Biomimicry [electronic resource] : exploring peptoids and recombinant protein polymers for biomedical applications

Nature has been evolving unparalleled molecular designs with extraordinary activity, simplicity, efficiency, and durability. The process of biomimicry takes inspiration from Nature. In this dissertation, I focused on the development of functional analogues of natural peptides and protein polymers for several applications that continue to challenge the biomedical field. Five applications were discussed: The first three sections focus on bioactive peptides that are generally shorter than 50 amino acids. The goal was to preserve the bioactivity of the natural peptides while reducing their natural sensitivity to proteases and fast in vivo clearance. The last two sections focus on developing protein polymer-based hydrogels. The goal was to generate biomimicking scaffolds for tissue regenerations. (i) Poly-N-substituted glycines, or peptoids, provide a biostable scaffold that can display a great diversity of side chains in highly tunable sequences via facile solid-phase synthesis. Current chemotherapeutics in oncology are often limited by side effect profiles and selection for drug resistance. Herein, I present a library of anticancer peptoids that mimic the cationic, amphipathic structural features of host defense peptides and explore their structure-activity relationship, and killing mechanisms. Several peptoids were found with broad cytotoxicity against cancer cells as well as the ability to overcome multidrug resistance. An initial in vivo study with a primary, orthotopic human breast cancer xenotransplantation model demonstrated anticancer efficacy of one of the studied peptoids. (ii) Cell-penetrating peptides have found numerous applications in biology and medicine as molecular transporters. We developed a library of cationic, amphipathic peptoids as a novel class of transporters and investigated the relationships between their structures, cellular uptake efficiency, and the associated cytotoxicity. Both guanidinium heads and bulky, aromatic hydrophobic residues were found to render the cationic, amphipathic constructs more permeable. Moreover, different internalization mechanisms were observed for peptoid transporters with distinct structures. One peptoid was identified as a promising transporter with excellent cellular uptake efficiency and low cytotoxicity. (iii) Bombesin (BBN) peptide can bind with high affinity and specificity to the GRP receptors (GRPR) which are upregulated invasive prostate cancer. BBN(7-14) provides a promising basis for developing radiometallated diagnostic or therapeutic radiopharmaceuticals to target GRPR positive prostate cancer. I report a design of a 4-arm PEG-based platform with multivalent BBN(7-14) for targeted delivery to the GRPR positive prostate cancer. The PEG-BBN conjugates displayed comparable tumor uptake as the free BBN while having both a lower liver uptake and higher tumor-to-blood ratio in a biodistribution study. (iv) Regenerative medicine is in need of bioactive extracellular matrix-like scaffolds that can interact with cells and allow tissue regeneration in a well-controlled manner. Via "controlled cloning", matrix metalloproteases (MMP) degradation sites were built into multiple sites along a protein polymer that can be enzymatically crosslinked into a previously established non-bioactive hydrogel systems. The incorporation of MMP degradation sites greatly improved cell infiltration into the hydrogel. (v) Lastly, a novel in situ forming hybrid, biomimetic hydrogel comprising bioactive recombinant protein polymers, hyaluronic acid (HA) and polyethylene glycol (PEG) was developed. In a preliminary study, this hydrogel was found to be biocompatible and bioactive, which opens up future studies with this hydrogel system.

Keywords: Bioengineering.
Advisor: Barron Annelise E. primary advisor. Thesis advisor
Contag Christopher H. primary advisor. Thesis advisor
Covert Markus primary advisor. Thesis advisor