Modified Guanidine-containing Polymers for Intracellular Protein Delivery

Authors

Alfonso BarriosFollow

Document Type

Dissertation

Degree

Doctor of Philosophy (PhD)

Major/Program

Chemistry

First Advisor's Name

Joong Ho Moonn

First Advisor's Committee Title

Committee chair

Second Advisor's Name

Yuan Liu

Second Advisor's Committee Title

Committee member

Third Advisor's Name

Bruce McCord

Third Advisor's Committee Title

Committee member

Fourth Advisor's Name

Anthony McGoron

Fourth Advisor's Committee Title

Committee member

Fifth Advisor's Name

Stanislaw Wnuk

Fifth Advisor's Committee Title

Committee member

Keywords

polymer chemistry

Date of Defense

6-13-2022

Abstract

Protein-based therapeutics have gained significant attention for treating or curing various diseases, especially those untreatable by small molecule-drugs. Despite their widespread success and adoption, the cellular membrane remains a major obstacle for proteins to reach the inner compartments of the cell and have had limited applicability spanning only extracellular targets. Consequently, the efficient intracellular delivery of proteins offers tremendous potential to reach new, unexplored, and otherwise “undruggable” targets. Acknowledging the therapeutic need, research efforts aimed at facilitating the delivery of proteins using polymer-based nanoparticles have emerged.

Guanidine-containing polymers provide a promising platform to address the common hurdles associated with protein delivery. Specifically, this work focuses on the design, synthesis, and development of polymeric carriers featuring a rational guanidine modification. A new class of carbamoylated guanidine-containing polymers were characterized, optimized, and evaluated for their efficacy in protein delivery. The developed functional group aided the biophysical properties of complexes, resulting in a dramatic increase in protein delivery compared to commercially available carriers. The

planarity and rigidity of the developed side chains aided complexation with cargo, stability in the harsh physiological environment, and subsequent cellular entry. Additionally, therapeutically relevant proteins were intracellularly delivered and assayed for their retained function, revealing the potential these carriers have for translational applications. Key insights into the fundamental identity of the carbamoylated guanidine functional group revealed novel design features that can be incorporated into delivery systems moving forward, expanding the field of protein delivery.

Identifier

FIDC010796

Recommended Citation

Barrios, Alfonso, "Modified Guanidine-containing Polymers for Intracellular Protein Delivery" (2022). FIU Electronic Theses and Dissertations. 5004.
https://digitalcommons.fiu.edu/etd/5004