degree: PhD, 2017, University of Toronto
URL: http://hdl.handle.net/1807/79178
► Current chemotherapeutics are plagued by poor solubility and selectivity, requiring toxic excipients in formulations and causing a number of dose limiting side effects. Nanoparticle delivery…
(more)
▼ Current chemotherapeutics are plagued by poor solubility and selectivity, requiring toxic excipients in formulations and causing a number of dose limiting side effects. Nanoparticle delivery has emerged as a strategy to more effectively deliver chemotherapeutics to the tumour site. Specifically, polymeric micelles enable the solubilization of hydrophobic small molecule drugs within the core and mitigate the necessity of excipients. Notwithstanding the significant progress made in polymeric micelle delivery, translation is limited by poor stability and low drug loading. In this work, a rational design approach is used to chemically modify poly(D,L-lactide-co-2-methyl-2-carboxytrimethylene carbonate)-graft-poly(ethylene glycol) (P(LA-co-TMCC)-g-PEG) in order to overcome these limitations and effectively deliver drug to tumours.
The PEG density of the polymer system was optimized to enhance the stability of our polymeric micelles. Higher PEG densities permitted the lyophilization of micelles and enhanced the serum stability of the system. To increase the drug loading of our system, we facilitated specific intermolecular interactions within the micelle core. For drugs that form colloidal aggregates, such as pentyl-PABC doxazolidine, polymers were used to stabilize the colloidal core against aggregation and protein adsorption. For more challenging molecules, where self-assembly cannot be controlled, such as docetaxel, we modified the polymeric backbone with a peptide from the binding site of the drug to achieve loadings five times higher than those achieved in conventional micelle systems. This novel docetaxel nanoparticle was assessed in vivo in an orthotopic mouse model of breast cancer, where it showed a wider therapeutic index than the conventional ethanolic polysorbate 80 formulation. The improved tolerability of this formulation enabled higher dosing regimens and led to heightened efficacy and survival in this mouse model. Combined, these studies validated P(LA-co-TMCC)-g-PEG nanoparticles as an effective delivery vehicle for two chemotherapeutics, and presents approaches amenable to the delivery of many other clinically relevant hydrophobic drugs or drug combinations.
Advisors/Committee Members: Shoichet, Molly S, Chemical Engineering Applied Chemistry.
Subjects/Keywords: Cancer; Drug Delivery; Micelle; Nanoparticle; Polymer; 0541
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APA (6th Edition):
Logie, J. (2017). Design and Synthesis of Self-Assembled Polymeric Nanoparticles for Cancer Drug Delivery. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/79178
Chicago Manual of Style (16th Edition):
Logie, Jennifer. “Design and Synthesis of Self-Assembled Polymeric Nanoparticles for Cancer Drug Delivery.” 2017. Doctoral Dissertation, University of Toronto. Accessed March 08, 2021.
http://hdl.handle.net/1807/79178.
MLA Handbook (7th Edition):
Logie, Jennifer. “Design and Synthesis of Self-Assembled Polymeric Nanoparticles for Cancer Drug Delivery.” 2017. Web. 08 Mar 2021.
Vancouver:
Logie J. Design and Synthesis of Self-Assembled Polymeric Nanoparticles for Cancer Drug Delivery. [Internet] [Doctoral dissertation]. University of Toronto; 2017. [cited 2021 Mar 08].
Available from: http://hdl.handle.net/1807/79178.
Council of Science Editors:
Logie J. Design and Synthesis of Self-Assembled Polymeric Nanoparticles for Cancer Drug Delivery. [Doctoral Dissertation]. University of Toronto; 2017. Available from: http://hdl.handle.net/1807/79178
University of Toronto
13.
Obermeyer, Jaclyn Marie.
Encapsulation-Free Local Delivery of BDNF Enhances Recovery in Stroke-Injured Rats.
Degree: PhD, 2018, University of Toronto
URL: http://hdl.handle.net/1807/92138
► Until the early 1990s it was common belief that the adult brain did not possess the capacity to change or regenerate. We now know that…
(more)
▼ Until the early 1990s it was common belief that the adult brain did not possess the capacity to change or regenerate. We now know that the adult brain is not static and is able to repair itself to a small degree. Through examination of endogenous processes, brain-derived neurotrophic factor (BDNF) has emerged as a key modulator of plasticity in both the healthy and stroke-injured brains, and benefits to recovery have been demonstrated upon its administration; yet, current delivery strategies are highly invasive or inefficient. The work presented herein describes an effective, biomaterial-based strategy for minimally invasive local delivery of BDNF using a revolutionized approach to control protein release.
BDNF incorporation into a composite consisting of poly(lactic-co-glycolic acid) (PLGA) nanoparticles and a hyaluronan and methyl cellulose (HAMC) hydrogel provided sustained release of the protein, using electrostatics to control release without encapsulation. When delivered epi-cortically to a rat endothelin-1 model of stroke injury, BDNF diffused from the HAMC/PLGA composite into the lesioned tissue and resulted in improved early forelimb recovery and delayed hindlimb performance enhancement. Tissue analysis revealed synaptic plasticity in the contralesional hemisphere at the time of sacrifice, suggesting that these behavioural effects were due to increased plasticity in the uninjured tissue. These studies validate the use of BDNF for plasticity-mediated stroke treatment and provide a minimally invasive strategy for effective, local delivery to the brain.
Advisors/Committee Members: Shoichet, Molly S, Chemical Engineering Applied Chemistry.
Subjects/Keywords: BDNF; biomaterials; drug delivery; hydrogel; nanoparticle; stroke; 0542
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APA (6th Edition):
Obermeyer, J. M. (2018). Encapsulation-Free Local Delivery of BDNF Enhances Recovery in Stroke-Injured Rats. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/92138
Chicago Manual of Style (16th Edition):
Obermeyer, Jaclyn Marie. “Encapsulation-Free Local Delivery of BDNF Enhances Recovery in Stroke-Injured Rats.” 2018. Doctoral Dissertation, University of Toronto. Accessed March 08, 2021.
http://hdl.handle.net/1807/92138.
MLA Handbook (7th Edition):
Obermeyer, Jaclyn Marie. “Encapsulation-Free Local Delivery of BDNF Enhances Recovery in Stroke-Injured Rats.” 2018. Web. 08 Mar 2021.
Vancouver:
Obermeyer JM. Encapsulation-Free Local Delivery of BDNF Enhances Recovery in Stroke-Injured Rats. [Internet] [Doctoral dissertation]. University of Toronto; 2018. [cited 2021 Mar 08].
Available from: http://hdl.handle.net/1807/92138.
Council of Science Editors:
Obermeyer JM. Encapsulation-Free Local Delivery of BDNF Enhances Recovery in Stroke-Injured Rats. [Doctoral Dissertation]. University of Toronto; 2018. Available from: http://hdl.handle.net/1807/92138
University of Toronto
14.
Ganesh, Ahil.
Controlling the Stability of Colloidal Drug Aggregates for Chemotherapeutic Delivery.
Degree: PhD, 2019, University of Toronto
URL: http://hdl.handle.net/1807/95863
► Colloidal aggregation presents a significant nuisance in drug discovery programs; the self-assembly of hydrophobic compounds into colloidal particles leads to numerous artifactual results in screening…
(more)
▼ Colloidal aggregation presents a significant nuisance in drug discovery programs; the self-assembly of hydrophobic compounds into colloidal particles leads to numerous artifactual results in screening assays. In biochemical enzyme inhibition assays colloids non-specifically adsorb proteins leading to partial unfolding and enzyme inactivation. In cell-based cytotoxicity assays colloids are unable to cross cell membranes leading to the drug being unable to bind to its intracellular target, resulting in apparent inactivity. Colloidal aggregation is not only common among drug screening candidates but also among clinically used drugs. Being composed entirely of active drug, colloidal drug aggregates have many properties that make them suitable as nanoparticle drug formulations. In this work, two methods to stabilize colloidal drug aggregates were developed to enable targeted delivery and in vivo utility.
First, exploiting the ability of drug colloids to adsorb proteins, we formed controlled protein coronas to stabilize colloids in both buffered solutions and serum-containing media. Coronas comprising antibodies not only stabilized colloids but also enabled their specific internalization by target cells. Second, incorporation of amphiphilic surfactants during colloid formation resulted in a hydrophilic polymer layer that sterically stabilized drug colloids. Incorporation of surfactants significantly reduced protein adsorption, stabilizing drug colloids in serum-containing media. We designed methods to test colloid stability in high serum media in vitro based on co-aggregation with fluorescent FRET pairs. Finally, we investigated the influence of stable colloidal drug aggregates on the in vivo pharmacokinetics of chemotherapeutics. Stable colloidal formulations showed increased plasma circulation half-lives compared to solubilized, monomeric formulations. Overall, we demonstrate methods to stabilize, study and utilize colloidal drug aggregates, turning a nuisance into an opportunity for drug formulation.
Advisors/Committee Members: Shoichet, Molly S, Chemical Engineering Applied Chemistry.
Subjects/Keywords: 0542
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APA (6th Edition):
Ganesh, A. (2019). Controlling the Stability of Colloidal Drug Aggregates for Chemotherapeutic Delivery. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/95863
Chicago Manual of Style (16th Edition):
Ganesh, Ahil. “Controlling the Stability of Colloidal Drug Aggregates for Chemotherapeutic Delivery.” 2019. Doctoral Dissertation, University of Toronto. Accessed March 08, 2021.
http://hdl.handle.net/1807/95863.
MLA Handbook (7th Edition):
Ganesh, Ahil. “Controlling the Stability of Colloidal Drug Aggregates for Chemotherapeutic Delivery.” 2019. Web. 08 Mar 2021.
Vancouver:
Ganesh A. Controlling the Stability of Colloidal Drug Aggregates for Chemotherapeutic Delivery. [Internet] [Doctoral dissertation]. University of Toronto; 2019. [cited 2021 Mar 08].
Available from: http://hdl.handle.net/1807/95863.
Council of Science Editors:
Ganesh A. Controlling the Stability of Colloidal Drug Aggregates for Chemotherapeutic Delivery. [Doctoral Dissertation]. University of Toronto; 2019. Available from: http://hdl.handle.net/1807/95863
University of Toronto
15.
Pakulska, Malgorzata Maria.
Combined Delivery of Chondroitinase ABC (ChABC) and Stromal Cell Derived Factor 1α (SDF1α) for Spinal Cord Regeneration.
Degree: PhD, 2016, University of Toronto
URL: http://hdl.handle.net/1807/89261
► Spinal cord injury (SCI) is a devastating condition that affects millions of people worldwide. Successful drug therapies for SCI have been difficult to achieve due…
(more)
▼ Spinal cord injury (SCI) is a devastating condition that affects millions of people worldwide. Successful drug therapies for SCI have been difficult to achieve due to the complex nature of the pathology. Increasingly, researchers are moving towards combination strategies using at least two therapeutics that target distinct injury pathways. Furthermore, sustained drug delivery to the spinal cord is complicated by the presence of the blood spinal cord barrier (BSCB) and cerebrospinal fluid flow. In this work, an injectable hydrogel was designed for the minimally invasive, localized, sustained delivery of two different protein therapeutics to the injured spinal cord: chondroitinase ABC (ChABC), an enzyme that degrades the glial scar, and stromal cell-derived factor 1Îą (SDF), a chemokine implicated in the migration of endogenous neural precursor cells (NPC) to the site of SCI.
Design of experiment (DOE) was used to explore the relationships between composition and mechanical properties of a physically and chemically crosslinked methylcellulose hydrogel (XMC). An optimal gel formulation that was injectable, minimally swelling, long-lasting, and safe in vivo, was chosen for future studies.
Active ChABC was released from XMC for at least 7 days using reversible affinity interactions. Additionally, a mathematical model was developed to provide a mechanistic understanding of affinity-based release systems and allow for rational design. Active SDF was released from XMC for at least 28 days by exploiting electrostatic interactions with negatively charged poly(lactic-co-glycolic acid) nanoparticles (PLGA np). This is the first evidence of long-term protein release using PLGA np without encapsulation.
The efficacy of this combined treatment was tested in a rat model of compressive SCI. ChABC treatment resulted in decreased chondroitin sulfate proteoglycan (CSPG) levels for up to two weeks after injury and a trend towards improved behavioural recovery. Treatment with SDF did not improve behavioural nor histological outcomes and did not show any synergy with ChABC.
Together these studies introduce XMC as a novel, injectable hydrogel platform for therapeutic protein delivery to the spinal cord and demonstrate two different methods of controlling protein release from this hydrogel.
2018-07-08 00:00:00
Advisors/Committee Members: Shoichet, Molly S, Chemical Engineering Applied Chemistry.
Subjects/Keywords: adult stem cells; chondroitinase abc; CXCL12; drug delivery; glial scar; spinal cord; 0541
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APA (6th Edition):
Pakulska, M. M. (2016). Combined Delivery of Chondroitinase ABC (ChABC) and Stromal Cell Derived Factor 1α (SDF1α) for Spinal Cord Regeneration. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/89261
Chicago Manual of Style (16th Edition):
Pakulska, Malgorzata Maria. “Combined Delivery of Chondroitinase ABC (ChABC) and Stromal Cell Derived Factor 1α (SDF1α) for Spinal Cord Regeneration.” 2016. Doctoral Dissertation, University of Toronto. Accessed March 08, 2021.
http://hdl.handle.net/1807/89261.
MLA Handbook (7th Edition):
Pakulska, Malgorzata Maria. “Combined Delivery of Chondroitinase ABC (ChABC) and Stromal Cell Derived Factor 1α (SDF1α) for Spinal Cord Regeneration.” 2016. Web. 08 Mar 2021.
Vancouver:
Pakulska MM. Combined Delivery of Chondroitinase ABC (ChABC) and Stromal Cell Derived Factor 1α (SDF1α) for Spinal Cord Regeneration. [Internet] [Doctoral dissertation]. University of Toronto; 2016. [cited 2021 Mar 08].
Available from: http://hdl.handle.net/1807/89261.
Council of Science Editors:
Pakulska MM. Combined Delivery of Chondroitinase ABC (ChABC) and Stromal Cell Derived Factor 1α (SDF1α) for Spinal Cord Regeneration. [Doctoral Dissertation]. University of Toronto; 2016. Available from: http://hdl.handle.net/1807/89261
University of Toronto
16.
Fisher, Stephanie Anne.
Development of a Breast Cancer Cell Microenvironment in Three-Dimensional Hyaluronic Acid Based Hydrogels.
Degree: PhD, 2018, University of Toronto
URL: http://hdl.handle.net/1807/89784
► Breast cancer cell invasion is influenced by the tumor microenvironment including the extracellular matrix, mechanical properties, stromal cells, and bioactive factors. To elucidate the role…
(more)
▼ Breast cancer cell invasion is influenced by the tumor microenvironment including the extracellular matrix, mechanical properties, stromal cells, and bioactive factors. To elucidate the role of the microenvironment on cell invasion, defined 3-dimensional hydrogel models are required because xenograft models are too complex and 2-dimensional models lack a matrix for cell invasion and often do not recapitulate the appropriate mechanical properties. Breast cancer cell invasion is also influenced by gradients of epidermal growth factor (EGF); however, studying the influence of EGF gradients is challenging due to their transient nature and convoluted in vivo models. In this work, a hyaluronic acid (HA) based hydrogel crosslinked with matrix metalloproteinase (MMP) cleavable peptides (HA/MMPx) was developed to study the role of the microenvironment on breast cancer cell invasion. Specifically, crosslink density, adhesive ligand density, and MMP cleavable peptides were evaluated. Defined EGF gradients were photochemically immobilized into HA/MMPx hydrogels to evaluate the invasion and drug response of breast cancer cells with different EGF receptor (EGFR) expression levels.
The crosslink and ligand densities of HA/MMPx hydrogels were decoupled to elucidate their effect on the invasion of MDA-MB-231 breast cancer cells. Increasing crosslink density decreased MDA-MB-231 invasion because more crosslinks had to be degraded for the cells to move through the hydrogel. Increasing adhesive ligand (GRGDS) density did not effect MDA-MB-231 invasion, but did increase cell number. The MMP cleavable crosslinker increased MDA-MB-231 cell invasion relative to a non-cleavable control, confirming that invasion is facilitated by cell-mediated matrix degradation. Immobilized EGF gradients in the HA/MMPx hydrogels differentially affected breast cancer cells with varying levels of EGFR expression: EGF gradients increased the invasion of moderate EGFR expressing MDA-MB-231 cells, decreased the invasion of high EGFR expressing MDA-MB-468 cells, and had no effect on low EGFR expressing MCF-7 cells. The EGFR inhibitor cetuixmab reversed the effects of EGF, decreasing MDA-MB-231 and increasing MDA-MB-468 cell invasion on EGF gradients. With these studies, we developed a versatile platform to study the influence of the microenvironment on breast cancer cell invasion and demonstrated the importance of including microenvironmental factors in culturing platforms when evaluating drugs that target these interactions.
Advisors/Committee Members: Shoichet, Molly S., Chemical Engineering Applied Chemistry.
Subjects/Keywords: Breast cancer; Epidermal growth factor; Gradients; Hydrogel; Invasion; Photochemistry; 0541
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MLA ·
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APA (6th Edition):
Fisher, S. A. (2018). Development of a Breast Cancer Cell Microenvironment in Three-Dimensional Hyaluronic Acid Based Hydrogels. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/89784
Chicago Manual of Style (16th Edition):
Fisher, Stephanie Anne. “Development of a Breast Cancer Cell Microenvironment in Three-Dimensional Hyaluronic Acid Based Hydrogels.” 2018. Doctoral Dissertation, University of Toronto. Accessed March 08, 2021.
http://hdl.handle.net/1807/89784.
MLA Handbook (7th Edition):
Fisher, Stephanie Anne. “Development of a Breast Cancer Cell Microenvironment in Three-Dimensional Hyaluronic Acid Based Hydrogels.” 2018. Web. 08 Mar 2021.
Vancouver:
Fisher SA. Development of a Breast Cancer Cell Microenvironment in Three-Dimensional Hyaluronic Acid Based Hydrogels. [Internet] [Doctoral dissertation]. University of Toronto; 2018. [cited 2021 Mar 08].
Available from: http://hdl.handle.net/1807/89784.
Council of Science Editors:
Fisher SA. Development of a Breast Cancer Cell Microenvironment in Three-Dimensional Hyaluronic Acid Based Hydrogels. [Doctoral Dissertation]. University of Toronto; 2018. Available from: http://hdl.handle.net/1807/89784
University of Toronto
17.
Elliott Donaghue, Irja.
Controlled Delivery of Therapeutic Proteins to the Injured Spinal Cord.
Degree: PhD, 2016, University of Toronto
URL: http://hdl.handle.net/1807/73176
► Spinal cord injury (SCI) results in severe disability and currently lacks effective clinical treatments. Pre-clinical and clinical research have demonstrated the potential for both cell…
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▼ Spinal cord injury (SCI) results in severe disability and currently lacks effective clinical treatments. Pre-clinical and clinical research have demonstrated the potential for both cell and protein therapeutic strategies; however, a critical challenge is the lack of localized, sustained delivery of bioactive therapeutics. A composite drug delivery system (DDS) consisting of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (np) dispersed in a hyaluronan/methyl cellulose (HAMC) hydrogel was previously found to provide sustained protein release in vitro and compatibility in vivo. This np/hydrogel DDS was further developed for the localized, sustained, and bioactive delivery of platelet-derived growth factor-AA (PDGF-AA), neurotrophin-3 (NT-3), and anti-NogoA. The release of PDGF-AA was sustained over 21 d and the PDGF-AA DDS induced the oligodendrocyte differentiation of neural stem/progenitor cells in vitro. The release of PDGF-AA was affected by the excipient poly(ethylene glycol) (PEG400), which had variable effects on protein stability. The delivery of NT-3 was sustained for up to 49 d in vitro and at least 28 d in vivo, and the NT-3 DDS induced axon growth and modest recovery of function in a model of compressive SCI. Surprisingly, electrostatic interactions occurred between soluble NT-3 and the DDS that delayed release. This discovery led to the development of an encapsulation-free np/hydrogel DDS that provides sustained, tunable release of NT-3 as well as stromal cell-derived factor (SDF) and brain-derived neurotrophic factor (BDNF) and is applicable to many other proteins. Finally, the np/hydrogel DDS was adapted for the combined, bioactive delivery of NT-3 and anti-NogoA. Combined delivery of NT-3 and anti-NogoA increased axon density, reduced the inhibitory environment, and promoted functional recovery after delivery to the injured spinal cord. This work demonstrates that the np/hydrogel DDS is effective for the delivery of growth/differentiation factors as well as therapeutic proteins for the treatment of spinal cord injury.
2016-07-20 00:00:00
Advisors/Committee Members: Shoichet, Molly S, Chemical Engineering Applied Chemistry.
Subjects/Keywords: drug delivery; hydrogel; nanoparticle; PLGA; protein; spinal cord injury; 0542
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APA (6th Edition):
Elliott Donaghue, I. (2016). Controlled Delivery of Therapeutic Proteins to the Injured Spinal Cord. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/73176
Chicago Manual of Style (16th Edition):
Elliott Donaghue, Irja. “Controlled Delivery of Therapeutic Proteins to the Injured Spinal Cord.” 2016. Doctoral Dissertation, University of Toronto. Accessed March 08, 2021.
http://hdl.handle.net/1807/73176.
MLA Handbook (7th Edition):
Elliott Donaghue, Irja. “Controlled Delivery of Therapeutic Proteins to the Injured Spinal Cord.” 2016. Web. 08 Mar 2021.
Vancouver:
Elliott Donaghue I. Controlled Delivery of Therapeutic Proteins to the Injured Spinal Cord. [Internet] [Doctoral dissertation]. University of Toronto; 2016. [cited 2021 Mar 08].
Available from: http://hdl.handle.net/1807/73176.
Council of Science Editors:
Elliott Donaghue I. Controlled Delivery of Therapeutic Proteins to the Injured Spinal Cord. [Doctoral Dissertation]. University of Toronto; 2016. Available from: http://hdl.handle.net/1807/73176
. 
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