Genetically Modified Bovine Milk-Derived Small Extracellular Vesicles In Drug Delivery

Authors

Alice Kah Hui Ngu, University of Nebraska-LincolnFollow

First Advisor

Janos Zempleni

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Nutrition

Date of this Version

7-2024

Document Type

Dissertation

Citation

A dissertation presented to the faculty of the Graduate College of the University of Nebraska in partial fulfillment of requirements for the degree of Doctor of Philosophy

Major: Nutrition

Under the supervision of Professor Janos Zempleni

Lincoln, Nebraska, July 2024

Comments

Copyright 2024, Alice Kah Hui Ngu. Used by permission

Abstract

Small extracellular vesicles (SEVs, “exosomes”) are natural nanoparticles that can be endogenously synthesized and also obtained from dietary sources, such as bovine milk SEVs (mEVs). mEVs have been extensively studied and discovered with contributive features that potentially play a role in drug delivery and other therapeutic purposes, such as diagnostic tools. Current studies have shown that mEVs have been used preclinically to carry in targeting drugs, nucleotides, biomolecules, and labels to target metabolic diseases and cancers. Extensive studies have focused on further modifying SEVs to enhance their versatility in pharmaceutical use. In this dissertation, we exhibited one of the ways to extend the half-life of mEVs in the host circulation and increase the specific homing of mEVs to the diseased area with decreased drug toxicity to the normal cells and tissues.

In the second chapter, we hypothesized that mEVs decorated with Don’t-eat-me peptides, CD47 and CD24 may decrease mEV elimination by macrophages. By generating CD47-MEV and CD24-MEV, we genetically modified bovine mammary alveolar MAC-T cells that have been proven to secrete mEVs. Our study showed that CD47 and CD24 significantly reduced the uptake of mEVs by female BMDMs ex vivo. The results of the in vivo study were not aligned with the ex vivo study, still, we conclude that the decoration of cell culture-derived mEVs with Don’t-eat-me peptides may have the potential to enhance the therapeutic potency of mEVs.

The third chapter discusses our approach to decorating mEVs with glioblastoma targeting peptides, ApoE, and CooP to enhance the specific homing efficiency of mEVs to human glioblastoma multiforme, in vitro and in vivo. Our current data suggested that ApoE and CooP significantly increased the uptake of mEVs by the human glioblastoma U87 cells, in vitro. Our progressing endevour is to administer ApoE-MEV and Coo-MEV in the mouse model engrafted with human glioblastoma multiforme.

Advisor: Janos Zempleni

Recommended Citation

Ngu, Alice Kah Hui, "Genetically Modified Bovine Milk-Derived Small Extracellular Vesicles In Drug Delivery" (2024). Dissertations and Doctoral Documents from University of Nebraska-Lincoln, 2023–. 131.
https://digitalcommons.unl.edu/dissunl/131