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

Lisa E. Cole, Tracie L. McGinnity, Lisa E. Irimata, Tracy Vargo-Gogola, Ryan K. Roeder

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 24–48 h 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 28 days after delivery. Statement of Significance: 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.

Original languageEnglish (US)
JournalActa Biomaterialia
DOIs
StateAccepted/In press - Jan 1 2018
Externally publishedYes

Fingerprint

Calcinosis
Diphosphonates
Gold
Nanoparticles
Polyethylene glycols
Breast
Ligands
Human Mammary Glands
Durapatite
Hydroxyapatite
Tissue
Spleen
Imaging techniques
Macrophages
Biomarkers
Liver
Drainage
Toxicity
Calcium

Keywords

  • Bisphosphonate
  • Breast microcalcifications
  • Computed tomography
  • Contrast agent
  • PEGylated gold nanoparticles
  • Targeted delivery

ASJC Scopus subject areas

  • Biotechnology
  • Biomaterials
  • Biochemistry
  • Biomedical Engineering
  • Molecular Biology

Cite this

Effects of bisphosphonate ligands and PEGylation on targeted delivery of gold nanoparticles for contrast-enhanced radiographic detection of breast microcalcifications. / Cole, Lisa E.; McGinnity, Tracie L.; Irimata, Lisa E.; Vargo-Gogola, Tracy; Roeder, Ryan K.

In: Acta Biomaterialia, 01.01.2018.

Research output: Contribution to journalArticle

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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 24–48 h 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 28 days after delivery. Statement of Significance: 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.",
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AU - Vargo-Gogola, Tracy

AU - Roeder, Ryan K.

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AB - 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 24–48 h 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 28 days after delivery. Statement of Significance: 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.

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