Effects of bisphosphonate ligands and PEGylation on targeted delivery of gold nanoparticles for contrast-enhanced radiographic detection of breast microcalcifications

Article

Abstract

A preclinical murine model of hydroxyapatite (HA) breast microcalcifications (µcals), which are an important clinical biomarker for breast cancer detection, was used to investigate the independent effects of high affinity bisphosphonate (BP) ligands and a polyethylene glycol (PEG) spacer on targeted delivery of gold nanoparticles (Au NPs) for contrast-enhanced radiographic detection. The addition of BP ligands to PEGylated Au NPs (BP-PEG-Au NPs) resulted in five-fold greater binding affinity for targeting HA µcals, as expected, due to the strong binding affinity of BP ligands for calcium. Therefore, BP-PEG-Au NPs were able to target HA µcals in vivo after intramammary delivery, which enabled contrast-enhanced radiographic detection of µcals in both normal and radiographically dense mammary tissues similar to previous results for BP-Au NPs, while PEG-Au NPs did not. The addition of a PEG spacer between the BP targeting ligand and Au NP surface enabled improved in vivo clearance. PEG-Au NPs and BP-PEG-Au NPs were cleared from all mammary glands (MGs) and control MGs, respectively, within 24-48h after intramammary delivery, while BP-Au NPs were not. PEGylated Au NPs were slowly cleared from MGs by lymphatic drainage and accumulated in the spleen. Histopathology revealed uptake of PEG-Au NPs and BP-PEG-Au NPs by macrophages in the spleen, liver, and MGs; there was no evidence of toxicity due to the accumulation of NPs in organs and tissues compared with untreated controls for up to 28days after delivery. Au NP imaging probes and therapeutics are commonly surface functionalized with PEG and/or high affinity targeting ligands for delivery. However, direct comparisons of PEGylated Au NPs with and without a targeting ligand, or ligand-targeted Au NPs with and without a PEG spacer, on in vivo targeting efficiency, biodistribution, and clearance are limited. Therefore, the results of this study are important for the rationale design of targeted NP imaging probes and therapeutics, including the translation of BP-PEG-Au NPs which enable improved sensitivity and specificity for the radiographic detection of abnormalities (e.g., µcals) in women with dense breast tissue.

Attributes

Attribute NameValues
Creator
  • Lisa Irimata

  • Tracy Vargo-Gogola

  • Ryan Roeder

Journal or Work Title
  • Acta Biomaterialia

Volume
  • 82

First Page
  • 122

Last Page
  • 132

Number of Pages
  • 10

Publication Date
  • 2018

Publisher
  • Elsevier

Date Created
  • 2018-12-07

Language
  • English

Departments and Units
Record Visibility and Access Public
Content License
  • All rights reserved

Digital Object Identifier

10.1016/j.actbio.2018.10.014

This DOI is the best way to cite this article.