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Author ORCID Identifier

https://orcid.org/0000-0002-1402-9934

AccessType

Open Access Dissertation

Document Type

dissertation

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Chemistry

Year Degree Awarded

2020

Month Degree Awarded

September

First Advisor

Sankaran Thayumanavan

Subject Categories

Biomaterials | Cell Biology | Materials Chemistry | Organic Chemistry | Polymer Chemistry

Abstract

Biologic drugs have gained enormous research attention in recent years as reflected by the development of multiple candidates to the clinical pipelines and an increased percentage of FDA approval. This is reasoned by the fact that biologics have been proven to deliver more predictive and promising benefits for many hard-to-cure diseases by ‘drugging the undruggable’ targets. However, the challenges associated with biologic drug development are multi-fold, viz, poor encapsulation efficacy, systemic instability, low cellular internalization and endosomal escape capability. Thus, it is essential to develop new molecular strategies that can not only address the associated drug delivery challenges, but also help strengthen the fundamental chemical understanding to meet the future need of this rapidly evolving field.

Designing a supramolecular container that is capable of stably holding sensitive active and releasing them at target site upon environmental changes is a promising solution to tackle many complex challenges associated with functional delivery of therapeutics. Addressing this requires a basic understanding of the structural and functional factors to be engineered into the delivery vehicle. To this end, we have explored the interactions between synthetic polymers with various biologics to form well-defined self-assembled structures, wherein the function of the encapsulated active is only revealed upon specific structural modulation of the polymer surrounding it. In this dissertation, we have discussed the development of three distinct self-assembly strategies to reversibly capture sensitive biologics, viz. protein, nucleic acid and antibody. A covalent self-assembly strategy is employed for proteins irrespective of their isoelectric points (chapter 2). Our second strategy utilizes non-covalent interactions (electrostatic and hydrophobic) for complexation with negatively charged nucleic acids (chapter 3). Finally, we studied a combination of covalent and non-covalent interactions for encapsulating large proteins and antibodies (chapter 4 and 5). This dissertation will focus on the inherent challenges associated with functional delivery of proteins and nucleic acids. It will highlight the advantages of rational designs to control the complex interplay between the structural features of the polymers and their biological outcomes.

DOI

https://doi.org/10.7275/18834742

Creative Commons License

Creative Commons Attribution-Noncommercial 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License

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