(2eu) Tailoring Therapeutic Peptides to Enable Reversible Encapsulation into Different Drug Carriers | AIChE

(2eu) Tailoring Therapeutic Peptides to Enable Reversible Encapsulation into Different Drug Carriers

Authors 

Bannon, M. - Presenter, New Jersey Institute of Technology
Research Interests

Therapeutic peptides are rapidly growing in the drug discovery space due to their potency, selectivity for specific targets, versatility, and low off-site toxicity. Despite their therapeutic potential, proteolytic degradation and/or renal clearance rapidly removes peptides from circulation, limiting their in vivo efficacy. Dynamically encapsulating therapeutic peptides into biocompatible carriers, such as lipid vesicles, polymer micelles, or hydrogels, presents an opportunity to not only increase the circulatory half-life of peptides, but also control their release. As dynamic encapsulation often relies on non-covalent hydrophobic or electrostatic interactions between drugs and their carriers, the subset of therapeutic peptides that are hydrophilic and contain multiple positive and negative charges is challenging to encapsulate. Since permanently modifying the peptide sequence can reduce peptide activity, developing therapeutic peptide prodrugs with temporary modifications provides a compelling opportunity to reversible encapsulate peptides into carriers without permanently decreasing their therapeutic activity. Esterified small molecule prodrugs have been developed and extensively studied; however there remains a knowledge gap in applying this strategy to therapeutic peptides, which contain multiple ester sites. Developing therapeutic peptides will facilitate their translation into the clinic, allowing patients to receive their aforementioned benefits.

Building on my graduate experiences thus far, I am interested in gaining the tools to bridge chemical and biological engineering to realize the therapeutic potential of peptides. Specifically, I am interested in:

  1. In vitro and in vivo analysis of drug activity and stability

My Ph.D. thesis has provided me with expertise in chemically tailoring therapeutic peptides for reversible encapsulation. It also gave me the beneficial experience of working with expert collaborators in the medical field, who assessed biological activity of peptides that we synthesized and chemically modified, and provided me with useful insight into the biological side of the drug delivery field. Through my tangential experience with drug activity studies, I have developed an interest in pairing my chemical engineering-based training with designing and/or performing these analyses. Additionally, while I have performed in vitro stability experiments with proteases, I am interested in learning how to fully assess the in vivo stability of therapeutic peptides, including such considerations as renal and hepatic clearance. Combining my training in chemical engineering with these skills will allow me to more thoroughly assess different aspects of developed therapeutic peptide prodrugs in a future lab.

  1. Design and analysis of drug carriers in relevant biological milieu

My Master’s thesis work focused on how polymer nanoparticles behaved in blood plasma, specifically focusing on particle-to-particle aggregation and protein surface binding, known as protein corona development. Throughout Ph.D. training, I have remained interested in building upon this experience, and learning techniques to analyze various types of drug carriers in blood plasma, including lipid vesicles, polymer micelles, polymer nanoparticles, and lipid nanoparticles, to name a few. Because of its higher patient compliance, convenience, and non-invasiveness, I am specifically interested in oral delivery routes, and how specific interactions with specific environments, such as the stomach and/or bloodstream, affect drug delivery, the stability of encapsulated drug cargo, and overall efficacy.

  1. Molecular structure-activity relationships for therapeutic peptides

With my experience in prodrug systems, I have gained a keen interest in learning why specific therapeutic peptides have specific functions, and, alternatively, why this class of drugs built from a select number of natural amino acid constituents is so versatile. Further, how important are individual amino acids to overall therapeutic function, and are there common trends with specific amino acids? I am interested in learning how to experimentally probe these questions, and possibly use molecular modeling to support these results. I am specifically interested in performing experiments to identify general relationships between amino acids and overall therapeutic peptide efficacy to inform drug design of future therapeutic peptides.

Research Experience

Master’s Thesis Research: Interactions between polymer nanoparticles and blood plasma applied to drug delivery

Otto H. York Dept. of Chemical and Materials Engineering, New Jersey Institute of Technology

Thesis Advisor: Kathleen McEnnis

My Master’s research involved characterizing interactions between polymer nanoparticles and blood plasma. We developed a protocol to use nanoparticle tracking analysis (NTA) to fluorescently track individual nanoparticles after incubation into blood plasma. NTA was used to both analyze how surface interactions with blood plasma proteins (i.e., protein corona development) increased the overall size of the nanoparticles and characterize particle-to-particle aggregation in blood plasma. By using NTA, we found protein corona development to increase polymer nanoparticle size by almost 100 nm, larger than sizes previously reported. Unexpectedly, particles decorated with a surface layer of poly(ethylene glycol) (PEG) developed a protein corona with similar thickness to their unmodified counterparts. We also used NTA to count the number of individual nanoparticles within aggregates, where PEGylated nanoparticles showed 5-times less aggregation than their unmodified counterparts (200 +/- 30 aggregated particles vs. 1000 +/- 200 aggregated particles per 1x 105 total particles). By using NTA to analyze nanoparticle interactions with blood plasma, we developed a method to accurately analyze protein corona development and particle-to-particle aggregation, two important in vitro analyses that can be used to inform the future design of drug carriers.

Ph.D. Dissertation Research: Tailoring therapeutic peptides to enable reversible encapsulation into different drug carriers

Department of Chemical Engineering, University of Virginia

Thesis Advisor: Rachel Letteri

We are currently tailoring both therapeutic peptides and designing drug carriers for various therapeutic uses, including wound healing, COVID-19, and ischemic heart disease. On the peptide front, we are using esterification to modify the hydrophilic, anionic carboxylic acids of therapeutic peptides and increase their relative hydrophobicity and cationic net charge, making them amenable to encapsulation into relevant drug carriers. Hydrolysis of the installed esters provides a route to restore these esterified therapeutic peptides back to their original, active form. Further, low pH environments and/or esterases, both of which are found in the body, can catalyze ester hydrolysis, providing in vivo metabolic targets for prodrug activation. Esterification has been used to enable encapsulation of small molecules and/or proteins into different carrier systems, where the increase in hydrophobicity and net cationic charge enables encapsulation into lipid vesicles and polymer micelles (through complexation with anionic/hydrophilic block copolymers), respectively. However, as therapeutic peptides often tote multiple carboxylic acids, we are investigating how the number and position of installed esters affects hydrophobicity, hydrolytic activation, encapsulation into various drug carriers, subsequent release from said carriers, and overall activity/efficacy of therapeutic peptides.

On the drug carrier side, we have developed and characterized a polymer-metal-organic framework (MOF) hydrogel platform to harness the high sorptive capacity of MOFs into a relatively processable hydrogel format. We characterized the resulting encapsulation and release of both a small molecule dye (methylene blue) and the therapeutic peptide Angiotensin 1-7 into/from the polymer-MOF composite hydrogels, finding that the composites had higher sorptive capacities relative to their polymer and/or MOF constituents, likely due to MOF dispersion within the polymer scaffold increasing the overall surface area of the MOF available for sorption. Additionally, the polymer-MOF composites sustained release of both methylene blue and Angiotensin 1-7 relative to their individual constituents, showing the opportunity for tunable release profiles and/or sustained release for a variety of applications, including drug delivery.