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Author ORCID Identifier

N/A

AccessType

Open Access Dissertation

Document Type

dissertation

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Chemistry

Year Degree Awarded

2018

Month Degree Awarded

May

First Advisor

Sankaran Thayumanavan

Subject Categories

Life Sciences

Abstract

Biologically active agents like drugs, proteins and nucleic acids have been widely explored as therapeutics for numerous diseases and particularly for anti-cancer therapy. Delivering drugs, proteins and nucleic acids efficiently and safely is however the looming challenge in the field of chemical biology. A significant percentage of drugs are poorly water-soluble which affects its pharmacological properties for instance bioavailability, stability and dose dependent toxicity. Drug development and discovery is a time consuming and expensive process which typically takes more than a decade and costs more than 10 million dollars. Nucleic acids are also known to degrade rapidly by nucleases. Therapeutic delivery using a delivery vehicle is realized to be advantageous in many fronts. Delivery vehicles, specifically nanocarriers improve the physiochemical properties of conventional drugs like water solubility, biodistribution, reduce dose dependent toxicity, bioavailability and help in targeting. For nucleic acids, they essentially protect it from degradation and aid in intracellular transfection. Polymeric nanocarrier systems show superior characteristics as therapeutic delivery vehicles. Polymers are extremely versatile in terms of synthesis, incorporating reactive functional groups for stimuli responsive behavior and facile tunability of hydrophobic and/or hydrophilic segments for structure property relationship. Self-crosslinked polymeric nanocarriers developed in our group have shown important properties for therapeutic delivery like redox responsive release mechanism, size tunability, encapsulation stability etc. We have utilized this system as the blueprint and developed it to improve and address some crucial properties of drug delivery vehicles. We designed a crosslinked polymeric nanogel system composed of molecules that are approved by the FDA as safe and non-toxic. The nanogels were found to be highly non-toxic when evaluated by in vitro cell viability assay and a more rigorous mouse pre-implantation embryo toxicity assay. We were also interested to tackle the issue of poor drug loading capacity of nanocarriers and designed a core crosslinked polymer and designed methods to quantify drug loading in crosslinked polymeric systems where we were also curious in studying the structure property relationship of different drugs with varying LogP values. Lastly, we designed a safe delivery system for nucleic acids which utilizes the cationic charge in the polymer for complexation with nucleic acid but through convenient crosslinking strategy we could eliminate the charged moieties making it a promising strategy for nucleic acid delivery.

DOI

https://doi.org/10.7275/11655159.0

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