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Versatile Polymer-Based Nanomedicines for Drug/Gene Delivery and Cell-based Therapy Applications
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- Author / Creator
- Diaz Dussan, Diana M.
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Advances in polymer science and nanotechnology have allowed the development of biomaterials for cell-based applications, such as the delivery of a variety of drugs and genes, as well as supporting technologies, such as stem cell therapies, tissue engineering and cryopreservation. The progress in the synthesis of innovative nano-structures such as liposomes, nanocapsules, polymeric nanoparticles, hydrogels and micelles, have enabled the potential in active and passive targeting delivery as well as the development of stimuli responsive matrices. Polymers play a crucial role in this field, nonetheless various challenges must be addressed such as, improving their loading capacity to enhanced targeted delivery and controlled release in the case of nanocarriers, and in simulating the biological microenvironment, supporting cellular differentiation when using as biological matrices. Complex design of multifunctional polymeric carriers, like stimuli-responsive glycopolymer-based nanoparticles, hydrogels and nanogels, has been demonstrated as an outstanding approach for introducing advanced multiresponsive properties and targeting molecules, triggering target drug/gene delivery and “smart” release. My contributions in this thesis explored the development of leading-edge strategies for the design of glycopolymer-based nanomedicines with a central hypothesis that carbohydrate ligand molecules specific to cell-surface biomarkers will enhance the interaction of these nano-drug systems with target cells by mimicking lectin ligands and antifreeze glycoproteins inspired by nature, which will translate into an increased therapeutic index for the integrated drug/gene and offer enriched cell-therapies capabilities.
In this thesis work, we explored the use of diverse polymer chemistries and architectures to develop gene, drug delivery systems and cryopreservation agents. To achieve this, first we explored the dynamic bond between benzoxaborole and the hydroxyl groups of the glycopolymer sugars to develop oxaborole-galactose based glycopolymers for the delivery of epidermal growth factor receptor (EFGR) siRNA to treat cervical carcinomas. This reversible interaction provided an effective release of the siRNA cargo inside the cancer cells displaying 60% gene silencing and lower cytotoxicity. Furthermore, we developed dynamic-sugar benzoxaborole polyplexes with a dual capability: a cationic segment to complex with the siRNA and an omega-end modified with an oxaborole group via thiol-ene click chemistry that responds to the acidic tumour microenvironment. This design facilitated the interaction with multiple polyplexes and release of the siRNA in a mildly acidic environment; showing enhanced gene silencing (70%) without elevating the system's cytotoxicity. Then, we decorated a Poly(glycidyl methacrylate) (PGMA)-based polymer with carbohydrate moieties for its application in gene therapy, where an optimum balance of the sugar content needed to be maintained to offer both knockdown efficiency and biocompatibility. In addition, a trehalose-based polyether was developed for cellular cryopreservation demonstrating high biocompatibility and post-thaw cell membrane integrity in cancer and normal cell lines under both controlled-rate and ultrarapid freezing protocols as well as the ability to form hydrogels as 3D cell culture scaffolds. Finally, a hypoxia-activated carbohydrate-based nanogel was explored for the delivery of Iodoazomycin Arabinoside (IAZA), a hypoxia-activated prodrug (HAP), for hypoxic cancer imaging and treatment. IAZA is a HAP that possesses structural features that enable its use as both an imaging and therapeutic agent. Thus, this novel engineered nanoformulation is a beyond state-of-the-art approach for theranostic management of hypoxic solid tumors. This technology delivers and provides controlled release of IAZA in physiological conditions, improving the biavailability of the drug in oxygen-deprived cancer cells and enhanced the theranostic effects when using this nanoformulation (nanoIAZA) in comparison to the parent drug itself. Superior therapeutic effects were observed with nanoIAZA when used as a chemotoxic agent (in vivo), and in combination with external beam radiation therapy in vitro (as a radiosensitizer). NanoIAZA described here shows the promise to release IAZA selectively inside hypoxic cancer cells over a longer period, attributing to enhanced drug dose build-up, resulting in further enhancement of therapeutic effects.
The glyco-nanomedicines systems explored in this thesis, have proved to facilitate targeted delivery combined with potential chemotherapeutic treatment — in the case of nanoIAZA as well as novel cryopreservation scaffolds with the trehalose-based hydrogels, thus offering effective multimodal vectors for biomedical management of diseases like cancer. Based on our proof-of-principle studies and results, I have made an attempt to unfold the pluripotential capability of these glyco-nanomedicines that legitimates and encourages the future design of non-viral glycopolymer-based delivery and scaffolds systems with clinical translation potential capabilities. -
- Graduation date
- Spring 2021
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- Type of Item
- Thesis
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- Degree
- Doctor of Philosophy
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- License
- This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.