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Author Notes:

Correspondence: Hui Mao, Department of Radiology and Imaging Sciences, Emory University, 1841 Clifton Road, Atlanta, Georgia 30329, USA, e-mail: hmao@emory.edu

Disclosures: The authors have declared that no competing interest exists.


Research Funding:

This study is supported in part by NIH grants (1U01CA19891301, R01CA154846-04 and U01CA151810-05) to HM and LY.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Medicine, Research & Experimental
  • Research & Experimental Medicine
  • Iron oxide nanoparticles
  • Active targeting
  • Enhanced permeability and retention
  • Molecular imaging
  • Drug delivery
  • MRI contrast enhancement
  • Gold nanoparticles
  • Nonspecific uptake
  • Particle size
  • Transferrin
  • Delivery
  • Localization
  • Pharmacokinetics
  • Biodistribution
  • Accumulation

Probing and Enhancing Ligand-Mediated Active Targeting of Tumors Using Sub-5 nm Ultrafine Iron Oxide Nanoparticles


Journal Title:



Volume 10, Number 6


, Pages 2479-2494

Type of Work:

Article | Final Publisher PDF


Rationale: “Active targeting” based on the ligand-target affinity is a common strategy to precisely deliver nanoparticle (NP) imaging probes or drug carriers to the diseased tissue. However, such ligand-mediated active targeting inevitably takes place with prerequisite “passive targeting”, driven by the enhanced permeability and retention (EPR) effect. Thus, the efficiency of active targeting in relation to off-targeted unbound NPs is of great importance in quantitative imaging of tumor biomarkers and delivery. With the notion that easy clearance of off-targeted uIONPs may lead to enhanced active targeting and tumor accumulation, we examined the NP size effect on “active targeting” of the transferrin receptor (TfR) using transferrin (Tf)-conjugated sub-5 nm (3 nm core) ultrafine iron oxide NPs (uIONPs) and larger IONPs (30 nm core). Methods: Green fluorescent dye (FITC)-labeled active targeting uIONPs (FITC-Tf-uIONPs) and red fluorescent dye (TRITC)-labeled passive targeting uIONPs (TRITC-uIONPs) were prepared. FITC-Tf-IONPs and TRITC-IONPs were used as comparison for the NP size effect. Multiphoton imaging, confocal fluorescence imaging, histological staining and computational analysis were applied to track different types of NPs in tumors at 1, 3 and 24 hours after co-injection of equal amounts of paired NPs, e.g., active targeting FITC-Tf-uIONPs and non-targeting TRITC-uIONPs, or FITC-Tf-IONPs and TRITC-IONPs into the same mice bearing 4T1 mouse mammary tumors. Results: Active targeting uIONPs exhibited an almost 6-fold higher level of tumor retention with deeper penetration comparing to non-targeting uIONPs at 24 hours after co-injection. However, accumulation of active targeting IONPs with a 30-nm core is only about 1.15-fold higher than non-targeting IONPs. The enhanced active targeting by uIONPs can be attributed to the size dependent clearance of unbound off-targeted NPs, as majority off-targeted uIONPs were readily cleared from the tumor by intravasation back into tumor blood vessels likely due to high interstitial pressure, even though they are not favorable for macrophage uptake. Conclusion: Ligand-mediated active targeting improves the delivery and accumulation of the sub-5 nm NPs. The improvement on active targeting is size-dependent and facilitated by NPs with sub-5 nm core sizes. Thus, sub-5 nm NPs may serve as favorable platforms for development of NP-based molecular imaging probes and targeted drug carriers.

Copyright information:

©2020 Ivyspring International Publisher.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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