Functionalized polypeptide- and lipid-based nanoparticles - synthesis and applications

Tan, Zhengzhong

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https://hdl.handle.net/2142/121192 Copy

Description

Title

Functionalized polypeptide- and lipid-based nanoparticles - synthesis and applications

Author(s)

Tan, Zhengzhong

Issue Date

2023-05-24

Director of Research (if dissertation) or Advisor (if thesis)

Leal, Cecilia

Doctoral Committee Chair(s)

• Leal, Cecilia
• Cheng, Jianjun

Committee Member(s)

• Evans, Christopher
• Inoue, Makoto

Department of Study

Materials Science & Engineerng

Discipline

Materials Science & Engr

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• Nanoparticles
• lipid
• polypeptide
• drug delivery
• mRNA delivery
• active targeting
• protein corona
• nanomedicine

Abstract

Nanomedicine possesses the unlimited potential to advance the biomedical field and has been gaining a lot of research interest in recent years. Drug carriers can provide various benefits for a myriad of drug modalities, for instance, they can increase the solubility of traditional hydrophobic drugs used for chemotherapy, and they can protect against the degradation of nucleic acid-based and protein-based therapeutics. Due to their optimal size, nanomedicine enables longer circulation times and the ability to permeate and accumulate in tissues with leaky vasculatures, such as solid tumors. Soft material nanoparticles, especially lipid-based and biopolymer/polypeptide-based generally offer better biocompatibility and more chemical versatility compared to viral or inorganic nanoparticle methods. In this thesis we explore these two classes of materials: lipids and polypeptides to establish new design principles for nanomedicine systems. Polypeptide materials have great potential as they comprise the same chemical groups as proteins in biological systems being able to mimic their properties such as forming secondary structures which are essential to higher-order protein folding and function. Lipid materials are among the most well-studied and impactful nanomedicine systems. Lipid nanoparticle (LNP)-based mRNA vaccines by Pfizer and Moderna have been estimated to have saved around 8 million lives worldwide during the coronavirus disease 2019 (Covid-19) pandemic, demonstrating the potential of LNP-based nanomedicine. Currently, most nanoparticles are "pegylated"(surfaces coated with polyethylene glycol-PEG moieties) to improve their stability for in vivo applications. However, there are concerns of allergic reactions caused by rising levels of anti-PEG antibodies in humans. This has motivated the nanomedicine scientific community to develop PEG-replacing materials for nanoparticle stabilization. α-helical polypeptide with dense oligo(ethylene glycol) (OEG) side chains have shown to induce less anti-PEG antibodies retaining a similar level of antifouling properties. We have developed a novel open-air synthesis of OEG-polypeptides from OEG-N-carboxyanhydrides (NCA) without complicated purification and the formulation of OEG-polypeptide-based nanoparticles which showed great non-fouling property and potential for drug delivery applications. The majority of nanoparticles used in therapy extravasate tissue without specific targeting. However, with the advance of genomics, we now know more and more specific disease hallmark receptors. Functionalizing nanoparticles with active targeting ligands is an emerging challenge in nanomedicine. Glycan molecules play an important role in cell signaling and receptor recognition. Glycopolypeptides- glycan-functionalized polypeptide materials, have been shown to be able to mimic natural glycoproteins and activate immune cells via the glycan receptor. We have developed a facile synthesis approach of glycopolypeptides, including poly (galactose-cysteine) and poly(mannose-cysteine), by polymerization of glyco-NCAs without the need of extensive purification steps. We also showed that glycopolypeptide-based nanoparticles can bind with glycan-specific lectins and have higher cellular uptake in vitro via mannose-mannose receptor interaction. While LNPs have already demonstrated their potential in combating various diseases, equipping LNPs with active targeting ability would be highly desirable. The recent Chemistry Nobel prize-winning (Carolyn Bertozzi) dibenzocyclooctyne (DBCO)-azide bioorthogonal "click" reaction is highly specific, efficient, and not disturbed by the biological environment. A number of different research groups have developed metabolic sugar labelling techniques. This approach uses azidosugars that can enter the metabolic pathway of cells and be re-expressed as azide-sialic acid on glycoproteins on the plasma membrane. Following the metabolic sugar labelling strategy, we synthesized DBCO-functionalized lipids with or without a PEG linker and formulated mRNA-encapsulating DBCO-functionalized LNPs. We show that they can chemically react with the azide groups on the cell surface from the metabolic sugar labelling, have higher uptake into cells labelled by azidosugars, and result in targeted mRNA delivery in prelabelled cells.

Graduation Semester

2023-08

Type of Resource

Thesis

Copyright and License Information

Copyright 2023 Zhengzhong (Kevin) Tan

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