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Development of Polylactide-based Reduction-responsive Degradable Nanomaterials for Multifunctional Biomedical Applications

Title:

Development of Polylactide-based Reduction-responsive Degradable Nanomaterials for Multifunctional Biomedical Applications

Ko, Na Re (2015) Development of Polylactide-based Reduction-responsive Degradable Nanomaterials for Multifunctional Biomedical Applications. PhD thesis, Concordia University.

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Abstract

Polylactide (PLA)-based nanomaterials have been extensively explored in biomedical applications due to their biocompatibility and biodegradability. However, PLA has two main limitations: hydrophobicity and slow degradation rate. My Ph.D. research focuses on the exploration of potential approaches to circumvent these challenges by synthesis of PLA-based amphiphilic block copolymers (ABPs) with stimuli-responsive degradation (SRD) and these ABPs are used to fabricate novel PLA-based nanomaterials.
SRD is highly desirable in the design of multi-functional polymer-based drug delivery systems. SRD involves the incorporation of dynamic covalent bonds into nanomaterials that can be cleaved in response to external stimuli such as light, ultrasound, low pH, and enzymes. This process leads to chemical or physical changes of nanomaterials to enhance the release of therapeutics or tune the morphologies. Reduction-responsive degradation uses disulfide-thiol chemistry. Disulfide linkages are cleaved either in response to a reductive environment or a disulfide-thiol exchange reaction in the presence of thiols. Using this unique system, PLA-based nanomaterials with disulfide linkages can be developed for tumor-targeting drug delivery.
Amphiphilic micellar aggregates have attracted much interest as a promising candidate for effective polymeric drug delivery. Micelles are formed through aqueous self-assembly of ABPs consisting of both hydrophilic and hydrophobic blocks. Hydrophobic cores encapsulate hydrophobic therapeutics and the surrounding hydrophilic coronas enhance colloidal stability. Adjusting this unique structure of ABP is a promising strategy for circumventing the hydrophobicity of PLA. Uniformed micelles in the nanoscale size range can prolong the blood residence and minimize side effects, and possess multiple cargos into a single vehicle, allowing multi-functional drug delivery.
In this thesis, several reduction-responsive degradable PLA-based ABPs have been reported. They were further used to fabricate various nanomaterials including micellar drug carriers; polyplexes; and nanofibers. These ABPs were synthesized by a combination method of ring opening polymerization and atom transfer radical polymerization. Due to their amphiphilic nature, ABPs can be self-assembled to form the micellar platforms possessing hydrophobic therapeutics in the core, which is surrounded with hydrophilic coronas. ABPs with positively charged hydrophilic blocks enable the formation of cationic micellar aggregates. These cationic micelles have subsequently been used as dual delivery carriers of drugs and genes. Furthermore, incorporating dual-located disulfide linkages at both the hydrophobic PLA core and the interface leads to a synergistically enhanced release of encapsulated drugs in cellular environments. Moreover, PLA nanofibers were fabricated via air-spinning technique of high-molecular weight PLAs. Their hydrophobic surface was modified with hydrophilic polymers via facile surface-initiated ATRP. The resulting surface-modified PLA fibers exhibit enhanced hydrophilicity and thermal stability, as well as tunable surface properties upon the cleavage of disulfide linkages. Under a reductive environment, these novel PLA-based nanomaterials are rapidly degraded upon the cleavage of disulfides, leading to controlled release of drugs and genes, as well as change of surface properties. These results suggest the disulfide-labeled PLA-based nanomaterials offer great potential and versatility in biomedical applications.

Divisions:Concordia University > Faculty of Arts and Science > Chemistry and Biochemistry
Item Type:Thesis (PhD)
Authors:Ko, Na Re
Institution:Concordia University
Degree Name:Ph. D.
Program:Chemistry
Date:July 2015
Thesis Supervisor(s):Oh, John
ID Code:980187
Deposited By: NA RE KO
Deposited On:27 Oct 2015 19:36
Last Modified:18 Jan 2018 17:50
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