Design of Ligand-Targeted Nanoparticles for Enhanced Cancer Targeting

Doctoral Dissertation
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Abstract

Ligand-targeted nanoparticles are increasingly used as drug delivery vehicles for cancer therapy, yet have not consistently produced successful clinical outcomes. Although these inconsistencies may arise from differences in disease models and target receptors, nanoparticle design parameters can significantly influence therapeutic efficacy. By employing a multifaceted synthetic strategy to prepare peptide-targeted nanoparticles with high purity, reproducibility, and precisely controlled stoichiometry of functionalities, this work evaluates the roles of polyethylene glycol (PEG) coating, ethylene glycol (EG) peptide-linker length, peptide hydrophilicity, peptide density, and nanoparticle size on tumor targeting in a systematic manner. These parameters were analyzed in multiple disease models by targeting human epidermal growth factor receptor 2 (HER2) in breast cancer and very late antigen-4 (VLA-4) in multiple myeloma to demonstrate the widespread applicability of this approach. By increasing the hydrophilicity of the targeting peptide sequence and simultaneously optimizing the EG peptide-linker length, the in vitro cellular uptake of targeted liposomes was significantly enhanced. Specifically, including a short oligolysine chain adjacent to the targeting peptide sequence effectively increased cellular uptake ~80-fold using an EG6 peptide-linker compared to ~10-fold using an EG45 linker. In vivo, targeted liposomes prepared in a traditional manner lacking the oligolysine chain demonstrated similar biodistribution and tumor uptake to non-targeted liposomes. However, by including the oligolysine chain, targeted liposomes using an EG45 linker significantly improved tumor uptake ~8-fold over non-targeted liposomes, while the use of an EG6 linker decreased tumor accumulation and uptake, owing to differences in cellular uptake kinetics, clearance mechanisms, and binding site barrier effects. To further improve tumor targeting and enhance the selectivity of targeted nanoparticles, a dual-receptor targeted approach was evaluated by targeting multiple cell surface receptors simultaneously. Liposomes functionalized with two distinct peptide antagonists to target VLA-4 and Leukocyte Peyer’s Patch Adhesion Molecule-1 (LPAM-1) demonstrated synergistically enhanced cellular uptake by cells overexpressing both target receptors and negligible uptake by cells that do not simultaneously express both receptors, providing a strategy to improve selectivity over conventional single receptor-targeted designs. Taken together, this process of systematic optimization of well-defined nanoparticle drug delivery systems has the potential to improve cancer therapy for a broader patient population.

Attributes

Attribute NameValues
URN
  • etd-06252014-144015

Author Jared F Stefanick
Advisor Basar Bilgicer
Contributor Edward Maginn, Committee Member
Contributor Basar Bilgicer, Committee Chair
Contributor Mark McCready, Committee Member
Contributor Jeremiah Zartman, Committee Member
Degree Level Doctoral Dissertation
Degree Discipline Chemical Engineering
Degree Name PhD
Defense Date
  • 2014-06-24

Submission Date 2014-06-25
Country
  • United States of America

Subject
  • active targeting

  • cancer

  • cellular uptake

  • liposome

  • peptide-targeted

  • nanoparticle

Publisher
  • University of Notre Dame

Language
  • English

Record Visibility and Access Public
Content License
  • All rights reserved

Departments and Units

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